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Series Editor: David J. Lockwood
Nanostructure Science and Technology
ThimmaiahGovindaraju
KatsuhikoArigaEditors
Molecular
Architectonics and
Nanoarchitectonics

Nanostructure Science and Technology
Series Editor
David J. Lockwood, FRSC, National Research Council of Canada, Ottawa, ON,
Canada

Nanostructure science and technology now forms a common thread that runs
through all physical and materials sciences and is emerging in industrial applications
as nanotechnology. The breadth of the subject material is demonstrated by the fact
that it covers and intertwines many of the traditional areas of physics, chemistry,
biology, and medicine. Within each main topic in thisﬁeld there can be many
subﬁelds. For example, the electrical properties of nanostructured materials is a
topic that can cover electron transport in semiconductor quantum dots, self-
assembled molecular nanostructures, carbon nanotubes, chemically tailored hybrid
magnetic-semiconductor nanostructures, colloidal quantum dots, nanostructured
superconductors, nanocrystalline electronic junctions, etc. Obviously, no one book
can cope with such a diversity of subject matter. The nanostructured material system
is, however, of increasing signiﬁcance in our technology-dominated economy and
this suggests the need for a series of books to cover recent developments.
The scope of the series is designed to cover as much of the subject matter as
possible–from physics and chemistry to biology and medicine, and from basic
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trated in basic science and mainly within physics and chemistry, but as time goes by
more importance will inevitably be given to subjects in applied science and will also
include biology and medicine. The series will naturally accommodate thisﬂow of
developments in the sciences and technology of nanostructures and maintain its
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biological and medical sciences, for example, not be ignored as, despite their
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the required cohesiveness from a judicious mix of edited volumes and monographs
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ciplinary texts.
Thus the series is planned to cover in a coherent fashion the developments in
basic research from the distinct viewpoints of physics, chemistry, biology, and
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Each volume will also reﬂect thisﬂow from science to technology. As time goes by,
the earlier series volumes will then serve as reference texts to subsequent volumes.
More information about this series athttp://www.springer.com/series/6331

Thimmaiah GovindarajuKatsuhiko Ariga
Editors
MolecularArchitectonics
andNanoarchitectonics

Editors
Thimmaiah Govindaraju
Bioorganic Chemistry Laboratory, New
Chemistry Unit and School of Advanced
Materials (SAMat)
Jawaharlal Nehru Centre for Advanced
Scientiﬁc Research
Bengaluru, Karnataka, India
Katsuhiko Ariga
International Center for Materials
Nanoarchitectonics (WPI-MANA), National
Institute for Materials Science (NIMS)
Ibaraki, Tsukuba, Japan
Department of Advanced Materials Science
Graduate School of Frontier Sciences, The
University of Tokyo
Chiba, Japan
ISSN 1571-5744 ISSN 2197-7976 (electronic)
Nanostructure Science and Technology
ISBN 978-981-16-4188-6 ISBN 978-981-16-4189-3 (eBook)
https://doi.org/10.1007/978-981-16-4189-3
©The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore
Pte Ltd. 2022
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Singapore

Preface
Introduction: Molecular Architectonics
to Nanoarchitectonics
Many current problems, including environmental, energy, and biomedical problems,
must be solved with rational developments of science and technology. The
performances depend not only on the quality of materials but also on the rational
organization of the internal structures of materials. Therefore, structural studies of
objects at nanoscopic, atomic, and molecular levels are a major concern of recent
sciences and technologies. Fortunately, the research developments of past decades
enable us to observe, analyze, and manipulate nanoscopic objects precisely, which is
of course known as a great success of nanotechnology. However, functional mate-
rials with a rational organization cannot be created directly by top-down nanotech-
nology-related approaches alone. Therefore, a new research paradigm must be
developed alongside nanotechnology to create functional materials from molecular
and nanoscale units. This task can be assigned to an emerging concept, molecular
architectonics and nanoarchitectonics.
Bengaluru, Karnataka, India Thimmaiah Govindaraju
Ibaraki, Tsukuba, Japan Katsuhiko Ariga
Kashiwa, Chiba, Japan
v

Contents
Part I Molecular Architectonics and Nanoarchitectonics
1 Molecular Architectonics................................. 3
Mouli Konar and Thimmaiah Govindaraju
2 Nanoarchitectonics..................................... 35
Katsuhiko Ariga
Part II Architectonics of Functional Molecules
3 Topological Supramolecular Polymer....................... 47
Yasuki Kato, Sougata Datta, and Shiki Yagai
4 Molecular Architectonics Guide to the Fabrication
of Self-Cleaning Materials................................ 71
Mouli Konar and Thimmaiah Govindaraju
5 Functional Discotic Liquid Crystals Through Molecular
Self-Assembly: Toward Efﬁcient Charge Transport Systems...... 89
Indu Bala, Joydip De, and Santanu Kumar Pal
Part III Architectonics of Peptides
6 Dopamine-Based Materials: Recent Advances in Synthesis
Methods and Applications................................ 133
Hong Li and Junbai Li
7 Peptide-Based Nanoarchitectonics: Self-Assembly and
Biological Applications.................................. 165
Luyang Zhao and Xuehai Yan
vii

8 Peptide Cross-βNanoarchitectures: Characterizing Self-Assembly
Mechanisms, Structure, and Physicochemical Properties......... 179
Christopher W. Jones, Hannah E. Distaffen, and Bradley L. Nilsson
9 Function-Inspired Design of Molecular Hydrogels:
Paradigm-Shifting Biomaterials forBiomedicalApplications...... 209
Ashish Dhayani, Preethem Srinath, Sujanthi Easwara Prasad,
Afsana Naaz, Mukesh Dhanka, Sanjeeb Kalita,
and Praveen Kumar Vemula
10 Smart Peptide Assembly Architectures to Mimic Biology’s
Adaptive Properties and Applications....................... 233
Debasish Haldar
Part IV Architectonics of Nucleic Acids
11 Bio-inspired Functional DNA Architectures.................. 259
Eugen Stulz
12 Functional Molecule-Templated DNA Molecular Architectonics. . . 281
Lakshmi Priya Datta, Debasis Ghosh, and Thimmaiah Govindaraju
13 Architectures of Nucleolipid Assemblies and Their Applications. . . 307
Manisha B. Walunj, Swagata Dutta, and Seergazhi G. Srivatsan
14 Nucleobase- and DNA-Functionalized Hydrogels and Their
Applications.......................................... 335
Apurba K. Das, Ankan Biswas, Sourav Bhowmik, and Tapas Ghosh
15 RNA Nanoarchitectures and Their Applications............... 365
Shahaji H. More, Abhishek Bastiray, and Ashwani Sharma
Part V Architectonics of Complex Systems and Advanced Objects
16 Covalent Organic Frameworks as Tunable Supports for HER,
OER, and ORR Catalysts: A New Addition to Heterogeneous
Electrocatalysts........................................ 389
Ramanathan Vaidhyanathan
17 Ligand-Functionalized Nanostructures and Their Biomedical
Applications.......................................... 445
Koushik Debnath and Nikhil R. Jana
18 Biomimetic Composite Materials and Their Biological
Applications.......................................... 459
Svetlana Batasheva, Ekaterina Naumenko, and Rawil Fakhrullin
viii Contents

19 Combining Polymers, Nanomaterials, and Biomolecules:
Nanostructured Films with Functional Properties and
Applications.......................................... 481
Andressa R. Pereira, Antonio F. A. A. Melo, Frank N. Crespilho,
and Osvaldo N. OliveiraJr
20 Responsive Polymeric Architectures and Their Biomaterial
Applications.......................................... 509
Lili Chen, Mazaya Najimina, and Mitsuhiro Ebara
Index................................................... 525
Contents ix

Part I
Molecular Architectonics and
Nanoarchitectonics

Chapter 1
Molecular Architectonics
Mouli Konar and Thimmaiah Govindaraju
1.1 Introduction
The generation of advanced molecular and material architectures with novel func-
tional properties and applications by custom design and engineering of molecular
assemblies of functional building blocks is referred to as molecular architectonics
[1,2]. The scheme of molecular architectonics enables the construction of 0D, 1D,
2D, and 3D architectures with a wide range of shapes and sizes from molecular,
nano-, micro-, to macroscale by the judicious manipulation of subtle noncovalent
forces at molecular level. The functional molecular building blocks custom designed
by conjugating the tailorable functional core with appropriate assembly-directing
auxiliary units are integrated into functionally organized state under meticulously
planned experimental conditions [1,2]. Nature has been evolved with numerous
elegant and sophisticated molecular and material architectures of DNA, proteins,
carbohydrates, and lipids, which serve as inspiration and guiding principles in the
ﬁeld of molecular architectonics [1–4]. The biomolecular assemblies help in under-
standing the intricate molecular recognition and host-guest interactions and facilitate
the creation of complex and delicate architectures with emergent properties and
applications [1,2,4,5]. In the scheme of molecular architectonics, the molecular
organizations are executed through solution-processable self-assembly,
co-assembly, hetero-assembly, templated assembly, and hierarchical assembly pro-
cesses by controlled manipulation of weak noncovalent forces such as hydrogen
bonding, hydrophobic, van der Waals, aromatic,π-πstacking, dipole-dipole, metal
coordination, anion-π, cation-πand, electrostatic interactions [1,2,6,7]. The
M. Konar · T. Govindaraju (*)
Bioorganic Chemistry Laboratory, New Chemistry Unit and School of Advanced Materials
(SAMat), Jawaharlal Nehru Centre for Advanced Scientiﬁc Research, Bengaluru, Karnataka,
India
e-mail:[email protected]
©The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
T. Govindaraju, K. Ariga (eds.),Molecular Architectonics and Nanoarchitectonics,
Nanostructure Science and Technology,
https://doi.org/10.1007/978-981-16-4189-3_1
3

controlled assembly of functional molecules is orchestrated by incorporating bio-
molecular auxiliaries with built-in information for molecular recognition. The bio-
molecules like amino acids, peptides, nucleobases, sugars, and lipids and their
derivatives and mimics serve as the assembly-directing auxiliaries through their
unique molecular recognition, minute structural mutations, and chirality (Fig.1.1)
[2–4,8–13]. The biomolecule-armed functional core assembly generates the
Fig. 1.1Chemical structures of representative functional cores and biomolecular auxiliaries such
as amino acids, peptides (dipeptide, cyclic dipeptide, oligo-/polypeptide), nucleobases, sugar, and
lipids and their synthetic/artiﬁcial derivatives or mimetics, including metal/organic nanoparticles
and quantum dots. The Watson-Crick (WC) or conventional and representative non-WC or
unconventional base pairing of nucleobases is shown
4 M. Konar and T. Govindaraju

molecular and material architectures with functional properties and applications in
biological and non-biological systems across the inter-related domains of health,
energy, and environment [1,2,5,14]. Furthermore, molecular architectonics has the
potential to contribute immensely to theﬁeld of nanoarchitectonics [6,15–17]. In
general, the simplicity, unique design principles, robustness, cost-effectiveness,
biological relevance, and structure-function tunability of the reductionistic and
bioinspired molecular architectonics strategies resulted in the creation of diverse
and fascinating architectures in 0D, 1D, 2D, and 3D with functional properties and
multitude of applications (Fig.1.2).
In this chapter, we discuss various molecular architectonics strategies with the
help of representative examples reported from our laboratory to advance the engi-
neering of molecular assemblies by precisely controlling the interplay of
noncovalent interactions. Numerous molecular systems such as benzene, pyrene,
naphthalene, quinoline, naphthalene monoimides (NMIs), pyromellitic diimides
(PMIs), naphthalenediimides (NDIs), and perylenediimides (PDIs) are employed
as functional cores because of their inherent opto-electronic, redox, and/or assembly
characteristics [2,8]. The special structural characteristics of these functional cores,
viz., molecular planarity, HOMO-LUMO tunability, optical, redox,π-acidity,
π-basicity, and semiconductive properties, can be tailored by biomolecular auxil-
iaries [1,2,8]. The diverse bioinspired strategies that are adapted to engineer the
assembly of designer functional building blocks suitably armed with auxiliary units
through skilled manipulation of experimental conditions are presented. The well-
ordered assembly architectures cater to various applications including self-cleaning,
sensing, opto-electronics, catalysis, bioimaging, drug delivery, and tissue engineer-
ing, among others. By systematically highlighting a number of strategies, we
underline the potential of molecular architectonics to address problems related to
the interconnected domains of health, energy, and environment. Finally, the chapter
is concluded by providing future directions with emphasis on harvesting the scheme
of molecular architectonics through innovative ideas to produce advanced and
multifunctional material architectures.
1.2 Self-Cleaning Materials
Self-cleaning materials exhibit special property and ability to keep their surface
clean without any human intervention. The special property of self-cleaning material
depends on the surface morphology or roughness, the water contact angle, and the
contact angle hysteresis [18]. In nature, the self-cleaning surfaces work in two
different ways: (i) water wets the exposed surfaces completely and the contaminants
are washed off with water and (ii) the exposed surfaces are not wetted by the water,
rather the water beads up into droplets and rolled off the surface along with the
contaminants or dust [19]. These two self-cleaning procedures with contrasting
surface properties are commonly known as superhydrophilic (extremely wettable)
and superhydrophobic (non-wettable) surfaces, respectively. Both superhydrophilic
1 Molecular Architectonics 5

Fig. 1.2Custom design of functional building blocks by the conjugation of functional core with
appropriate auxiliary units. The molecular assembly-engineering (self-assembly, co-assembly,
templated assembly, and hierarchical assembly) of functional building blocks in the scheme of
molecular architectonics to produce molecular and material architectures of various shapes, sizes,
and dimensions (0D, 1D, 2D, and 3D) with diverse functional properties and biological and
non-biological applications
6 M. Konar and T. Govindaraju

and superhydrophobic property-based self-cleaning phenomena are found in the
nature [20]. For instance, the self-cleaning effects ofﬁsh scale and pitcher plant
are due to their superhydrophilic property, and that of rose petal, lotus leaf, and lizard
skin are attributed to their superhydrophobic property. The self-cleaning phenome-
non of lotus leaf is termed as“lotus effect”and has been the subject of current
research interest due to its interesting hierarchical surface architectures and techno-
logical implications [21]. An extensive research on various types of natural self-
cleaning surfaces has revealed that the basic criterion of a superhydrophilic or
superhydrophobic surface to exhibit self-cleaning behaviors is their hierarchical
surface roughness with the water contact angle (WCA) values<10
ﬁ
and>150
ﬁ
,
respectively. A number of modern theories have been proposed including Wenzel
theory and Cassie-Boxter theory to establish a plausible relationship between the
surface roughness and WCA of lotus leaf self-cleaning surface (Fig.1.3a)
[25]. Although both the superhydrophilic and superhydrophobic surfaces can be
mimicked artiﬁcially, the latter is industrially preferred as non-wettable self-cleaning
surface. The numerous advantages of superhydrophobic surfaces include low-cost
fabrication procedure, biocompatibility, and diverse application possibilities in the
preparation of anti-corrosion, antibacterial, and anti-fogging coatings, among
others [26].
We have mimicked the self-cleaning property of lotus leaf by adapting a solution-
processable molecular architectonics-guided bottom-up strategy to fabricate
superhydrophobic and self-cleaning surface. In this method, the well-known breath
ﬁgure technique (BFT) was explored to fabricate large area honeycomb-type
superhydrophobic surface by using the solution of NDI-based small functional
molecule in dichloromethane (DCM) (Fig.1.3b)[22]. The functional building
block (1) was designed by the symmetrical functionalization of NDI core with two
N-tBoc (tert-butoxycarbonyl)-protected guanidinocarbonyl pyrrole (GCP) auxil-
iaries. The BFT-driven self-assembly of1in DCM was engineered into
honeycomb-like rough hydrophobic surface on a substrate. The microscopy and
optical proﬁler investigations of the honeycomb array surface revealed that the
hydrophobic hexagonal microwells (~10–15μm) were comprised of stacked
nanobelt architectures deposited around the condensed water droplets (formed by
the evaporative cooling of volatile solvent, DCM). The surface roughness, hydro-
phobicity, and overall wettability of honeycomb array surface were made compara-
ble to that of lotus leaf surface upon successive gold sputtering followed by
functionalization with 2H-perﬂuorodecanethiol (FSH). Interestingly, the FSH-
functionalized surface exhibited superhydrophobic property and the self-cleaning
effect with WCA of 156
ﬁ
and contact angle hysteresis value of only 1
ﬁ
(Fig.1.3c–g).
This unique study is a rare example of fabricating superhydrophobic self-cleaning
surfaces employing small functional molecule in BFT. The molecular design strat-
egy was further extended to fabricate the colored honeycomb array surface of1by
uniformly incorporating theﬂuorescent dyes rhodamine B and isoleucine methyl
ester-appended perylenediimide (Fig.1.3h and i), which mayﬁnd use in
bioelectronics, cell sorting, and miniaturized bioanalytical assays. Based on the
molecular self-assembly approach, Lee et al. have reported a biomimetic surface
1 Molecular Architectonics 7

Fig. 1.3(a) Dynamics of water droplets on various rough surfaces (normal, Wenzel, Cassie-
Baxter, and hierarchical rough surfaces), self-cleaning effect on the hierarchical rough surface,
and natural lotus effect. (b) Optical proﬁler image of the honeycomb-like hierarchical rough surface
generated by the BFT-induced self-assembly of1.(candd) WCA (156
ﬁ
) on the FSH-functionalized
honeycomb-like surface and contact angle hysteresis (1
ﬁ
). (e–g) Self-cleaning effect on the
FSH-functionalized honeycomb-like array surface. (handi) Confocal micrographs of
honeycomb-like arrays of1incorporated with rhodamine and isoleucine methyl ester-appended
PDI. Panels (b–i) are adapted with permission. Copyright 2012, Wiley-VCH [22]. (j–l) Surface
morphologies of the amorphousﬁlm and aniline- and pentaﬂuoroaniline-treatedﬁlms of
diphenylalanine (2), inset showing the respective WCAs. Panels (j–l) are adapted with permission.
Copyright 2009, Royal Society of Chemistry [23]. (m) Chemical structures of D-gluconamide (3)
with variable substituents, and the schematic shows the dynamic assembly architectures of 3 offer-
ing coordination center (deprotonated amide NH) for Pb
2+
to catalyze the glucose hydrolysis. Panel
(m) is adapted with permission. Copyright 2020, American Chemical Society [24]
8 M. Konar and T. Govindaraju

strategy to fabricate self-cleaning superhydrophobic material. The self-assembly of
diphenylalanine (Phe-Phe,2) from anhydrous hexaﬂuoroisopropanol (HFIP) formed
hierarchical surface with enhanced hydrophobicity upon treatment with aniline and
pentaﬂuoroaniline solvent vapors [23]. The hierarchical surface roughness reduced
the wettability of the pentaﬂuoroaniline-treatedﬁlm to impart superhydrophobic
property (WCA ~151
ﬁ
) (Fig.1.3j–l).
These studies highlight the potential of molecular architectonics to guide the
fabrication of hierarchical assembly architectures and surfaces over multiple scale
lengths with desired surface hydrophobicity (or hydrophilicity),
superhydrophobicity (superhydrophilicity), surface roughness, and functional
features among other characteristic properties for advanced applications in self-
cleaning, surface coatings, optoelectronics, (bio)electronics, cell sorting, and mini-
aturized bioanalytical device fabrications.
1.3 Biomimetic Catalysis
Mimicking the function of enzyme is considered a holy grail in theﬁeld of catalysis.
The meticulously designed molecular assembly architectures encompassing all the
catalytic components are anticipated to mimic enzyme active center with improved
catalytic efﬁciency under milder conditions. We have designed enzyme mimics by
adapting the scheme of molecular architectonics by orchestrating the assembly of
metal-coordinated amphiphiles (D-gluconamide-Pb
II
complex) and effectively
improved the catalytic activity toward glucose hydrolysis in aqueous alkaline solu-
tion [24]. Notably, Pb
II
alone acts as Lewis acid catalyst in glucose hydrolysis to
form value-added formic acid (FA), lactic acid (LA), and levulinic acid, among
others, while the reactions are performed under extremely harsh conditions including
high temperature [27]. To improve the catalytic efﬁciency of Pb
II
toward glucose
hydrolysis at ambient temperature, we designed a number of D-gluconamide amphi-
philic ligands (3,R¼propyl, phenyl, naphthalene, and pyrene units). These
amphiphilic ligands were found to be capable of coordinating with the lead ions
(Pb
II
) through amide-NH deprotonation under the alkaline conditions. The amphi-
philes were self-assembled to create second coordination spheres around the Pb
II
center. This dynamic assembly architecture exhibited superior catalytic efﬁciency
toward the glucose hydrolysis at ambient temperature compared to dispersed state of
amphiphile or Pb
II
alone (Fig.1.3m). Such biomimetic catalyst systems designed
based on the dynamic metal-coordination assembly architectures of functional
amphiphilic molecules can serve as perfect model systems for developing advanced
catalyst to convert the chemical or biowaste into value-added chemicals.
The second coordination spheres are considered as essential criteria for the
functioning of metalloproteins or metalloenzymes. The second coordination sphere
inﬂuences the microenvironment of the metal ion and therefore has the profound
ability to modulate the reactivity and selectivity of metal complex (metalloprotein).
The second coordination sphere in conﬁned space around the active catalytic center
1 Molecular Architectonics 9

(usually metal ion) is therefore considered as the basis of designing the synthetic
metal complexes as advanced catalytic systems. In this context, Borovik and
coworkers have signiﬁcantly contributed toward mimicking the second coordination
sphere of natural metalloenzymes for synthetic systems [28]. They have shown that
the binding and activation of dioxygen by transition metal (Fe
II
and Mn
II
) complexes
to form highly reactive metal-oxo complexes is controlled by the second coordina-
tion sphere of the metal complexes, as exempliﬁed with the respiratory proteins,
oxygenases, and synthetic complexes [29]. The dynamic process of formation of
metal-oxo systems by binding of dioxygen to metal complexes is governed by the
noncovalent interactions such as intramolecular hydrogen bonds involving
dioxygen-derived ligands. Such noncovalent interaction-assisted metal complexes
and their assemblies can be architectonically evolved and applied for a variety of
reaction types in large-scale industrial purposes.
1.4 Organic Electronics
Engineering the molecular assemblies ofπ-conjugated small organic molecules
leading to electrically conductive materials is the basis of advanced organic elec-
tronics. Currently, organic electronic materials are potentially used in the fabrication
of photovoltaic devices, organicﬁeld-effect transistors (OFETs),ﬂexible displays,
sensors, and bioelectronics [30–32]. The major advantages of organic electronic
materials over the traditional inorganic conductive or semiconductive materials are
their low production cost and tunability with respect to conductive, mechanical, and
thermal properties. Further, the fabrication of bioelectronic materials and devices
using biomolecule or biomimetic functional molecules through bottom-up molecular
architectonics strategies can effectively improve their biocompatibility and biomed-
ical applications. In the scheme of molecular architectonics, we have meticulously
tailored the molecular assembly properties of the organic semiconductor NDI by
conjugating with D- and L-phenylalanine methyl esters as auxiliaries (4and5). By
the minute structural alteration in theα-substituents of amino acids, we were able to
engineer the self-assemblies of4and5into free-ﬂoating crystalline 2D nanosheets
with micrometer lateral dimensions (Fig.1.4a and b)[33]. The striking features of
these NDI nanosheets was their high metallic conductivity (1.6 Scm
ﬂ1
) comparable
to heavily doped conducting polymers and small molecules, which was the highest
reported value among the undoped organic semiconductors (Fig.1.4c). Interestingly,
the molecular ordering of5was further engineered into container architectures such
as nanocup, mesocup, and bowl (macrocup) architectures by employing chlorinated
co-solvents (Fig.1.4d). The container architectures with attoliter volume capacity
can be used as miniaturized containers for biological assays apart from their utiliza-
tion as bioelectronic materials. It has been seen that the lateral organization of4or
5into nanosheet was attributed to the balancedπ-πstacking interactions between the
NDI chromophores initiated and reinforced by the hydrophobic methyl ester moiety
of phenylalanine, whereas strong halogen bonding interactions between NDI and
10 M. Konar and T. Govindaraju

chlorinated co-solvents were responsible for the formation of container architectures
(Fig.1.4e and f). The metallic conductivity of the nanosheets of5motivated us to
undertake the structure-function relationship study by evaluating various structurally
related NDIs having conductive property [34]. Comparative spectroscopy studies of
5and other NDIs appended with L-phenylglycine methyl ester (6), L-isoleucine
methyl ester (7), L-tyrosine methyl ester (8), and L-tryptophan methyl ester (9)
revealed their assembly interactions in 90% aqueous acetonitrile media, viz.,
exciplex (5and6), excimer (7), and charge transfer (CT) (8and9) complexation
modes (Fig.1.4g). These different modes of molecular interactions of the individual
NDI cores orchestrated their molecular assemblies into morphologically and dimen-
sionally distinctive architectures such as 0D spheres (7), 1Dﬁbers (9), 2Dﬂakes (8),
and nanosheets (5and6) (Fig.1.4h). A space-charge-limited current (SPLC) studies
showed the electron mobility of all NDIs within the range of 10
ﬂ8
to 1 cm
2
V
ﬂ1
s
ﬂ1
,
while the highest electron mobility (1 cm
2
V
ﬂ1
s
ﬂ1
) was observed for5(Fig.1.4i and
Fig. 1.4(a–c) Microscopy (ﬂuorescence and AFM) images of the large 2D nanosheets formed by
the self-assembly of NDI derivative5(or4) and its current-voltage (I-V) plot showing the metallic
conductivity of 1.6 Scm
ﬂ1
, as determined by conductive AFM measurements. (d) Morphological
alteration of assembly of5into nanocup, mesocup, and bowl architectures in the presence of
halogen co-solvents. (eandf) Proposed 2D molecular organization of5and the proposed halogen
bonding patterns in crystalline state, which drive the formation of container architectures (nanocups,
mesocups, and bowl). Panels (aandf) are adapted with permission. Copyright 2011, Wiley-VCH
[33]. (gandh) Formation of exciplex (5and6, 2D), excimer (7, 0D), and CT complexation (8, 2D,
and9, 1D) upon respective self-assemblies of different amino acid-conjugated NDI derivatives5–9
to access the inﬂuence of minute structural mutations in theα-functionalities of amino acids. (iand
j) Schematic diagram of SCLC device and the correspondingI-Vplots of the self-assembled
architectures of5–9. Panels (g–j) are adapted with permission. Copyright 2016, American Chem-
ical Society [34]
1 Molecular Architectonics 11

j). This bulk electronic mobility further supported the metallic conductivity (1.6
Scm
ﬂ1
) of L-phenylalanine methyl ester-functionalized NDI derivative (5) deter-
mined by the conductive atomic force microscopy (cAFM) study.
In another study, asymmetrically functionalized NDIs with ethyl and D- or
L-alanine methyl ester moieties as imide substitutions (10or11, respectively)
were synthesized to investigate their self-assembly in 80% aqueous
dimethylsulfoxide (DMSO). Molecular engineering of self-assembled NDI10pro-
duced hierarchical crystalline greenﬂuorescent nanosheets of 10–40 mm lateral
dimensions. The greenﬂuorescent NDI nanosheets showed a nonlinear conductive
behavior with conductance value of 2.22 nS as measured by the scanning tunneling
microscopy (STM) technique (Fig.1.5a). These hierarchical 2D sheets were formed
due to chiral self-assemblies assisted by the extensive intermolecularπ-stacking and
π-extending interaction modes of NDI chromophores to produce hierarchical layered
nanosheets (Fig.1.5b)[35]. The molecular architectonics-guided unique crystalline
molecular packing with semiconductive property is useful in organic electronic
applications.
Further, we developed amino acid- and peptide-based semiconducting materials
with NDI core in an attempt to master the art of custom design and engineering the
assembly of advanced and complex molecular systems. These amino acid- or
peptide-containing functional molecular systems were anticipated to impart
extended intermolecular interactions in their assembly process. Manipulating the
electronic properties of NDI and pyrene aromatic cores, we accomplished the
molecular co-assembly (two-component system) of alanine (L or D) methyl ester-
functionalized NDI(12) as acceptor (A) and di-pyrene tweezer (13) as donor
(D) through CT interactions. The chiral mixed-stack CT interaction-driven
co-assembly resulted in the formation of crystalline nanoﬁbrous hydrogel through
the hydrogen bonding-supported tweezer-inclusion-sandwich (TIS) process
(Fig.1.5c and d)[36]. The unique hydrogen bonding and CT interactions allowed
spontaneous unidirectional macroscopic polarization in the nanoﬁber architecture
under ambient conditions. For theﬁrst time, the extended TIS-CT molecular
co-organization of12(A) and13(D) allowed to fabricate thin-ﬁlm ferroelectric
capacitor with a Ps ~ 4 at room temperature with potential applications in multistate
memory devices and smart multicomponent organic electronics (Fig.1.5e).
In a crystallography-guided study, peptide-conjugated NDIs were crystallized to
understand the inﬂuence of minute structural mutations on the molecular ordering
and conductive properties of their assembly architectures [37]. The NDI derivatives
functionalized with non-proteinogenic achiral peptide (Aib-Aib14, Aib–
α-aminoisobutyric acid) and proteinogenic chiral peptide (L-Ala-L-Ala or
D-Ala-D-Ala,15or16, respectively) auxiliaries were crystallized with 1D and 2D
molecular ordering. The 1D and 2D molecular orderings were found to be the result
of face-to-face (14) and edge-to-edge (15/16)NDI-NDI core interactions. The
solution-processable achiral face-to-face and chiral edge-to-edge NDI-NDI molecu-
lar orderings of14and15/16
(H-type and J-type, respectively) were found to be
stabilized by CH----CO and NH----O (for14)andβ-bridge-like CO---NH hydrogen
bonding interactions along the respective crystallographic axes (Fig.1.5f). The
12 M. Konar and T. Govindaraju

detailed studies have suggested chiral transcription from the peptide backbones to
the molecular organization of the NDI core both in solution and solid states. The
investigation of conductive properties by two-probe method showed two times more
conductivity (3.510
ﬂ6
Sm
ﬂ1
)of1Dﬁber architectures of14compared to that of
2D sheets of15(1.610
ﬂ6
Sm
ﬂ1
) (Fig.1.5g and h). This suggests that the face-to-
Fig. 1.5Chemical structure of the asymmetrically functionalized NDI derivatives with ethyl and
D- or L-alanine methyl ester moieties as imide substitutions10and11.(a) The characteristic I-V
plot obtained for nanosheets of10/11using STM technique. (b) Schematic representation of
molecular organization of10/11to form hierarchical greenﬂuorescent nanosheets. Panels (a and
b) are adapted with permission. Copyright 2013, Royal Society of Chemistry [35]. (c) Schematic
representation of co-assembly of guest12and host13(tweezer) via tweezer-inclusion-sandwich
(TIS)-charge transfer (CT) (TIS-CT) complexation to form nanoﬁbrous hydrogel supported by the
unidirectional hydrogen bonding and CT interactions. (dande) Field emission scanning electron
microscopy (FESEM) image of the xerogelﬁlm and the photo-responsive ferroelectric switching
measurements of the xerogel thinﬁlm. Panels (c–e) are adapted with permission. Copyright 2016,
American Chemical Society [36]. (f) Space-ﬁlling 1D and 2D molecular ordering representation of
the peptide (with non-proteinogenic amino acids)-conjugated NDI14(Aib-Aib) and (with
proteinogenic amino acids)15/16(Ala-Ala) in crystalline state. (gandh) Schematic representation
ofI-Vdevice fabricated by the nanotapes of14and nanosheets of15and the correspondingI-Vplot.
Panels (f–h) are adapted with permission. Copyright 2015, Royal Society of Chemistry [37]
1 Molecular Architectonics 13

face molecular arrangement maximizes the electronic coupling among the NDI
molecules (14) in comparison to the edge-to-edge NDI organization (15).
These amino acid and peptide auxiliary-mediated engineering of NDI assemblies
and co-assemblies exempliﬁes the potential of molecular architectonics to produce
complex architectures andﬁne-tuning of structural and functional outcomes with
implications in optoelectronics and biomedical applications.
1.5 Chirality, Homochirality, and Protein Folding
Nature has a mysterious bias for molecular homochirality (L-amino acids and
D-sugars) to guide the life processes by translating the complex assembly informa-
tion from the basic building blocks to the molecular and material architectures.
Inscription of chirality on achiral functional molecule by employing a suitable chiral
auxiliary to induce handedness in the assembly architectures and to extract
chiroptical properties is fast becoming an actively pursued research activity in the
advanced materials engineering. To understand the chiral transcription from chiral
auxiliary to achiral functional core, we considered incorporating NDI core with
chiral auxiliaries, viz., aliphatic (D-/L-alanine,17/18), aromatic (D-/L-phenylala-
nine,19/20), and heterocyclic aromatic (D-/L-tryptophan,21/22) amino acid auxil-
iaries, while an achiral ethylamine-functionalized NDI (ene,23) was used as a
control probe [38]. Engineering of their molecular self-assemblies led to all the
four modes of aromatic interactions of NDI core, viz., cofacial, brickwork, herring-
bone, and slipped stacks (Fig.1.6a). Detailed photophysical studies have indicated
that chiral substitution (amino acid) induced the preferential helical bias to NDI
resulting in the four distinct crystal packing modes of NDI core in their solid or
solution states. Morphological analyses revealed the self-assembly of NDI-amino
acid conjugates into 0D nanospheres (17/18and21/22) and 1D nanoﬁbers (19/20)in
their gel state, whereas the achiral NDI (23) produced laterally extended 2D nano-
and mesosheet architectures from its solution (cyclohexene/chloroform, 80/20,v/v).
On account of these unique properties, the material architectures derived from
NDI-amino acid conjugates cater to a wide range of applications from materials to
biomedicine.
The characteristic chirality transcription and helical assemblies of the NDI-amino
acid conjugates prompted us to investigate the assembly properties of homochiral,
heterochiral, and achiral NDI-peptide conjugates. These functional building blocks
were designed by symmetrically functionalizing the NDI core with homochiral (LL,
24, and DD,25), heterochiral (LD,26, and DL,27), phenylalanine dipeptide
(Phe-Phe), and achiral (AA,28) glycine dipeptide (Gly-Gly) auxiliaries
[39]. Photophysical investigation unveiled the chirality transcription, ampliﬁcation,
and retentive helical memory within the respective noncovalent supramolecular
assembly architectures. Remarkably, the helical ordering of homochiral (24and
25)and heterochiral (26and27)NDIs is organized into hierarchically piled 1D
nanobelt and 0D mesosphere architectures, respectively, with the retention of
14 M. Konar and T. Govindaraju

Fig. 1.6(a) NDI derivatives with different auxiliaries17–23and their molecular organization
leading to the formation of all possible crystal packing modes of NDI core such as cofacial,
brickwork, herringbone, and slipped stacked and the respective photographs of the solid-state
emissions. Panel (a) is adapted with permission. Copyright 2014, Royal Society of Chemistry
[38]. (b) Proposed model of M helicity and P helicity (with the schematic illustration of sergeants-
and-soldiers effect) of the NDI-peptide conjugates. As shown in table, homochiral (LL and DD,24
and26), heterochiral (LD and DL,25and27), and achiral (AA,28) dipeptide-conjugated NDIs are
studied. (c-f) FESEM images of the self-assembled architectures of24,25,26, and27, respectively.
Panels (b–f) are adapted with permission. Copyright 2012, Wiley-VCH [39]. (g) PDI derivatives
with different nonpolar auxiliaries (29–31) and the schematic representation demonstrating the
abiotic helical assembly-reassembly phenomenon of29and its correlation with the protein folding
pathway (biotic). Panel (g) is adapted with permission. Copyright 2013, American Chemical
Society [40]
1 Molecular Architectonics 15

chirality ofﬁrst stereocenter adjacent to the NDI core (i.e., M helicity for24and27
and P helicity for25and27) (Fig.1.6b–f). On the other hand, chirality was
introduced within the assembly of28with achiral auxiliary upon mixing with either
of the homochiral NDIs. These unprecedented observations support the biological
homochirality mechanism of spontaneous deracemization and ampliﬁcation.
Protein folding is a process by which a nascent polypeptide attains its 3D
functional state consisting of secondary structural features ofα-helix,β-sheet, and
random coil, among others. The entire process of protein folding takes place within
merely a narrow time scale limit involving several complex intermediate steps,
which remains to be a challenging task to understand. For the comprehensive
understanding of the biotic protein folding mechanism, we demonstrated an abiotic
design strategy with PDI core functionalized with nonpolar isoleucine (29), phenyl-
alanine (30), and alanine (31) methyl esters [40]. Serendipitously, we have witnessed
an extremely slow assembly dynamics of29, needed over a period of 1 day toward
its helical organization. Such slow kinetics is quite unusual for any thermodynam-
ically controlled self-assembly processes of synthetic molecules and suggests kinet-
ically controlled process. A critical focus on the temperature-dependent CD studies
implied the heat-induced irreversible chiral denaturation followed by random aggre-
gate formation (during cooling) having no bias for speciﬁc handedness. Eventually
the formation of chiral assemblies from the thermally denatured random aggregate
state in the presence of nondenatured aggregated seeds of29revealed its correlation
to the protein folding phenomenon (biotic). Such characteristic assembly dynamics
was not observed in either of30or31(Fig.1.6g). This protein folding-like intriguing
slow helical assembly and temperature-induced irreversible denaturation of29
(abiotic) suggests its plausible implications (reductionistic approach) in understand-
ing the protein folding and disease-associated misfolding phenomena.
1.6 Biosensors
Engineering biomolecule-directed programmable molecular self-assemblies,
co-assemblies, and templated assemblies is one of the simple and cost-effective
routes to fabricate advanced biosensors with ultrasensitivity and selectivity. The
scheme of molecular architectonics aids in the design of tailorable biomimetic
architectures used in the development of ultrasensitive biosensors for the detection
of environmental, biomedical, food, and defense-related analytes. Mercury (Hg) is a
globally widespread toxic heavy metal and one of the top six hazardous environ-
mental pollutants. Therefore, developing a reliable and ultrasensitive method for the
detection and monitoring of organic and inorganic forms of Hg accumulation in
drinking water is of prime interest. We developed a dual-responsive (chiroptical and
conductivity) and templated DNA nanoarchitectures for the detection of Hg by
exploiting its strong and speciﬁc interaction with thymine (T-Hg-T) [41]. Adenine
(A)-conjugated NDI (BNA) molecule and the complementary deoxyribo-
oligothymidine (dT
n,n¼6, 10, 20) were subjected to mutually templated
16 M. Konar and T. Govindaraju

co-assembly in buffer medium (pH 7). The templated co-assembly between BNA
and dT
nresulted in the formation of hybrid DNA ensemble of the type [BNAn-dTn]
which undergo hierarchical organization to form 2D nanosheets. [BNA
n-dTn]
exhibit interesting chiroptical and conductive property, and the lateral dimensions
of the 2D nanosheets were found to be directly dependent on the length of the dT
n
sequence. Remarkably, addition of Hg
2+
displaces BNA units from [BNA
n-dT
n]
ensemble due to the formation of metallo-DNA duplex of the type [dT-Hg-dT]
n,
which result in distinct change in the chiroptical and conductivity properties
(Fig.1.7a). This observation has enabled us to fabricate aﬁeld-effect transistor
(FET) device using [BNA
10-dT10] material for the selective detection of inorganic/
organic Hg in water with high selectivity and sub-nanomolar sensitivity ( 0.1 nM,
0.02 ppb). The chiroptical method of detection by circular dichroism spectroscopy
measurements also revealed the ultrasensitivity of [BNA
n-dT
n] for the detection of
Hg. The observed detection limit is 100 times lower than the US Environmental
Protection Agency (USEPA) tolerance limit (10 nM, 2 ppb) of the Hg
2+
in drinking
water (Fig.1.7b and c). We employed FET device for the detection of Hg in real
samples from various water bodies, and the method can be used for the detection of
Hg in biological samples.
In another interesting design, a histidine (H)-functionalized perylenediimide
(PDI) bolaamphiphile (HPH) was developed as theﬂuorescence- and surface-
enhanced Raman spectroscopy (SERS)-based dual-responsive optical marker for
the ultrasensitive detection of Hg [42]. The self-assembly of HPH led to J-type
ﬂuorescent aggregate that transformed into H-type non-ﬂuorescent metallo-
supramolecular aggregates upon binding to Hg
2+
. Thisﬂuorometric change allowed
selective detection of Hg
2+
in water with a detection limit of 510
ﬂ9
M (0.1 ppb).
Remarkably, a detection limit of as low as 6010
ﬂ18
M or 60 attomolar (0.01 parts
per quadrillion, ppq) for Hg
2+
was achieved by SERS measurements, which is the
highest ever reported sensitivity for the detection of Hg. A signiﬁcant change in the
SERS signal was observed upon interaction of Hg
2+
with the marker (HPH)
immobilized on SERS-active gold (Au) surface and facilitated the host-guest com-
plexation-driven assembly between the adjacent HPH molecules (Fig.1.7d). The
SERS-based ultrasensitive method allows the detection of Hg
2+
levels 10 order
lower than the USEPA tolerance limit in drinking water. These two simple and
advanced molecular architectonics-based molecular engineering strategies are
expected to inspire the development of numerous unique biosensor platforms and
opto-electronic devices for the ultrasensitive detection and investigation of various
analytes.
The changes in the optical properties of self-assembly or co-assembly architec-
tures of functional chromophore by the external agents (analyte) were harvested to
detect benzene, a well-known aromatic carcinogen. In this optoelectronic architec-
tonics strategy, we investigated the photophysical properties of molecular assembly
architectures of10(discussed in“Organic Electronics”section) in different aromatic
solvents, namely, benzene, toluene, and xylene. Theﬂuorometric studies of10in
polar (DMSO and water) and nonpolar aromatic (benzene, toluene, and xylene)
solvents suggested distinct self-assembly-inducedﬂuorescence response attributed
1 Molecular Architectonics 17

to excimer and exciplex formation [35]. The detailed studies revealed that10is
capable of selectively sensing benzene, toluene, and xylene through distinct and
visibleﬂuorescence color and response within blue to yellow-green region. This
Fig. 1.7(a) Molecular architectonics-guided co-assembly of NDI derivative BNA and dT
nto form
hybrid DNA ensemble [BNA
n-dT
n] and their hierarchical organization to 2D nanosheets. Hg
displaces BNA from [BNA
n-dT
n] to form metallo-DNA architectures [dT
n-Hg
n-dT
n] through strong
Hg-T interactions. (bandc) Schematic ofﬁeld-effect transistor (FET) device fabricated using
[BNA
n-dT
n] for the ultrasensitive detection of organic and inorganic Hg
2+
and the concentration-
dependent conductometric sensing of CH
3Hg
+
. Panels (a–c) are adapted with permission. Copy-
right 2016, American Chemical Society [41]. (d) Attomolar detection of Hg
2+
by SERS upon
interaction with the HPH immobilized on the SERS active gold surface. Panel (d) is adapted with
permission. Copyright 2018, Elsevier [42]. (eandf) Sensing of aromatic solvents by the different
ﬂuorescence responses (colors) of self-assembled10in polar (DMSO and water) and nonpolar
aromatic (benzene, toluene, and xylene) solvents. Lower panel showing speciﬁc detection of
carcinogenic benzene by reversibleﬂuorometric response usingﬁlter paper-based test kit. Panels
(eandf) are adapted with permission. Copyright 2013, Royal Society of Chemistry [35]. (g)
Schematic representation of biosensing of CTAB and Fe
2+
/Cu
2+
by the assembly-disassembly
modulation of PDI derivative32with various aggregation and disaggregation states (State I,
State II, State III, and State IV). Panel (g) is adapted with permission. Copyright 2014, American
Chemical Society [43]
18 M. Konar and T. Govindaraju

selective spectroscopy response encouraged us to develop aﬁlter paper-based
reversibleﬂuorometric test kit for the detection of carcinogenic benzene (Fig.1.7e
and f).
We further established an assembly-disassembly platform for the optical detec-
tion of cationic surfactants and metal ions like Fe
3+
/Cu
2+
in water media [43]. The
ﬂuorescence property of self-assembly architectures of an amphiphilic PDI deriva-
tive functionalized with L-3,4-dihydroxyphenylalanine (L-DOPA) auxiliary (32)
was reversibly modulated to realize switching off-on states. The monomeric32
showed bright yellowﬂuorescence in DMSO (State I), which transformed into
weaklyﬂuorescent aggregated species upon self-assembly in water (State II). Inter-
estingly, the presence of a cationic surfactant cetyltrimethylammonium bromide
(CTAB) disrupted the assembly pattern of32in water as a result of host-guest
interactions among the PDI and CTAB molecules, which modiﬁed the assembly of
32intoﬂuorescent State III (Fig.1.7g). In other ward, CTAB-mediated modulation
of assembly property of32restored the bright yellowﬂuorescence color of mono-
meric32under the micellar environment. The disaggregatedﬂuorescent state in
micellar medium was switched into the metal-bound non-ﬂuorescent off state (State
IV) in the presence of Fe
3+
/Cu
2+
due to metal chelation by L-DOPA moieties of32,
which resulted in the formation of metallo-supramolecular aggregates (Fig.1.7g).
The metal-drivenﬂuorescence off state was reversed into theﬂuorescence on state
(State III) by addition of external metal ion chelator, diethylenetriaminepentaacetic
acid (DTPA). This study explicitly pointed out the signiﬁcant role of external agents
in controlling the architectural outcomes and functional properties through reversible
assembly-disassembly modulation.
The art of creation of co-assembly architectures was exploited to selectively
recognize and detect G-quadruplexes (GQs). GQ is a non-canonical guanine (G)-
rich secondary structure of DNA found in the 3
0
end of chromosomes (telomere) and
promoter regions of oncogene. GQs are known to play important biological
functions including telomere maintenance, transcription, and replication, while
considered important as diagnostic and therapeutic targets for cancers [44]. The
pyrene-conjugated polyethylenimine (PEI-Py,33) showed GQ-speciﬁcﬂuorescence
emission attributed to pyrene excimer formation (Fig.1.8a). The selective excimer
emission of33for GQ containing oncogene sequences can be developed into
diagnostic and therapeutic tools in cancer therapy.
The co-assembly architectures of two pyrene-dipeptides (34and35) of opposite
polarity were developed for the efﬁcient detection of nitroaromatics (NACs) such as
nitrophenol, trinitrobenzene, and trinitrotoluene [45]. Development of reliable chem-
ical sensor tools for the selective and sensitive detection of toxic NAC explosives is
essential to secure the public health and environment. The designer pyrene-dipeptide
conjugates34and35co-assembled through antiparallelβ-sheet interactions, which
resulted in the formation of 3Dﬂuorescent hydrogel withﬁbrillar network. This
hydrogel system withﬁbrillar network of pyrene chromophore served as a host for
the selective intercalation of NAC guests. The electron-rich pyrene chromophore
formed sandwich-like ground-state (pyrene-NAC-pyrene) assembly upon exposure
to electron-deﬁcient NACs causing long-range exciton migration along the extended
1 Molecular Architectonics 19

Fluorescence Reporting
of G-quadruplex
G-quadruplex
Metal ion
N
H
NH
2
O
O
H
N
N
H
O
O
OH
O
N
N
N
NH
3
O
O
O
H
H
H
N
H
N
N
N
N
H
N
HN HN
HN HN
(a)
(b)
33
34
35
Hydrogen bond-guided
AIE assembly
ACQ chromophore Cyclic dipeptides (CDP)
Hydrogen bond aggregators
O
NO
N
H
H
H
2N
O
O
O
R
+
AIEgenAIEgen-analyte
interaction
Analyte
(NAC/Drugs)
≡
Fluorescence
modulation
O
NO
N
N
O
O
H
H
R
(c)
36
Fig. 1.8(a) Schematic representation for the detection of G-quadruplex by PEI-Py conjugate33
upon the interaction with G-rich DNA sequence. Panel (a) is adapted with permission. Copyright
2015, Elsevier [44], Copyright 2018. (b) Molecular co-assembly of pyrene-conjugated dipeptide
amphiphiles34and35with opposite polarities to form 1D nanoﬁber architecture supported by
antiparallelβ-sheet formation. Photographs of hydrogels (ﬂuorescent) as shown by the inverted gel
vials and the schematic of the helical bicomponent assembly of dipeptides (34and35) in nanoﬁbers.
Panel (b) is adapted with permission. Copyright 2018, Royal Society of Chemistry [45]. (c)
Schematic illustration showing the design strategy of CDP-NMI conjugate36and CDP hydrogen
bonding-guided AIEgenic assembly behavior and the corresponding applications in the detection of
20 M. Konar and T. Govindaraju

andπ-conjugated nanoﬁbers within the hydrogel (Fig.1.8b). This aids in the
tunneling of excited-state electrons of pyrene into the low-lying LUMO of NAC in
a non-radiative decay process, which results in theﬂuorescence off state and thus
suggests selective response toward NACs. To amplify the NAC sensitivity of the
hydrogel system, we prepared a thinﬁlm of the hydrogel, which enabled visual
detection of NACs. This bioinspired co-assembly architecture design strategy pro-
vides a newer insight into the fabrication of novel sensors for the detection of
explosives and other analytes.
Extending our peptide-chromophore assembly architecture-based strategies for
explosive sensor, we rationally designed a series of cyclic dipeptide-tethered
naphthalimides (CDP-NIs) (for detailed discussion on CDP, see“Drug Delivery
and Tissue Engineering”section) [46]. The CDP units are tethered to NI core to
modulate the aggregation-induced emission (AIE) property of the latter to explore its
applications. The intriguing intermolecular hydrogen bonding ability of CDP auxil-
iary was anticipated to modulate the self-assembly of NI chromophore in
transforming its aggregation-caused quenching (ACQ) state to aggregation-induced
emission (AIE) state in aqueous media. Interestingly, theﬂuorescence intensity of
the AIEgenic assembly of CDP-NI36was found to exhibit maximum AIE
quenching in the presence of picric acid (NAC) with a limit of detection (LOD) of
ε0.4 ppm (1.7μM). Further exploration revealed selective modulation of AIEgenic
property of36in the presence of phenolic drugs, doxorubicin and rifampicin. The
sensitivity of AIEgenic36toward doxorubicin and rifampicin exhibited LOD in
nanomolar range, viz.,ε18 nM (9.7 ppb) andε202 nM (164 ppb), respectively
(Fig.1.8c). CDP modulated AIEgenic property of chromophores is expected to
inspire the design of smart sensor systems for various bioactive analytes.
1.7 Drug Delivery and Tissue Engineering
Development of novel molecular and material architectures as biomaterials for drug
delivery and tissue engineering applications is of prime importance to improve
human health [3]. A considerable progress has been achieved in designing advanced
biomaterials in the past two decades. In this section, biomolecule-derived biomate-
rial fabrication strategies for drug delivery and speciﬁc tissue engineering applica-
tions involving electrically active cells and tissues are discussed.
CDPs are six-membered heterocyclic lactams and are the smallest cyclic peptides
[11]. CDP derivatives are found in many living organisms as secondary metabolite
natural products. CDPs form intermolecular hydrogen bonding in the form of
molecular chains and layers, which guide the formation of diverse molecular
⁄
Fig. 1.8(continued) NAC (picric acid) and phenolic drugs (doxorubicin and rifampicin) in water
media. Panel (c) is adapted with permission. Copyright 2020, American Chemical Society [46]
1 Molecular Architectonics 21

Fig. 1.9(a) The unique molecular self-assembly of CDP to form molecular chains and molecular
layers through multiple hydrogen bonding sites. (bandc) Single-crystalline self-assembled archi-
tectures of different CDPs (L,D-Phe, L,L-Ala, cyclo(L-Ala-D-Ala), and L,L-Phe) and the plot of
22 M. Konar and T. Govindaraju

architectures (Fig.1.9a). The unique self-assembly propensity and inherent struc-
tural rigidity made CDP a versatile building unit to produce material architectures
that are mechanically robust and resistant toward proteolytic cleavage. In a
bioinspired reductionistic strategy, we exploited the synergistic interactions of
multiple hydrogen bonding networks and aromatic interactions by studying a series
of CDP derivatives cyclo(L-Phg-D-Phg) (L,D-Phe), cyclo(L-Ala-L-Ala) (L,L-Ala),
cyclo(L-Ala-D-Ala), and cyclo(L-Phg-L-Phg) (L,L-Phe) for their mechanical
strength (Fig.1.9b)[47]. The detailed investigation on the mechanical properties
of CDP architectures using nanoindentation technique revealed superior mechanical
stiffness and strength of cyclo(L-Phg-D-Phg) similar to natural silk (Fig.1.9c). This
study demonstrated the possibility to produce large-scale low-density organic mate-
rials with excellent mechanical strength following CDP-based reductionistic
approach, which are sought-after biomimetic materials in the biomaterial research.
We have also employed the CDP moiety as the functional core or auxiliary candidate
in the scheme of molecular architectonics for drug delivery and tissue engineering
applications. We have designed a number of proteinogenic and non-proteinogenic
aromatic amino acids containing CDPs (37–41) to evaluate their antioxidant prop-
erty (Fig.1.9d)[48]. The thorough structure-activity-based investigation revealed
the superior antioxidative property of CDPs containing DOPA units (CDPs40and
41) compared to ascorbic acid and food additive butylated hydroxytoluene (BHT).
Cellular studies have indicated that these CDPs are non-cytotoxic in murine adrenal
PC12 cells. Further effort to prepare a biocompatible electrospun SF scaffold
incorporated with antioxidant CDP40(CDP/SF composite) resulted excellent rad-
ical scavenging properties and therefore can potentially be utilized as therapeutic and
tissue engineering scaffolds (Fig.1.9e). We developed CDP-based low molecular
⁄
Fig. 1.9(continued) elastic modulus (E) versus strength showing the high mechanical strength of
CDP architectures in comparison to various materials including silk. Panels (bandc) are adapted
with permission. Copyright 2015, Nature Publishing Group [47]. (d) Chemical structures of
antioxidant CDPs (37–41) studied to assess their respective radical scavenging properties and a
comparative plot of antioxidant property of all CDPs. (e) Antioxidant property of CDPs upon
incorporating into electrospun silkﬁbroin (SF). SEM micrographs of native SF and CDP/SF
electrospun scaffolds (left to right). The inset showing the respective radical scavenging abilities
of the SF and CDP-SF by the change in DPPH coloration. Panels (dande) are adapted with
permission. Copyright 2017, Wiley-VCH [48]. Chemical structure of CDP gelators42and43and
the FESEM images of xerogels formed by42in (f) CHCl
3,(g) CCL
4,(h) hexane, and (i) toluene
and that of43in (j) toluene and (k) CHCl
3showing ordered microporous hierarchical arrays. Panels
(f–k) are adapted with permission. Copyright 2012, Royal Society of Chemistry [49]. Chemical
structure of another set of CDP gelators44–47and (l) schematic representation of self-assembly of
45showing the gel formation in the presence of guest moleculesβ-cyclodextrin at their minimal
gelation concentrations. Panel (l) is adapted with permission. Copyright 2017, American Chemical
Society [50]. (m) Representative chemical structures of CDPAs (C8–C18) and their morphological
evolution into different nano- and micro-architectures and use of CDPA architecture as drug
delivery vehicle to deliver drug and induce cancer cell death. Panel (m) is adapted with permission.
Copyright 2020, American Chemical Society [51]
1 Molecular Architectonics 23

weight gelators (LMWGs) due to their mechanical robustness and utility in bioma-
terial applications [49]. Asymmetric cyclo(Gly-L-Lys)ε-amino derivatives (42and
43) with tert-butyloxycarbonyl (tBoc,42) andﬂuorenylmethoxycarbonyl (Fmoc,43)
Lysε-amino protection were designed. CDPs42and43were subjected to self-
assembly in both aqueous and organic solvents by sequential heating-cooling
methods to evaluate their propensity to form hydrogels and organogels. The results
showed that42form organogels (in hexane, carbon tetrachloride, toluene, and
chloroform) and43formed both organogel (toluene) and hydrogel (Fig.1.9f–k).
Interestingly, the Fmoc group of43imparted high mechanical strength to the
organogel formed in chloroform with ordered microporous hierarchical morphology
through extensive intermolecular hydrogen bonding andπ-πaromatic interactions.
We demonstrated the encapsulation of dye and drug molecules such as rhodamine B
and curcumin within the gel network without affecting the gel architecture, which
infer possible utility as drug delivery vehicle. To understand the structure-function
relationship, we studied the gelation property of four CDPs, namely, cyclo(L-Tyr-L-
Glu(OtBu)) (44), cyclo(L-Phe-L-Glu(OtBu)) (45), cyclo(L-Phe-L-Asp(OtBu)) (46),
and cyclo(L-Leu-L-Glu(OtBu)) (47)[50]. CDP45showed the superior tendency to
form cytocompatible and thermostable ambidextrous gels with a minimal gelation
concentration of 0.3 wt%, qualiﬁed as supergelator (Fig.1.9l). The hydrogel forming
self-assembled 2Dﬁbrous networks was stabilized by intermolecular N–HΠΠΠO
hydrogen bonding, while t-Boc and phenyl group introduced hydrophobic andπ-π
stacking interactions. Notably,45formed an injectable hydrogel entrapped with
curcumin under the ambient conditions, which highlights the possible use as inject-
able hydrogel formulations in drug delivery-related applications.
CDP-based molecular architectonics strategy was adapted to develop a drug
delivery system by utilizing robust and cytocompatible CDP amphiphiles
(CDPAs). A number of cyclo(Gly-L-Asp) functionalized with alkyl chains of vary-
ing length (n¼C8–C18) were designed (C8–C18) (Fig.1.9m) and judiciously
engineered their molecular self-assembly into diverse nanoarchitectures such as
nanotubes, nanospheres, nano-/microsheets, andﬂowers in organic or aqueous
solvents [51]. The formation of various molecular assembly architectures was
found to be inﬂuenced by the hydrophobic interactions of alkyl chains and hydrogen
bonding interactions of CDP. The facile co-assembly tendency of CDPAs with
nucleosides and nucleotides through speciﬁ
c noncovalent interactions was studied
to assess their ability to act as potential drug delivery vehicles. Thein cellulostudies
of CDPA co-assembly with an anticancer drug 5-bromo-2
0
-deoxyuridine (BrdU)
resulted in the BrdU-triggered cellular cytotoxicity to HeLa cells (Fig.1.9n). The
cellular studies together with the computational modelling of CDPAs and their
co-assembly with the drug molecule conﬁrmed the molecular level interactions of
CDPAs and the drug molecules, which conﬁrmed the utility of CDPA architectures
as robust platforms for drug delivery applications.
In another interesting study, we designed a CDP-containing peptidomimetic
system with improved cell-penetrating and excellent cytocompatibility properties
for DNA delivery applications. The customized design strategy was conceived
speciﬁcally to impart properties that are required for effective DNA delivery into
24 M. Konar and T. Govindaraju

cells and transfection by overcoming the trivial drawbacks of cytotoxic polycationic
peptides. CDP peptidomimetics were synthesized by incorporating lysine and
aspartic acid-based unnatural CDP (kd) amino acid units at the alternative positions
in lysine (K) decapeptide and glutamic acid (E) decapeptide to obtainK
5kd
5and
E
5kd
5, respectively. The optimized and minimum cationic charge ofﬁve K units and
rigidity attributed tokdunits renderedK
5kd
5with high serum stability, bioavail-
ability, and cytocompatibility compared to known cationic cell-penetrating peptides
(CPPs) such as stearyl R8. In fact,K
5kd5effectively combine the characteristics of
CPPs by reducing their cytotoxicity and the rigid rod-like structure of polyproline-
based CPPs to promote speciﬁc noncovalent interaction-driven DNA delivery and
transfection. The CDP peptidomimeticE
5kd5was ineffective for DNA delivery
application due to its anionic nature. The NMR and SAXS studies have revealed
efﬁcient interaction ofK
5kd
5with DNA and membrane lipid (DOPC) through
speciﬁc hydrogen bonding of backbone CDP units (kd) in addition to electrostatic
interactions imparted by the K units, which promoted speciﬁc and selective delivery
of DNA into cells in comparison to the nonspeciﬁc interaction-driven delivery by
cationic CPPs and polymers. As a result,K
5kd5showed effective delivery of
plasmid DNAs in HeLa and HEK293 cells, and the transfection was conﬁrmed by
the expression of greenﬂuorescent protein (GFP) andβ-galactosidase
(Fig.1.10a)[52].
In this section, we discuss innovative molecular architectonics design strategies
based on small molecules targeting DNA. Threading intercalators are small mole-
cules that bind to DNA through dual mode of interaction, viz., intercalation and
groove binding, which are useful molecular tools in the development of advanced
DNA-based architectures with biomedical applications. In the scheme of molecular
architectonics, threading intercalators recognizing long sequences of DNA com-
pared to traditional intercalators or groove binders are capable of modulating the
DNA condensation-decondensation process with tremendous implications in DNA-
or gene-targeted diagnostics and therapeutics. We have designed a set of imidazole-
functionalized NDI derivatives to investigate their threading intercalation ability
[53]. In this design strategy, NDI chromophore with planer geometry was chosen
as an intercalating scaffold and functionalized with imidazolyl auxiliary to facilitate
the groove-binding ability. Among all the compounds studied, NIm6 showed the
best threading intercalation ability with a long half-life of 51 min. The threading
process was achieved by the intercalation of NDI chromophore between the DNA
base pairs and simultaneous binding of imidazolyl moieties in the adjacent major and
minor grooves. The imidazolium moieties aided the DNA groove binding through
electrostatic and hydrogen bonding interactions, which in turn led to favorable
enthalpy change for the threading intercalation process (Fig.1.10b). Furthermore,
the cytotoxic effect of NIm6 in HeLa cells and inhibition of topoisomerase I activity
upon binding to the supercoiled DNA inferred the biological implication of
threading intercalating agent. In an interesting study aimed at understanding the
various factors inﬂuencing the DNA condensation and decondensation process, we
exploited the threading intercalation property in the design of DNA condensing
agent. A set of threading intercalators (BIN, BIHQ, and BIAQ) with ethyl bridge
1 Molecular Architectonics 25

connecting bisimidazolium system to the terminal naphthyl or quinolinyl aromatic
moieties via amide or ether linkages were designed [54]. The design strategy of
introducing naphthyl or quinolinyl moieties at the termini of bisimidazolium linker
was conceptualized to promote DNA intercalation, while imidazolium moiety is
expected to provide speciﬁc hydrogen bonding interaction, in addition to minimum
electrostatic interactions. The speciﬁc intercalation and hydrogen bonding-driven
Fig. 1.10Chemical structures of CDP peptidomimeticsK
5kd
5andE
5kd
5. (a) Schematic repre-
sentation showing cellular uptake, DNA delivery, and transfection efﬁciency ofK
5kd
5. Panel (a)is
adapted with permission. Copyright 2017, Royal Society of Chemistry [52]. (b) Geometry-
optimized structure of DNA complex with NIm6 which shows the threading intercalation mode
of interaction of NIm6. Panel (b) is adapted with permission. Copyright 2016, Wiley-VCH
[53]. Chemical structures of BIN, BIHQ, and BIAQ. (c) Schematic showing threading intercalation
of BIHQ-induced DNA nanocondensate formation and the endogenous metal ion-induced
decondensation to release the DNA and its effective transfection. Panel (c) is adapted with
permission. Copyright 2020, American Chemical Society [54]
26 M. Konar and T. Govindaraju

binding interactions reduced the complete dependence of molecules on nonspeciﬁc
electrostatic interactions for DNA recognition. The AFM imaging illustrated the
thread-like morphology of the free DNA that transformed to distinct
nanoarchitectures with an average size of 100 nm upon treatment with BIHQ. The
distinguishable architectural form of free DNA and BIHQ-bound DNA indicated
threading intercalation-driven formation of DNA nanocondensates. Further, the
acidic pH-dependent turn-onﬂuorescence response of quinoline moiety of the ligand
BIHQ allowed the tracking of cellular uptake and delivery of DNA nanocondensates
into cell through the endocytic pathway. Remarkably, further study revealed
decondensation of nanocondensate by the physiological concentrations of endoge-
nous metal ions such as Mg
2+
and K
+
, followed by effective transfection
(Fig.1.10c). This strategy highlights the design and potential of small molecule-
based threading intercalators for the development of tailorable nonviral vectors for
the DNA or gene delivery applications. The threading intercalation-based conden-
sation of DNA into nanocondensates and their decondensation by endogenous metal
ions have potential implications in understanding the chromatin condensation-
decondensation dynamics.
Recently, we have formulated an injectable silkﬁbroin (SF) hydrogel (iSFH) for
controlled and sustained delivery of insulin in the treatment of diabetic conditions
[55]. The sustained insulin delivery is highly desirable and sought-after to maintain
the physiological glucose homeostasis, as it avoids the complications related to
multiple subcutaneous insulin injections leading to poor patient compliance and
insulin amyloidosis at the site of injection. To address this long-standing issue, we
utilized biocompatible SF protein to produce injectable mesoporous hydrogel for-
mulation within 50 min in the presence of biocompatible viscous additives (ethylene
glycol and triethylene glycol). It is worth noting that the high mechanical stiffness of
natural SF is extremely useful for hydrogelation, electrospinning, and preparation of
composite scaffolds with excellent biocompatibility to cater to biomedical applica-
tions including drug delivery, cell transfection, tissue engineering, vaccine
thermostabilization, and biocidal coating materials, among others [56]. Interestingly,
the mesoporous hydrogel prepared by SF showed excellent insulin encapsulation
ability. The subcutaneous injection of the insulin-encapsulated SF hydrogel in
diabetic T1DM Wistar rats and follow-up studies have demonstrated potential for
slow and controlled release of the encapsulated insulin over a period of 4 days with
effective maintenance of normal physiological glucose levels and homeostasis
(Fig.1.11a and b). The encapsulation, storage, and controlled release of active
insulin indicate the possible use of silk hydrogel to develop oral delivery formula-
tions of insulin in the near future for the treatment of diabetic conditions. This study
demonstrates the advanced engineering of macromolecular organization supported
by small molecule additives for technologically advanced drug delivery formula-
tions to treat chronic and metabolic disorders such as diabetic conditions.
We rationally designed a protein mimetic di-block copolymer of tryptophan-
functionalized methacrylic acid (PTMA) polyampholyte [57]. The zwitterionic
PTMA was found to serve as an artiﬁcial chaperone and protect protein from
aggregation-inducing conditions with possible therapeutic implications in
1 Molecular Architectonics 27

Insulin DepotDiabetic
Diabetic Wister Rat
Subcutaneous
Injection
Normal Glucose
Level for 96 h
(f)
(g)
(h)
48
49
Log (Time)
Log (% cumulative
release)
PTMA
(c)
(d) (e)
Self-
assembly
SF ProteinSF Hydrogel
(a)
Resistance (Ω)
SF
Film
SM
Film
SF
Mat
SM
Mat
(p)(o)(m) (n)
(i)
(j) (k) (l)
(b)
Aggregation (% )
Covalent Modification
Physical Modification
Peptide Sequences
YIGSR
GYIGSR
49-SF Film
Proliferation Neuron-like
Differentiation
SF Film
49-SF Film
STZ
injection
Blood glucose
level monitor
Insulin-iSFH
injection
Blood glucose
level (mg/dL)
esoculgdoolB
)Ld/gm(level
Time (h)Time (h)
Insulin-iSFH Insulin iSFH PBS Only
(c)
Fig. 1.11(a) Photograph of the formation of injectable SF hydrogel (iSFH) and FESEM image of
the corresponding xerogel. (b) Schematic illustration of in vivo delivery and therapeutic efﬁcacy of
insulin-loaded iSFH evaluated in streptozotocin (STZ)-induced diabetic Wistar rat through the
subcutaneous injection of iSFH-loaded insulin and monitoring the slow release of the entrapped
insulin to maintain normal glucose level over a period 4 days. The controlled release data show the
blood glucose levels monitored after subcutaneous injection of iSFH in diabetic and control groups.
28 M. Konar and T. Govindaraju

Alzheimer’s disease (AD). The experimental studies have shown that PTMA protect
heat-induced aggregation of lysozyme and modulate amyloid-beta (Aβ) aggregation,
an important pathological event in AD. These observations and results conﬁrmed the
credentials of PTMA to serve as synthetic chaperone to protect the structure of
essential proteins and prevent the aggregation and accumulation of toxic peptide or
proteins (Fig.1.11c and d). In addition, PTMA efﬁciently sequester lithium in
neutral pH (~ pH 7) conditions and release under acidic conditions (~pH 6)
(Fig.1.11e). Lithium is used as a neuroprotective agent to treat various
depression-related conditions including AD. The absence of effective delivery
options resulted in the use of very high concentrations of lithium causing numerous
side effects. The PTMA-guided lithium encapsulation, storage, and pH-responsive
(therapeutic window) release of lithium ions are highly desirable for therapeutic
value. This synergistic and dual-responsive biomimetic polymer-based protein
aggregation modulation and controlled lithium delivery strategy has the potential
in the development of therapeutic options for AD.
We explored the engineering of SF scaffolds for tissue engineering applications
involving cells and tissues that require electrical impulses for their growth and
differentiation. The skeletal muscle tissue engineering (SMTE) is a process of
repairing and regeneration of impaired muscle tissue [59]. The electroactive scaf-
folds are used to support the assembly and differentiation of myoblasts into high
aspect ratio functional myotubes [59]. In order to avoid the risk of oxidative stress-
mediated immunogenic response and poor biocompatibility and biodegradability
issues of synthetic polymers as conducting scaffolds for SMTE, we focused on the
design and fabrication of novel extracellular matrix (ECM) mimicking and natural
biopolymer-based customized scaffolds. In this context, natural SF protein with
⁄
Fig. 1.11(continued) Panels (aandb) are adapted with permission. Copyright 2020, American
Chemical Society [55]. (c–e) Chemical structure of polyampholyte PTMA and its protein aggrega-
tion (Aβ) modulation and encapsulation, storage, and pH stimuli-responsive release of lithium ions
(monitored by the quenching and recovery ofﬂuorescence, respectively). Panels (c–e) are adapted
with permission. Copyright 2020, American Chemical Society [57]. (f) Schematic showing the
surface functionalization of SFﬁlms through physical adsorption and covalent grafting of peptides
48(YIGSR) and49(GYIGSR). (g and h) Stem cell proliferation and differentiation into neuronal-
like cells on49SFﬁlm (ﬂuorescence images). Panels (f–h) are adapted with permission. Copyright
2016, American Chemical Society [58]. (i) FESEM image of the electrospunﬁber mats of silk-
melanin (SM) composite which show aligned nanoﬁbers. (j) Electrical conducting properties
(as measured by the reduction in resistance) of electrospun scaffolds (SFﬁlm, SMﬁlm, SF mat,
and SM mat). (kandl) TEM andﬂuorescence images of myotubes on the SM scaffold mat conﬁrm
the myogenic cell differentiation of C2C12 mouse myoblast cells. Panels (i–l) are adapted with
permission. Copyright 2016, Wiley-VCH [59]. (m–p) Neuronal cell differentiation (SH-SY5Y
cells) visualized byﬂuorescence imaging uponβ-tubulin staining on the surface of the random
and aligned nanoﬁbers of SF and SM scaffolds. Neuronal cell differentiation monitored on silk
ﬁbroin random nanoﬁbers (SFR), silkﬁbroin/melanin random nanoﬁbers (SMR), silkﬁbroin
aligned nano
ﬁbers (SFA), and silkﬁbroin/melanin aligned nanoﬁbers (SMA) after 3 days of cell
culture study. Panels (m–p) are adapted with permission. Copyright 2019, Elsevier [60]
1 Molecular Architectonics 29

excellent mechanical property and biocompatibility can serve as the base scaffold
material [59,61]. Taking advantage of the superior scaffold characteristics of SF, we
have demonstrated silk composite biomaterial scaffold-based fabrication strategies
and their applications in stem cell differentiation and SMTE. The free-standing SF
ﬁlms surface functionalized with integrin-binding laminin peptides YIGSR (48) and
GYIGSR (49) by physical adsorption and chemical covalent attachment were
fabricated [58]. The functionalized SFﬁlms exhibited good cytocompatibility to
bone marrow-derived human mesenchymal stem cells (hMSCs) and promoted their
proliferation and cell maintenance in an undifferentiated pluripotent stage. The SF
ﬁlm showed differentiation of hMSCs into neuronal cells in the presence of a
chemical cue, retinoic acid (Fig.1.11f–h). The detailed study revealed that SFﬁlm
covalently tethered with49showed superior proliferation and neuronal cell differ-
entiation as compared to SFﬁlms with physically adsorbed (48or49) or covalently
tethered peptide epitope48. The sustained undifferentiated stem cell maintenance
and on-demand differentiation capabilities of suitably functionalized SFﬁlms make
them excellent tissue engineering scaffolds. In a unique study, we prepared SF
composite scaffold by the physical incorporation of a naturally occurring polymeric
skin pigment melanin to impart conducting and antioxidative properties
[59,62]. The electrospunﬁber mats of silk-melanin (SM) composite were found to
exhibit antioxidant and conducting property (Fig.1.11i and j). The SF mats were
evaluated for their effectiveness in promoting in vitro myogenesis. The combined
inﬂuence of surface topography (aligned nanoﬁbers in the mat) and antioxidant and
conductivity property of SM scaffoldﬁlms has successfully promoted the formation
of aligned myotubes in vitro through effective cell attachment, proliferation, and
differentiation processes (Fig.1.11k and l). This study validated the potential of SM
scaffolds in SMTE with promising applications in wound healing and wear and tear-
related skeletal muscle tissue repair. We have also demonstrated the utility of radical
scavenging property of SM composite in the protection and differentiation of
neuronal cells. The human neuroblastoma cells (SH-SY5Y) were grown on random
and aligned electrospun nanoﬁbrous SF and SM scaffoldﬁlms (such as SF random
nanoﬁbers (SFR), SF/melanin random nanoﬁbers (SMR), SF aligned nanoﬁbers
(SFA), and SF/melanin aligned nanoﬁbers (SMA)) [60]. The cellular viability,
proliferation, adhesion, and differentiation assays have shown that SM scaffolds
with aligned nanoﬁbrous morphology promoted improved neuronal growth and
differentiation characteristics, which could be a highly promising strategy for effec-
tive neuronal differentiation- and regeneration-related applications (Fig.1.11m–p).
1.8 Conclusion and Future Prospects
We have summarized the principles of molecular architectonics in producing
advanced molecular and material architectures with novel functional properties
and practical applications. The scheme of molecular architectonics advocates the
custom design and engineering of assembly and co-assembly of functional building
30 M. Konar and T. Govindaraju

blocks through the controlled and meticulous manipulation of noncovalent interac-
tions. The biomolecules and their derivatives or mimetics conjugated to functional
core serve as assembly-directing auxiliaries in the bottom-up fabrication of desired
0D, 1D, 2D, and 3D molecular and material architectures with well-deﬁned nano- to
macroscale sizes and shapes. In molecular architectonics, judicious and skilled
experimental conditions including external stimuli play a key role in controlling
the molecular organization into smart architectures. The sophisticated molecular
assembly-engineering strategies provided access to advanced, mechanically robust,
ﬂexible, and cytocompatible molecular and material architectures with exciting
optical, electrical, chiroptical, catalytic, sensing, and surface properties and applica-
tions. The detailed structure-property-function relationship studies resulted in
diverse applications across self-cleaning, biomimetic catalysis, organic electronics
and bioelectronics, homochirality and protein folding, sensors, bioimaging, drug
delivery and tissue engineering, diagnostics, and therapeutics, among others. As a
whole, the principles of molecular architectonics are anticipated to aid in the art of
mastering the programmed molecular assemblies and co-assemblies with tailorable
structure, property, and function.
The biomimetic and bioinspired molecular architectonics strategies envision new
avenues for solution-processable bottom-up fabrication of advanced and emergent
materials. The practice of the molecular architectonics is futuristic in nature and
provides the opportunity to gain deeper insights into the subtle and complex
interplay of poorly understood noncovalent interactions at the molecular level,
which in turn allow the innovative and preprogramed molecular assembly engineer-
ing to create advanced molecular and material architectures with emergent properties
and functional applications to solve long-standing problems related to health,
energy, and environment. Apart from the design and construction of functional
organic materials and biomaterials, the principles of molecular architectonics guide
the generation of a wide range of well-deﬁned inorganic, organic-inorganic hybrid,
nanoparticle, quantum dot, and macromolecular architectures.
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Nanoarchitectonics and conductivity modulation of an N-type organic semiconductor through
peptide conjugation. Chem Commun 51:8315–8318
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zation of Naphthalene Diimide in the solid state: tunable (chiro-) optical, viscoelastic and
nanoscale properties. RSC Adv 4:20154–20163
39. Pandeeswar M, Avinash MB, Govindaraju T (2012) Chiral transcription and retentive helical
memory: probing peptide auxiliaries appended with Naphthalenediimides for their
one-dimensional molecular organization. Chem-Eur J 18:4818–4822
40. Avinash MB, Govindaraju T (2013) Extremely slow dynamics of an abiotic helical assembly:
unusual relevance to the secondary structure of proteins. J Phys Chem Letters 4:583–588
41. Pandeeswar M, Senanayak SP, Govindaraju T (2016) Nanoarchitectonics of small molecule and
DNA for ultrasensitive detection of mercury. ACS Appl Mater Interfaces 8:30362–30371
42. Makam P, Shilpa R, Kandjani AE, Periasamy SR, Sabri YM, Madhu C, Bhargava SK,
Govindaraju T (2018) SERS andﬂuorescence-based ultrasensitive detection of mercury in
water. Biosens Bioelectron 100:556–564
43. Dwivedi AK, Pandeeswar M, Govindaraju T (2014) Assembly modulation of PDI derivative as
a supramolecularﬂuorescence switching probe for detection of cationic surfactant and metal
ions in aqueous media. ACS Appl Mater Interfaces 6:21369–21379
44. Narayanaswamy N, Unnikrishnan M, Gupta M, Govindaraju T (2015) Fluorescence reporting
of G-Quadruplex structures and modulating their Dnazyme activity using Polyethylenimine-
pyrene conjugate. Bioorg Med Chem Lett 25:2395–2400
45. Madhu C, Roy B, Makam P, Govindaraju T (2018) Bicomponentβ-sheet assembly of dipeptide
ﬂuorophores of opposite polarity and sensitive detection of nitro-explosives. Chem Commun
54:2280–2283
46. Balachandra C, Govindaraju T (2020) Cyclic dipeptide-guided aggregation-induced emission
of Naphthalimide and its application for the detection of phenolic drugs. J Org Chem
85:1525–1536
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tionistic peptide engineering for exceptional mechanical properties. Sci Rep 5:16070
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dipeptides and silkﬁbroin biomaterials. Eur J Org Chem 2017:4363–4369
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1 Molecular Architectonics 33

50. Manchineella S, Murugan NA, Govindaraju T (2017) Cyclic dipeptide-based ambidextrous
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tide Amphiphiles and their application in drug delivery. ACS Appl Bio Mater 3:3413–3422
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threading Intercalators of DNA. Chembiochem 17:2162–2171
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34 M. Konar and T. Govindaraju

Chapter 2
Nanoarchitectonics
Katsuhiko Ariga
2.1 History of Nanoarchitectonics
The most important terminology in current science and technology is probably nano.
Especially in application-orientedﬁelds, nanotechnology has become an extremely
inﬂuential magic concept. People may think that any dream applications become
possible with nanotechnology. This key term, nanotechnology, is said to have
originated thanks to the foresight of Richard Feynman, There’s Plenty of Room at
the Bottom, in 1959 [1–3]. He foresaw a multitude of scientiﬁc and technological
possibilities in nanoscale spaces. Technological and engineering possibilities of
nanotechnology were socially reevaluated in a declaration in 2001 under US Pres-
ident Bill Clinton to promote nanotechnology, called the National Nanotechnology
Initiative. This historicalﬂow is also supported by innovations regarding various
observation and evaluation tools for nanoscale objects, such as the invention of
scanning tunneling microscopy (STM) and nanofabrication techniques. The inven-
tions of STM and related scanning probe microscopy (SPM) in atomic force
microscopy (AFM) allow us to observe and manipulate objects at the level of
atoms and molecules. In fact, the manipulation of artiﬁcial arrangements of Xe
atoms to draw“IBM”has been demonstrated. In parallel, various micro- and
nano-fabrication techniques have been developed.
Another conceptual proposal was brought by Kim Eric Drexler, in his book
entitledEngines of Creation: The Coming Era of Nanotechnology, in 1986 [4]. As
K. Ariga (*)
International Center for Materials Nanoarchitectonics (WPI-MANA), National Institute for
Materials Science (NIMS), Ibaraki, Tsukuba, Japan
Department of Advanced Materials Science, Graduate School of Frontier Sciences, The
University of Tokyo, Chiba, Japan
e-mail:[email protected]
©The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
T. Govindaraju, K. Ariga (eds.),Molecular Architectonics and Nanoarchitectonics,
Nanostructure Science and Technology,
https://doi.org/10.1007/978-981-16-4189-3_2
35

imaginary machine construction, molecular and biomolecular nanotechnology and
the design of assemblers to produce functional systems were described. Not limited
to the concept of machine-type assembly, scientiﬁc developments in biology and
chemistry, such as the promotion of the understanding and technological develop-
ment of biocentric dogma from DNA to proteins, the initiation and demonstration of
the concept of molecular machines, and the exploration of self-assembly and self-
organization in supramolecular chemistry may support this idea as a core method-
ology. These trends are considered to be bottom-up types of nanotechnology,
particularly in theﬁelds of chemistry and biochemistry.
These concepts and strategies can be more generalized as fabrication of functional
material systems from nanoscale building blocks. The term architectonics related to
small objects was used in the paper“Architectonic Quantum Dots of Solids”written
by Heath and colleagues in 1999 at the University of California, Los Angeles
(UCLA) [5]. The use of a new conceptual term, nanoarchitectonics, was initiated
in 2000 by Masakazu Aono, who organized an international symposium, theﬁrst
International Symposium onNanoarchitectonicsUsing Suprainteractions in
Tsukuba, Japan. This is theﬁrst initiation of a new concept–nanoarchitectonics.
Aono intends to combine the nanotechnology initiated by Feynman with other
scientiﬁc disciplines to create a common methodology for creating functional mate-
rials with nanoscale units [6–8].
Theﬁrst appearance of the term nanoarchitectonics in the titles of articles in
scientiﬁc journals was made by Stefan Hecht of the Free University of Berlin,
Germany, in his paperWelding, Organizing, and Planting Organic Molecules on
Substrate Surfaces–Promising Approaches towards Nanoarchitectonics from the
Bottom up[9]. Several research organizations and projects with the term
nanoarchitectonics were initiated at the same time. In 2003, the“Interfacial
Nanoarchitectonics”research center was established at the National Institute of
Advanced Industrial Science and Technology in Tsukuba, led by Toshimi Shimizu.
In 2003, the Functional Engineered Nano Architectonics research center was
established at the University of California, Los Angeles. The founder of
nanoarchitectonics, Masakazu Aono, established the International Center for Mate-
rials Nanoarchitectonics (WPI-MANA) at the National Institute for Materials Sci-
ence in Tsukuba in 2007. Nanoarchitectonics was recognized as one of the key
research areas in a report in 2017 by Institutes of Science and Development and The
National Science Library, Chinese Academy of Sciences, with the aid of Clarivate
Analytics.
These historicalﬂows are summarized in Fig.2.1. As clearly recognized, the
concept of nanoarchitectonics emerged and evolved along with the beginning of the
twenty-ﬁrst century.
36 K. Ariga

2.2 Essence of Nanoarchitectonics
A new concept called nanoarchitectonics is created by combining nanotechnology
with other researchﬁelds such as organic chemistry, supramolecular chemistry,
materials science, and biotechnology [10–12]. Nanoarchitectural approaches should
produce functional materials using nanoarchitectonics units through combined
and/or selected efforts of atomic/molecular manipulation, organic synthesis, self-
assembly/self-organization, micro-fabrication, and biological process (Fig.2.2)
[13,14]. These processes and effects are working in harmony with
nanoarchitectonics uncertainties such as thermalﬂuctuations. The contribution of
multiple principles to construction is beneﬁcial for hierarchical architectural struc-
tures. The basic concept of nanoarchitectonics is general enough to be applied to
variousﬁelds of research such as sensors [15–18], catalysts [19–22], devices [23–
26], energy-related applications [27–30], environmental issues [31–34], and bio-
medical problems [35–38]. In addition to these practicalﬁelds, the concept of
Fig. 2.1Historicalﬂows of nanotechnology and nanoarchitectonics
2 Nanoarchitectonics 37

nanoarchitectonics is effective in the basic sciences including materials synthesis
[39–42], structure controls [43–46], and the biological sciences [47–50].
Although self-assembly is also a central concept in organically based supramo-
lecular chemistry, it can be widely applied in the assembly processes of various
nanoblocks, including quantum objects, inorganic nanomaterials, and biological
materials. Actually, self-assembly plays indispensable roles in nanoarchitectonics
[51]. The basic idea of self-assembly processes is based on equilibrium, without
energy input or external stimuli. Therefore, self-assembly processes tend to provide
a symmetric and simple structure. In contrast, the notion of self-organization is used
for the architecture of structures with energyﬂows from outside the system, and self-
organization processes are far from equilibrium. This nature of self-organization
Fig. 2.2Nanoarchitectonics concept created through combining nanotechnology with other
researchﬁelds such as organic chemistry, supramolecular chemistry, materials science, and
biotechnology
38 K. Ariga

beneﬁts architects of asymmetric, vector, and hierarchical structures, which is
universally used in biological structural organization. Nanoarchitectonics has a
strong characteristic similar to self-organization. Nanoarchitectonics procedures
can involve multiple energy-intensive processes in a staggered order and/or fashion
harmonization. The integration of some artiﬁcial energy-intensive processes and
multiple fabrication processes into the spontaneous self-assembly of nano units
results in asymmetric and hierarchical architecture in the nanoarchitectonics process
[52]. Nanoarchitectonics approaches are rather closer in nature to the processes of
formation of biological structures than conventional self-assembly.
Nanoarchitectonics processes are not completely same as architectonics processes
in macroscopic scales [53]. In contrast to macroscopic, architectonics processes of
materials and structural systems on the nanometer or mesoscale (nanoarchitectonics
processes) do not always proceed decisively according to their design and programs.
Uncontrolled and unexpected disturbances andﬂuctuations have major impacts in
nanoscale regions. The physical phenomena and behavior of materials in nanoscale
regions cannot escape from the effects of thermal/staticﬂuctuations and the mutual
interactions that inevitably occur between atoms, molecules, and constituent mate-
rials. The results, such as material structures and properties, are not simply deter-
mined by known input data. At the nanoscale, an input signal to a particular target
can also interfere with surrounding entities or components and cause additional
mutual interactions. Therefore, the synthesis and fabrication of materials or the use
of components at the nanoscale are quite different from the authoritative and
predictable fabrication processes at the microscale. The fabrication of nanoscale
materials based on nanoarchitectonics requires concerted coordination of the various
interactions and effects, as well as many techniques and tricks to control the
organization of the materials and stimulate spontaneous processes such as self-
assembly.
2.3 Example of Nanoarchitectonics
Several nanoarchitectonics processes in various scales are exempliﬁed below. As
molecular-level nanoarchitectonics processes, nanotechnology-based organic chem-
istry has been recently demonstrated. Unlike the traditional approach to organic
chemistry, the combination of nanotechnology and organic synthesis with the help
of advanced probe microscopy techniques allows us to manipulate organic modiﬁ-
cation in molecules in site-speciﬁc manner [54]. Scanning probe microscopy has
seen major advances in imaging technology, where probes can be used to remove
speciﬁc atoms from a molecule and change its structure. It would be a starting point
for the fabrication of functional materials from molecular units that can be consid-
ered an organic nanoarchitecture.
For example, Kawai and co-workers demonstrate site-speciﬁc substitution of Br
atoms on a three-dimensional graphene nanotape by a fullerene molecule using a tip
of scanning probe microscope (Fig.2.3)[55]. The Br atoms were removed by
2 Nanoarchitectonics 39

moving the probe tip to a vertical position several hundred picometers away from the
Br atoms and then applying voltage of about 2.5 V to the target site. The detachment
of Br atoms leaves highly active unpaired electrons on carbon. The reactive and
unstable electrons are retained under ultra-high vacuum at extremely low tempera-
ture. The three-dimensional nature of the graphene nanotape can also prevent
unwanted reactions between the unpaired electrons and the surface. A fullerene
molecule can then be attached to the active site with unpaired electrons. The
fullerene molecule is previously adsorbed on the surface and is picked up by the
probe tip. By pushing the fullerene molecule onto the active diradical site, the
fullerene molecule is covalently attached to the desired positions of the graphene
nanotape. In this organic nanoarchitectural approach, chemical reactions can be
performed with a site-speciﬁc mode under selected conditions. It is a nice demon-
stration of the premise of the nanoarchitectural approach to prepare functional
materials from the molecular bottom.
Figure2.4demonstrates a nanoarchitectonics example in micrometer scale. These
objects can be architected from fullerene molecules. A new fullerene object, fuller-
ene microhorns, was produced by in situ structural modiﬁcation of fullerene
microtubes [56]. Fullerene precursor microtubes were spontaneously formed by
Fig. 2.3Site-speciﬁc substitution of Br atoms on a three-dimensional graphene nanotape by a
fullerene molecule using a tip of scanning probe microscope
40 K. Ariga

addingtert-butyl alcohol to a mesitylene solution of a mixture of C60and C70
fullerenes. The structural transformation of the formed fullerene microtubes into
fullerene microhorns was carried out by adding a few drops of a mixture oftert-butyl
alcohol and mesitylene to fullerene microtubes deposited on the surface of a silicon
wafer and then slowly evaporating the solvent. After careful observation, it was
found that one fullerene microtube disintegrates into two fullerene microhorns
within seconds. Solvent dissolution occurred selectively in the central region of
the fullerene microtube, forming two microhorns of length equal to half the length of
the original fullerene microtube. Such a manipulable microscale hollow object, the
fullerene microhorn, was then subjected to micron-sized object recognition. Among
the microparticles studied, silica particles are preferentially trapped and attached to
fullerene microspheres compared to other particles of similar size, such as C
70
fullerene particles, polystyrene latex particles, hydroxylate particles, and carboxylate
particles. The zeta potential measurement showed that the zeta potential of the
Fig. 2.4Fullerene
microhorns produced by in
situ structural modiﬁcation
of fullerene microtube
2 Nanoarchitectonics 41

fullerene microhorns was negative (ﬁ51.1 mV), while the silica nanoparticles had a
positive value (+1.2 mV) for zeta potential under the same conditions. Electrostatic
interaction has a key role in this selective particle recognition.
Nanoarchitectonics of living objects is also possible. Jia et al. applied this cell
culture strategy at the liquid-liquid two-dimensional interface to human mesenchy-
mal stem cells and demonstrated the differentiation of stem cells into neurocytes
without the use of expensive reagents (Fig.2.5)[57]. At the liquid interface between
aqueous cell culture medium andﬂuorocarbon layer, protein two-dimensional
nanolayers spontaneously formed from proteins contained in the cell culture medium
together with externally addedﬁbronectin. According to the transformation of the
protein nanosheet into hierarchicalﬁbrous structures, the mesenchymal stem cells
cultured on the surface of the nanolayer were conﬁrmed to differentiate into neurons
without the addition of differentiation-inducing factors. The formation of prolonged
focal adhesion with increased activation of focal adhesion kinase is promoted by
adaptation to elongatedﬁbronectinﬁbers, leading to neuronal differentiation of
mesenchymal stem cells. Spatial rearrangement of extracellular matrix proteins in
the presence of altered cell traction forces induces changes in cell fates. Instead of
conventional solid surfaces, such as plasticﬁlms, the use of a liquid-liquid dynamic
two-dimensional interface is essential to induce the formation of adaptive protein
nanosheets that are able to deform and remodel in response to cellular mechanical
Fig. 2.5Nanoarchitectonics of living objects at the liquid-liquid two-dimensional interface for
differentiation of stem cells into neurocyte without the use of expensive reagents
42 K. Ariga

Another Random Scribd Document
with Unrelated Content

his opinion, had done, and would do, more pecuniary damage
to New Orleans, than the British army would have done if they
had conquered it in 1815. He verified this opinion by referring to
the immense dividend, upwards of half a million a year, drawn
from the branch there; the immense amounts of specie drawn
from it; the produce carried off to meet the domestic bills of
exchange; and the eight and a half millions of debt existing
there, of which five millions were created in the last two years
to answer electioneering purposes, and the collection of which
must paralyze, for years, the growth of the city. From further
damage to New Orleans, the veto message would save that
great city. Jackson would be her saviour a second time. He
would save her from the British bank as he had done from the
British army; and if any federal bank must be there, let it be an
independent one; a separate and distinct bank, which would
save to that city, and to the Valley of the Mississippi, of which it
was the great and cherished emporium, the command of their
own moneyed system, the regulation of their own commerce
and finances, and the accommodation of their own citizens.
"Mr. B. addressed himself to the Jackson bank men, present
and absent. They might continue to be for a bank and for
Jackson; but they could not be for this bank, and for Jackson.
This bank is now the open, as it long has been the secret,
enemy of Jackson. It is now in the hands of his enemies,
wielding all its own money—wielding even the revenues and the
credit of the Union—wielding twelve millions of dollars, half of
which were intended to be paid to the public creditors on the
first day of July, but which the bank has retained to itself by a
false representation in the pretended behalf of the merchants.
All this moneyed power, with an organization which pervades
the continent, working every where with unseen hands, is now
operating against the President; and it is impossible to be in
favor of this power and also in favor of him at the same time.
Choose ye between them! To those who think a bank to be
indispensable, other alternatives present themselves. They are

not bound nor wedded to this. New American banks may be
created. Read, sir, Henry Parnell. See his invincible reasoning,
and indisputable facts, to show that the Bank of England is too
powerful for the monarchy of Great Britain! Study his plan for
breaking up that gigantic institution, and establishing three or
four independent banks in its place, which would be so much
less dangerous to liberty, and so much safer and better for the
people. In these alternatives, the friends of Jackson, who are in
favor of national banks, may find the accomplishment of their
wishes without a sacrifice of their principles, and without
committing the suicidal solecism of fighting against him while
professing to be for him.
"Mr. B. addressed himself to the West—the great, the
generous, the brave, the patriotic, the devoted West. It was the
selected field of battle. There the combined forces, the national
republicans, and the national republican bank, were to work
together, and to fight together. The holy allies understand each
other. They are able to speak in each other's names, and to
promise and threaten in each other's behalf. For this campaign
the bank created its debt of thirty millions in the West; in this
campaign the associate leaders use that debt for their own
purposes. Vote for Jackson! and suits, judgments, and
executions shall sweep, like the besom of destruction,
throughout the vast region of the West! Vote against him! and
indefinite indulgence is basely promised! The debt itself, it is
pretended, will, perhaps, be forgiven; or, at all events, hardly
ever collected! Thus, an open bribe of thirty millions is virtually
offered to the West; and, lest the seductions of the bribe may
not be sufficient on one hand, the terrors of destruction are
brandished on the other! Wretched, infatuated men, cried Mr. B.
Do they think the West is to be bought? Little do they know of
the generous sons of that magnificent region! poor, indeed, in
point of money, but rich in all the treasures of the heart! rich in
all the qualities of freemen and republicans! rich in all the noble
feelings which look with equal scorn upon a bribe or a threat.

The hunter of the West, with moccasins on his feet, and a
hunting shirt drawn around him, would repel with indignation
the highest bribe that the bank could offer him. The wretch
(said Mr. Benton, with a significant gesture) who dared to offer
it, would expiate the insult with his blood.
"Mr. B. rapidly summed up with a view of the dangerous
power of the bank, and the present audacity of her conduct.
She wielded a debt of seventy millions of dollars, with an
organization which extended to every part of the Union, and she
was sole mistress of the moneyed power of the republic. She
had thrown herself into the political arena, to control and
govern the presidential election. If she succeeded in that
election, she would wish to consolidate her power by getting
control of all other elections. Governors of States, judges of the
courts, representatives and senators in Congress, all must
belong to her. The Senate especially must belong to her; for,
there lay the power to confirm nominations and to try
impeachments; and, to get possession of the Senate, the
legislatures of a majority of the States would have to be
acquired. The war is now upon Jackson, and if he is defeated,
all the rest will fall an easy prey. What individual could stand in
the States against the power of the bank, and that bank flushed
with a victory over the conqueror of the conquerors of
Bonaparte? The whole government would fall into the hands of
this moneyed power. An oligarchy would be immediately
established; and that oligarchy, in a few generations, would
ripen into a monarchy. All governments must have their end; in
the lapse of time, this republic must perish; but that time, he
now trusted, was far distant; and when it comes, it should come
in glory, and not in shame. Rome had her Pharsalia, and Greece
her Chæronea; and this republic, more illustrious in her birth
than Greece or Rome, was entitled to a death as glorious as
theirs. She would not die by poison—perish in corruption—no! A
field of arms, and of glory, should be her end. She had a right to
a battle—a great, immortal battle—where heroes and patriots

could die with the liberty which they scorned to survive, and
consecrate, with their blood, the spot which marked a nation's
fall.
"After Mr. B. had concluded his remarks, Mr. Clay rose and
said:—
"The senator from Missouri expresses dissatisfaction that the
speeches of some senators should fill the galleries. He has no
ground for uneasiness on this score. For if it be the fortune of
some senators to fill the galleries when they speak, it is the
fortune of others to empty them, with whatever else they fill the
chamber. The senator from Missouri has every reason to be well
satisfied with the effect of his performance to-day; for among
his auditors is a lady of great literary eminence. [Pointing to
Mrs. Royal.] The senator intimates, that in my remarks on the
message of the President, I was deficient in a proper degree of
courtesy towards that officer. Whether my deportment here be
decorous or not, I should not choose to be decided upon by the
gentleman from Missouri. I answered the President's arguments,
and gave my own views of the facts and inferences introduced
by him into his message. The President states that the bank has
an injurious operation on the interests of the West, and dwells
upon its exhausting effects, its stripping the country of its
currency, &c., and upon these views and statements I
commented in a manner which the occasion called for. But, if I
am to be indoctrinated in the rules of decorum, I shall not look
to the gentleman for instruction. I shall not strip him of his
Indian blankets to go to Boon's Lick for lessons in deportment,
nor yet to the Court of Versailles, which he eulogizes. There are
some peculiar reasons why I should not go to that senator for
my views of decorum, in regard to my bearing towards the chief
magistrate, and why he is not a fit instructor. I never had any
personal rencontre with the President of the United States. I
never complained of any outrages on my person committed by
him. I never published any bulletins respecting his private
brawls. The gentleman will understand my allusion. [Mr. B. said:

He will understand you, sir, and so will you him.] I never
complained, that while a brother of mine was down on the
ground, senseless or dead, he received another blow. I have
never made any declaration like these relative to the individual
who is President. There is also a singular prophecy as to the
consequences of the election of this individual, which far
surpasses, in evil foreboding, whatever I may have ever said in
regard to his election. I never made any prediction so sinister,
nor made any declaration so harsh, as that which is contained in
the prediction to which I allude. I never declared my
apprehension and belief, that if he were elected, we should be
obliged to legislate with pistols and dirks by our side. At this last
stage of the session I do not rise to renew the discussion of this
question. I only rose to give the senator from Missouri a full
acquittance, and I trust there will be no further occasion for
opening a new account with him.
"Mr. B. replied. It is true, sir, that I had an affray with General
Jackson, and that I did complain of his conduct. We fought, sir;
and we fought, I hope, like men. When the explosion was over,
there remained no ill will, on either side. No vituperation or
system of petty persecution was kept up between us. Yes, sir, it
is true, that I had the personal difficulty, which the senator from
Kentucky has had the delicacy to bring before the Senate. But
let me tell the senator from Kentucky there is no 'adjourned
question of veracity' between me and General Jackson. All
difficulty between us ended with the conflict; and a few months
after it, I believe that either party would cheerfully have relieved
the other from any peril; and now we shake hands and are
friendly when we meet. I repeat, sir, that there is no 'adjourned
question of veracity' between me and General Jackson, standing
over for settlement. If there had been, a gulf would have
separated us as deep as hell.
"Mr. B. then referred to the prediction alleged by Mr. Clay, to
have been made by him. I have seen, he said, a placard, first
issued in Missouri, and republished lately. It first appeared in

1825; and stated that I had said, in a public address, that if
General Jackson should be elected, we must be guarded with
pistols and dirks to defend ourselves while legislating here. This
went the rounds of the papers at the time. A gentleman, well
acquainted in the State of Missouri (Col. Lawless), published a
handbill denying the truth of the statement, and calling upon
any person in the State to name the time and place, when and
where, any such address had been heard from me, or any such
declaration made. Colonel Lawless was perfectly familiar with
the campaign, but he could never meet with a single individual,
man, woman, or child, in the State, who could recollect to have
ever heard any such remarks from me. No one came forward to
reply to the call. No one had ever heard me make the
declaration which was charged upon me. The same thing has
lately been printed here, and, in the night, stuck up in a placard
upon the posts and walls of this city. While its author remained
concealed, it was impossible for me to hold him to account, nor
could I make him responsible, who, in the dark, sticks it to the
posts and walls: but since it is in open day introduced into this
chamber I am enabled to meet it as it deserves to be met. I see
who it is that uses it here, and to his face [pointing to Mr. Clay]
I am enabled to pronounce it, as I now do, an atrocious
calumny.
"Mr. Clay.—The assertion that there is 'an adjourned question
of veracity' between me and Gen. Jackson, is, whether made by
man or master absolutely false. The President made a certain
charge against me, and he referred to witnesses to prove it. I
denied the truth of the charge. He called upon his witness to
prove it. I leave it to the country to say, whether that witness
sustained the truth of the President's allegation. That witness is
now on his passage to St. Petersburg, with a commission in his
pocket. [Mr. B. here said aloud, in his place, the Mississippi and
the fisheries—Mr. Adams and the fisheries—every body
understands it.] Mr. C. said, I do not yet understand the senator.
He then remarked upon the 'prediction' which the senator from

Missouri had disclaimed. Can he, said Mr. C, look to me, and say
that he never used the language attributed to him in the placard
which he refers to? He says, Col. Lawless denies that he used
the words in the State of Missouri. Can you look me in the face,
sir [addressing Mr. B.], and say that you never used that
language out of the State of Missouri?
"Mr. B. I look, sir, and repeat that it is an atrocious calumny;
and I will pin it to him who repeats it here.
"Mr. Clay. Then I declare before the Senate that you said to
me the very words—
"[Mr. B. in his place, while Mr. Clay was yet speaking, several
times loudly repeated the word 'false, false, false.']
Mr. Clay said, I fling back the charge of atrocious calumny
upon the senator from Missouri.
A call to order was here heard from several senators.
"The President, pro tem., said, the senator from Kentucky is
not in order, and must take his seat.
"Mr. Clay. Will the Chair state the point of order?
"The Chair, said Mr. Tazewell (the President pro tem.), can
enter in no explanations with the senator.
"Mr. Clay. I shall be heard. I demand to know what point of
order can be taken against me, which was not equally
applicable to the senator from Missouri.
"The President, pro tem., stated, that he considered the
whole discussion as out of order. He would not have permitted
it, had he been in the chair at its commencement.
"Mr. Poindexter said, he was in the chair at the
commencement of the discussion, and did not then see fit to
check it. But he was now of the opinion that it was not in order.

"Mr. B. I apologize to the Senate for the manner in which I
have spoken; but not to the senator from Kentucky.
"Mr. Clay. To the Senate I also offer an apology. To the
senator from Missouri none.
"The question was here called for, by several senators, and it
was taken, as heretofore reported."
The conclusion of the debate on the side of the bank was in the
most impressive form to the fears and apprehensions of the country,
and well calculated to alarm and rouse a community.' Mr. Webster
concluded with this peroration, presenting a direful picture of
distress if the veto was sustained, and portrayed the death of the
constitution before it had attained the fiftieth year of its age. He
concluded thus—little foreseeing in how few years he was to invoke
the charity of the world's silence and oblivion for the institution
which his rhetoric then exalted into a great and beneficent power,
indispensable to the well working of the government, and the well
conducting of their affairs by all the people:
"Mr. President, we have arrived at a new epoch. We are
entering on experiments with the government and the
constitution of the country, hitherto untried, and of fearful and
appalling aspect. This message calls us to the contemplation of
a future, which little resembles the past. Its principles are at
war with all that public opinion has sustained, and all which the
experience of the government has sanctioned. It denies first
principles. It contradicts truths heretofore received as
indisputable. It denies to the judiciary the interpretation of law,
and demands to divide with Congress the origination of
statutes. It extends the grasp of Executive pretension over
every power of the government. But this is not all. It presents
the Chief Magistrate of the Union in the attitude of arguing
away the powers of that government over which he has been
chosen to preside; and adopting, for this purpose, modes of
reasoning which, even under the influence of all proper feeling

towards high official station, it is difficult to regard as
respectable. It appeals to every prejudice which may betray
men into a mistaken view of their own interests; and to every
passion which may lead them to disobey the impulses of their
understanding. It urges all the specious topics of State rights,
and national encroachment, against that which a great majority
of the States have affirmed to be rightful, and in which all of
them have acquiesced. It sows, in an unsparing manner, the
seeds of jealousy and ill-will against that government of which
its author is the official head. It raises a cry that liberty is in
danger, at the very moment when it puts forth claims to power
heretofore unknown and unheard of. It affects alarm for the
public freedom, when nothing so much endangers that freedom
as its own unparalleled pretences. This, even, is not all. It
manifestly seeks to influence the poor against the rich. It
wantonly attacks whole classes of the people, for the purpose of
turning against them the prejudices and resentments of other
classes. It is a state paper which finds no topic too exciting for
its use; no passion too inflammable for its address and its
solicitation. Such is this message. It remains, now, for the
people of the United States to choose between the principles
here avowed and their government. These cannot subsist
together. The one or the other must be rejected. If the
sentiments of the message shall receive general approbation,
the constitution will have perished even earlier than the moment
which its enemies originally allowed for the termination of its
existence. It will not have survived to its fiftieth year."
On the other hand, Mr. White, of Tennessee, exalted the merit of
the veto message above all the acts of General Jackson's life, and
claimed for it a more enduring fame, and deeper gratitude than for
the greatest of his victories: and concluded his speech thus:
"When the excitement of the time in which we act shall have
passed away, and the historian and biographer shall be
employed in giving his account of the acts of our most

distinguished public men, and comes to the name of Andrew
Jackson; when he shall have recounted all the great and good
deeds done by this man in the course of a long and eventful life,
and the circumstances under which this message was
communicated shall have been stated, the conclusion will be,
that, in doing this, he has shown a willingness to risk more to
promote the happiness of his fellow-men, and to secure their
liberties, than by the doing of any other act whatever."
And such, in my opinion, will be the judgment of posterity—the
judgment of posterity, if furnished with the material to appreciate
the circumstances under which he acted when signing the message
which was to decide the question of supremacy between the bank
and the government.

CHAPTER LXIX.
THE PROTECTIVE SYSTEM.
The cycle had come round which, periodically, and once in four
years, brings up a presidential election and a tariff discussion. The
two events seemed to be inseparable; and this being the fourth year
from the great tariff debate of 1828, and the fourth year from the
last presidential election, and being the long session which precedes
the election, it was the one in regular course in which the candidates
and their friends make the greatest efforts to operate upon public
opinion through the measures which they propose, or oppose in
Congress. Added to this, the election being one on which not only a
change of political parties depended, but also a second trial of the
election in the House of Representatives in 1824-'25, in which Mr.
Adams and Mr. Clay triumphed over General Jackson, with the
advantage on their side now of both being in Congress: for these
reasons this session became the most prolific of party topics, and of
party contests, of any one ever seen in the annals of our Congress.
And certainly there were large subjects to be brought before the
people, and great talents to appear in their support and defence.
The renewal of the national bank charter—the continuance of the
protective system—internal improvement by the federal government
—division of the public land money, or of the lands themselves—
colonization society—extension of pension list—Georgia and the
Cherokees—Georgia and the Supreme Court—imprisoned
missionaries—were all brought forward, and pressed with zeal, by
the party out of power; and pressed in a way to show their
connection with the presidential canvass, and the reliance upon
them to govern its result. The party in power were chiefly on the
defensive; and it was the complete civil representation of a military
attack and defence of a fortified place—a siege—with its open and

covert attacks on one side, its repulses and sallies on the other—its
sappings and minings, as well as its open thundering assaults. And
this continued for seven long months—from December to July; fierce
in the beginning, and becoming more so from day to day until the
last hour of the last day of the exhausted session. It was the most
fiery and eventful session that I had then seen—or since seen,
except one—the panic session of 1834-'35.
The two leading measures in this plan of operations—the bank
and the tariff—were brought forward simultaneously and quickly—on
the same day, and under the same lead. The memorial for the
renewal of the bank charter was presented in the Senate on the 9th
day of January: on the same day, and as soon as it was referred, Mr.
Clay submitted a resolution in relation to the tariff, and delivered a
speech of three days' duration in support of the American system.
The President, in his message, and in view of the approaching
extinction of the public debt—then reduced to an event of certainty
within the ensuing year—recommended the abolition of duties on
numerous articles of necessity or comfort, not produced at home.
Mr. Clay proposed to make the reduction in subordination to the
preservation of the "American system" and this opened the whole
question of free trade and protection; and occasioned that field to be
trod over again with all the vigor of a fresh exploration. Mr. Clay
opened his great speech with a retrospect of what the condition of
the country was for seven years before the tarriff of 1824, and what
it had been since—the first a period of unprecedented calamity, the
latter of equally unprecedented prosperity:—and he made the two
conditions equally dependent upon the absence and presence of the
protective system. He said:
"Eight years ago, it was my painful duty to present to the
other House of Congress an unexaggerated picture of the
general distress pervading the whole land. We must all yet
remember some of its frightful features. We all know that the
people were then oppressed and borne down by an enormous
load of debt; that the value of property was at the lowest point

of depression; that ruinous sales and sacrifices were every
where made of real estate; that stop laws and relief laws and
paper money were adopted to save the people from impending
destruction; that a deficit in the public revenue existed, which
compelled government to seize upon, and divert from its
legitimate object, the appropriation to the sinking fund, to
redeem the national debt; and that our commerce and
navigation were threatened with a complete paralysis. In short,
sir, if I were to select any term of seven years since the
adoption of the present constitution, which exhibited a scene of
the most wide-spread dismay and desolation, it would be
exactly the term of seven years which immediately preceded the
establishment of the tariff of 1824."
This was a faithful picture of that calamitous period, but the
argument derived from it was a two-edged sword, which cut, and
deeply, into another measure, also lauded as the cause of the public
prosperity. These seven years of national distress which immediately
preceded the tariff of 1824, were also the same seven years which
immediately followed the establishment of the national bank; and
which, at the time it was chartered, was to be the remedy for all the
distress under which the country labored: besides, the protective
system was actually commenced in the year 1816—
contemporaneously with the establishment of the national bank.
Before 1816, protection to home industry had been an incident to
the levy of revenue; but in 1816 it became an object. Mr. Clay thus
deduced the origin and progress of the protective policy:
"It began on the ever memorable 4th day of July—the 4th of
July, 1789. The second act which stands recorded in the statute
book, bearing the illustrious signature of George Washington,
laid the corner stone of the whole system. That there might be
no mistake about the matter, it was then solemly proclaimed to
the American people and to the world, that it was necessary for
"the encouragement and protection of manufactures," that
duties should be laid. It is in vain to urge the small amount of

the measure of protection then extended. The great principle
was then established by the fathers of the constitution, with the
father of his country at their head. And it cannot now be
questioned, that, if the government had not then been new and
the subject untried, a greater measure of protection would have
been applied, if it had been supposed necessary. Shortly after,
the master minds of Jefferson and Hamilton were brought to act
on this interesting subject. Taking views of it appertaining to the
departments of foreign affairs and of the treasury, which they
respectively filled, they presented, severally, reports which yet
remain monuments of their profound wisdom, and came to the
same conclusion of protection to American industry. Mr.
Jefferson argued that foreign restrictions, foreign prohibitions,
and foreign high duties, ought to be met, at home, by American
restrictions, American prohibitions, and American high duties.
Mr. Hamilton, surveying the entire ground, and looking at the
inherent nature of the subject, treated it with an ability which, if
ever equalled, has not been surpassed, and earnestly
recommended protection.
"The wars of the French revolution commenced about this
period, and streams of gold poured into the United States
through a thousand channels, opened or enlarged by the
successful commerce which our neutrality enabled us to
prosecute. We forgot, or overlooked, in the general prosperity,
the necessity of encouraging our domestic manufactures. Then
came the edicts of Napoleon, and the British orders in council;
and our embargo, non-intercourse, non-importation, and war,
followed in rapid succession. These national measures,
amounting to a total suspension, for the period of their
duration, of our foreign commerce, afforded the most
efficacious encouragement to American manufactures; and
accordingly, they every where sprung up. Whilst these measures
of restriction and this state of war continued the manufacturers
were stimulated in their enterprises by every assurance of
support, by public sentiment, and by legislative resolves. It was

about that period (1808) that South Carolina bore her high
testimony to the wisdom of the policy, in an act of her
legislature, the preamble of which, now before me, reads:
'Whereas the establishment and encouragement of domestic
manufactures is conducive to the interest of a State, by adding
new incentives to industry, and as being the means of
disposing, to advantage, the surplus productions of the
agriculturist: And whereas, in the present unexampled state of
the world, their establishment in our country is not only
expedient, but politic, in rendering us independent of foreign
nations.' The legislature, not being competent to afford the
most efficacious aid, by imposing duties on foreign rival articles,
proceeded to incorporate a company.
"Peace, under the Treaty of Ghent, returned in 1815, but
there did not return with it the golden days which preceded the
edicts levelled at our commerce by Great Britain and France. It
found all Europe tranquilly resuming the arts and the business
of civil life. It found Europe no longer the consumer of our
surplus, and the employer of our navigation, but excluding, or
heavily burdening, almost all the productions of our agriculture
and our rivals in manufactures, in navigation, and in commerce.
It found our country, in short, in a situation totally different from
all the past—new and untried. It became necessary to adapt our
laws, and especially our laws of impost, to the new
circumstances in which we found ourselves. It has been said
that the tariff of 1816 was a measure of mere revenue; and that
it only reduced the war duties to a peace standard. It is true
that the question then was, how much, and in what way, should
the double duties of the war be reduced? Now, also, the
question is, on what articles shall the duties be reduced so as to
subject the amount of the future revenue to the wants of the
government? Then it was deemed an inquiry of the first
importance, as it should be now, how the reduction should be
made, so as to secure proper encouragement to domestic
industry. That this was a leading object in the arrangement of

the tariff of 1816, I well remember, and it is demonstrated by
the language of Mr. Dallas.
"The subject of the American system was again brought up in
1820, by the bill reported by the chairman of the Committee on
Manufactures, now a member of the bench of the Supreme
Court of the United States, and the principle was successfully
maintained by the representatives of the people; but the bill
which they passed was defeated in the Senate. It was revived in
1824, the whole ground carefully and deliberately explored, and
the bill then introduced, receiving all the sanctions of the
constitution. This act of 1824 needed amendments in some
particulars, which were attempted in 1828, but ended in some
injuries to the system; and now the whole aim was to save an
existing system—not to create a new one."
And he summed up his policy thus:
"1. That the policy which we have been considering ought to
continue to be regarded as the genuine American system.
"2. That the free trade system, which is proposed as its
substitute, ought really to be considered as the British colonial
system.
"3. That the American system is beneficial to all parts of the
Union, and absolutely necessary to much the larger portion.
"4. That the price of the great staple of cotton, and of all our
chief productions of agriculture, has been sustained and upheld,
and a decline averted by the protective system.
"5. That, if the foreign demand for cotton has been at all
diminished by the operation of that system, the diminution has
been more than compensated in the additional demand created
at home.
"6. That the constant tendency of the system, by creating
competition among ourselves, and between American and

European industry, reciprocally acting upon each other, is to
reduce prices of manufactured objects.
"7. That, in point of fact, objects within the scope of the
policy of protection have greatly fallen in price.
"8. That if, in a season of peace, these benefits are
experienced, in a season of war, when the foreign supply might
be cut off, they would be much more extensively felt.
"9. And, finally, that the substitution of the British colonial
system for the American system, without benefiting any section
of the Union, by subjecting us to a foreign legislation, regulated
by foreign interests, would lead to the prostration of our
manufactures, general impoverishment, and ultimate ruin."
Mr. Clay was supported in his general views by many able
speakers—among them, Dickerson and Frelinghuysen of New Jersey;
Ewing of Ohio; Holmes of Maine; Bell of New Hampshire; Hendricks
of Indiana; Webster and Silsbee of Massachusetts; Robbins and
Knight of Rhode Island; Wilkins and Dallas of Pennsylvania; Sprague
of Maine; Clayton of Delaware; Chambers of Maryland; Foot of
Connecticut. On the other hand the speakers in opposition to the
protective policy were equally numerous, ardent and able. They
were: Messrs. Hayne and Miller of South Carolina; Brown and
Mangum of North Carolina; Forsyth and Troup of Georgia; Grundy
and White of Tennessee; Hill of New Hampshire; Kane of Illinois;
Benton of Missouri; King and Moore of Alabama; Poindexter of
Mississippi; Tazewell and Tyler of Virginia; General Samuel Smith of
Maryland. I limit the enumeration to the Senate. In the House the
subject was still more fully debated, according to its numbers; and
like the bank question, gave rise to heat; and was kept alive to the
last day.
General Smith of Maryland, took up the question at once as
bearing upon the harmony and stability of the Union—as unfit to be
pressed on that account as well as for its own demerits—avowed
himself a friend to incidental protection, for which he had always

voted, and even voted for the act of 1816—which he considered
going far enough; and insisted that all "manufacturers" were doing
well under it, and did not need the acts of 1824 and 1828, which
were made for "capitalists"—to enable them to engage in
manufacturing; and who had not the requisite skill and care, and
suffered, and called upon Congress for more assistance. He said:
"We have arrived at a crisis. Yes, Mr. President, at a crisis
more appalling than a day of battle. I adjure the Committee on
Manufactures to pause—to reflect on the dissatisfaction of all
the South. South Carolina has expressed itself strongly against
the tariff of 1828—stronger than the other States are willing to
speak. But, sir, the whole of the South feel deeply the
oppression of that tariff. In this respect there is no difference of
opinion. The South—the whole Southern States—all, consider it
as oppressive. They have not yet spoken; but when they do
speak, it will be with a voice that will not implore, but will
demand redress. How much better, then, to grant redress? How
much better that the Committee on Manufactures heal the
wound which has been inflicted? I want nothing that shall injure
the manufacturer. I only want justice.
"I am, Mr. President, one of the few survivors of those who
fought in the war of the revolution. We then thought we fought
for liberty—for equal rights. We fought against taxation, the
proceeds of which were for the benefit of others. Where is the
difference, if the people are to be taxed by the manufacturers or
by any others? I say manufacturers—and why do I say so?
When the Senate met, there was a strong disposition with all
parties to ameliorate the tariff of 1828; but I now see a change,
which makes me almost despair of any thing effectual being
accomplished. Even the small concessions made by the senator
from Kentucky [Mr. Clay] have been reprobated by the lobby
members, the agents of the manufacturers. I am told they have
put their fiat on any change whatever, and hence, as a
consequence, the change in the course and language of

gentlemen, which almost precludes all hope. Those interested
men hang on the Committee on Manufactures like an incubus. I
say to that committee, depend upon your own good judgments
—survey the whole subject as politicians—discard sectional
interests, and study only the common weal—act with these
views—and thus relieve the oppressions of the South.
"I have ever, Mr. President, supported the interest of
manufactures, as far as it could be done incidentally. I
supported the late Mr. Lowndes's bill of 1816. I was a member
of his committee, and that bill protected the manufactures
sufficiently, except bar iron. Mr. Lowndes had reported fifteen
dollars per ton. The House reduced it to nine dollars per ton.
That act enabled the manufacturers to exclude importations of
certain articles. The hatters carry on their business by their sons
and apprentices, and few, if any, hats are now imported. Large
quantities are exported, and preferred. All articles of leather,
from tanned side to the finest harness or saddle, have been
excluded from importation; and why? Because the business is
conducted by their own hard hands, their own labor, and they
are now heavily taxed by the tariff of 1828, to enable the rich to
enter into the manufactures of the country. Yes, sir, I say the
rich, who entered into the business after the act of 1824, which
proved to be a mushroom affair, and many of them suffered
severely. The act of 1816, I repeat, gave all the protection that
was necessary or proper, under which the industrious and frugal
completely succeeded. But, sir, the capitalist who had invested
his capital in manufactures, was not to be satisfied with ordinary
profit; and therefore the act of 1828."
Mr. Clay, in his opening speech had adverted to the Southern
discontent at the working of the protective tariff, in a way that
showed he felt it to be serious, and entitled to enter into the
consideration of statesmen; but considered this system an overruling
necessity of such want and value to other parts of the Union, that
the danger to its existence laid in the abandonment, and not in the

continuance of the "American system." On this point he expressed
himself thus:
"And now, Mr. President, I have to make a few observations
on a delicate subject, which I approach with all the respect that
is due to its serious and grave nature. They have not, indeed,
been rendered necessary by the speech of the gentleman from
South Carolina, whose forbearance to notice the topic was
commendable, as his argument throughout was characterized
by an ability and dignity worthy of him and of the Senate. The
gentleman made one declaration which might possibly be
misinterpreted, and I submit to him whether an explanation of it
be not proper. The declaration, as reported in his printed
speech, is: 'the instinct of self-interest might have taught us an
easier way of relieving ourselves from this oppression. It wanted
but the will to have supplied ourselves with every article
embraced in the protective system, free of duty, without any
other participation, on our part than a simple consent to receive
them.' [Here Mr. Hayne rose, and remarked that the passages,
which immediately preceded and followed the paragraph cited,
he thought, plainly indicated his meaning, which related to
evasions of the system, by illicit introduction of goods, which
they were not disposed to countenance in South Carolina.] I am
happy to hear this explanation. But, sir, it is impossible to
conceal from our view the fact that there is great excitement in
South Carolina; that the protective system is openly and
violently denounced in popular meetings; and that the
legislature itself has declared its purpose of resorting to
counteracting measures: a suspension of which has only been
submitted to, for the purpose of allowing Congress time to
retrace its steps. With respect to this Union, Mr. President, the
truth cannot be too generally proclaimed, nor too strongly
inculcated, that it is necessary to the whole and to all the parts
—necessary to those parts, indeed, in different degrees, but
vitally necessary to each; and that, threats to disturb or dissolve
it, coming from any of the parts, would be quite as indiscreet

and improper, as would be threats from the residue to exclude
those parts from the pale of its benefits. The great principle,
which lies at the foundation of all free governments, is, that the
majority must govern; from which there is nor can be no appeal
but to the sword. That majority ought to govern wisely,
equitably, moderately, and constitutionally; but, govern it must,
subject only to that terrible appeal. If ever one, or several
States, being a minority, can, by menacing a dissolution of the
Union, succeed in forcing an abandonment of great measures,
deemed essential to the interests and prosperity of the whole,
the Union, from that moment, is practically gone. It may linger
on, in form and name, but its vital spirit has fled for ever!
Entertaining these deliberate opinions, I would entreat the
patriotic people of South Carolina—the land of Marion, Sumpter,
and Pickens; of Rutledge, Laurens, the Pickneys; and Lowndes;
of living and present names, which I would mention if they were
not living or present—to pause, solemnly pause! and
contemplate the frightful precipice which lies directly before
them. To retreat, may be painful and mortifying to their
gallantry and pride; but it is to retreat to the Union, to safety,
and to those brethren, with whom, or, with whose ancestors,
they, or their ancestors, have won, on the fields of glory,
imperishable renown. To advance, is to rush on certain and
inevitable disgrace and destruction.
"The danger to our Union does not lie on the side of
persistance in the American system, but on that of its
abandonment. If, as I have supposed and believe, the
inhabitants of all north and east of James River, and all west of
the mountains, including Louisiana are deeply interested in the
preservation of that system, would they be reconciled to its
overthrow? Can it be expected that two thirds, if not three
fourths, of the people of the United States would consent to the
destruction of a policy believed to be indispensably necessary to
their prosperity? When too, this sacrifice is made at the instance
of a single interest, which they verily believe will not be

promoted by it? In estimating the degree of peril which may be
incident to two opposite courses of human policy, the statesman
would be short-sighted who should content himself with viewing
only the evils, real or imaginary, which belong to that course
which is in practical operation. He should lift himself up to the
contemplation of those greater and more certain dangers which
might inevitably attend the adoption of the alternative course.
What would be the condition of this Union, if Pennsylvania and
New-York, those mammoth members of our confederacy, were
firmly persuaded that their industry was paralyzed, and their
prosperity blighted, by the enforcement of the British colonial
system, under the delusive name of free trade? They are now
tranquil, and happy, and contented, conscious of their welfare
and feeling a salutary and rapid circulation of the products of
home manufactures and home industry throughout all their
great arteries. But let that be checked, let them feel that a
foreign system is to predominate, and the sources of their
subsistence and comfort dried up; let New England and the
West, and the Middle States, all feel that they too are the
victims of a mistaken policy, and let these vast portions of our
country despair of any favorable change, and then, indeed,
might we tremble for the continuance and safety of this Union!"
Here was an appalling picture presented: dissolution of the Union,
on either hand, and one or the other of the alternatives obliged to
be taken. If persisted in, the opponents to the protective system, in
the South, were to make the dissolution; if abandoned, its friends, in
the North, were to do it. Two citizens, whose word was law to two
great parties, denounced the same event, from opposite causes, and
one of which causes was obliged to occur. The crisis required a hero-
patriot at the head of the government, and Providence had reserved
one for the occasion. There had been a design, in some, to bring
Jackson forward for the Presidency, in 1816, and again, in 1820,
when he held back. He was brought forward, in 1824, and defeated.
These three successive postponements brought him to the right
years, for which Providence seemed to have destined him, and

which he would have missed, if elected at either of the three
preceding elections. It was a reservation above human wisdom or
foresight; and gave to the American people (at the moment they
wanted him) the man of head, and heart, and nerve, to do what the
crisis required: who possessed the confidence of the people, and
who knew no course, in any danger, but that of duty and patriotism;
and had no feeling, in any extremity but that God and the people
would sustain him. Such a man was wanted, in 1832, and was found
—found before, but reserved for use now.
The representatives from the South, generally but especially those
from South Carolina, while depicting the distress of their section of
the Union, and the reversed aspect which had come upon their
affairs, less prosperous now than before the formation of the Union,
attributed the whole cause of this change to the action of the federal
government, in the levy and distribution of the public revenue; to
the protective system, which was now assuming permanency, and
increasing its exactions; and to a course of expenditure which
carried to the North what was levied on the South. The democratic
party generally concurred in the belief that this system was working
injuriously upon the South, and that this injury ought to be relieved;
that it was a cause of dissatisfaction with the Union, which a regard
for the Union required to be redressed; but all did not concur in the
cause of Southern eclipse in the race of prosperity which their
representatives assigned; and, among them, Mr. Dallas, who thus
spoke:
"The impressive and gloomy description of the senator from
South Carolina [Mr. Hayne], as to the actual state and wretched
prospects of his immediate fellow-citizens, awakens the liveliest
sympathy, and should command our attention. It is their right; it
is our duty. I cannot feel indifferent to the sufferings of any
portion of the American people; and esteem it inconsistent with
the scope and purpose of the federal constitution, that any
majority, no matter how large, should connive at, or protract the
oppression or misery of any minority, no matter how small. I

disclaim and detest the idea of making one part subservient to
another; of feasting upon the extorted substance of my
countrymen; of enriching my own region, by draining the
fertility and resources of a neighbor; of becoming wealthy with
spoils which leave their legitimate owners impoverished and
desolate. But, sir, I want proof of a fact, whose existence, at
least as described, it is difficult even to conceive; and, above all,
I want the true causes of that fact to be ascertained; to be
brought within the reach of legislative remedy, and to have that
remedy of a nature which may be applied without producing
more mischiefs than those it proposes to cure. The proneness to
exaggerate social evils is greatest with the most patriotic.
Temporary embarrassment is sensitively apprehended to be
permanent. Every day's experience teaches how apt we are to
magnify partial into universal distress, and with what difficulty
an excited imagination rescues itself from despondency. It will
not do, sir, to act upon the glowing or pathetic delineations of a
gifted orator; it will not do to become enlisted, by ardent
exhortations, in a crusade against established systems of policy;
it will not do to demolish the walls of our citadel to the sounds
of plaintiff eloquence, or fire the temple at the call of
impassioned enthusiasm.
"What, sir, is the cause of Southern distress? Has any
gentleman yet ventured to designate it? Can any one do more
than suppose, or argumentatively assume it? I am neither
willing nor competent to flatter. To praise the honorable senator
from South Carolina, would be
'To add perfume to the violet—
Wasteful and ridiculous excess.'
But, if he has failed to discover the source of the evils he
deplores, who can unfold it? Amid the warm and
indiscriminating denunciations with which he has assailed the
policy of protecting domestic manufactures and native produce,

he frankly avows that he would not 'deny that there are other
causes, besides the tariff, which have contributed to produce
the evils which he has depicted.' What are those 'other causes?'
In what proportion have they acted? How much of this dark
shadowing is ascribable to each singly, and to all in
combination? Would the tariff be at all felt or denounced, if
these other causes were not in operation? Would not, in fact, its
influence, its discriminations, its inequalities, its oppressions, but
for these 'other causes,' be shaken, by the elasticity and energy,
and exhaustless spirit of the South, as 'dew-drops from the
lion's mane?' These inquiries, sir, must be satisfactorily
answered before we can be justly required to legislate away an
entire system. If it be the root of all evil, let it be exposed and
demolished. If its poisonous exhalations be but partial, let us
preserve such portions as are innoxious. If, as the luminary of
day, it be pure and salutary in itself, let us not wish it
extinguished, because of the shadows, clouds, and darkness
which obscure its brightness or impede its vivifying power.
"That other causes still, Mr. President, for Southern distress,
do exist, cannot be doubted. They combine with the one I have
indicated, and are equally unconnected with the manufacturing
policy. One of these it is peculiarly painful to advert to; and
when I mention it, I beg honorable senators not to suppose that
I do it in the spirit of taunt, of reproach, or of idle declamation.
Regarding it as a misfortune merely, not as a fault; as a disease
inherited, not incurred; perhaps to be alleviated, but not
eradicated, I should feel self-condemned were I to treat it other
than as an existing fact, whose merit or demerit, apart from the
question under debate, is shielded from commentary by the
highest and most just considerations. I refer, sir, to the
character of Southern labor, in itself, and in its influence on
others. Incapable of adaptation to the ever-varying charges of
human society and existence, it retains the communities in
which it is established, in a condition of apparent and
comparative inertness. The lights of science, and the

improvements of art, which vivify and accelerate elsewhere,
cannot penetrate, or, if they do, penetrate with dilatory
inefficiency, among its operatives. They are merely instinctive
and passive. While the intellectual industry of other parts of this
country springs elastically forward at every fresh impulse, and
manual labor is propelled and redoubled by countless
inventions, machines, and contrivances, instantly understood
and at once exercised, the South remains stationary,
inaccessible to such encouraging and invigorating aids. Nor is it
possible to be wholly blind to the moral effect of this species of
labor upon those freemen among whom it exists. A disrelish for
humble and hardy occupation; a pride adverse to drudgery and
toil; a dread that to partake in the employments allotted to
color, may be accompanied also by its degradation, are natural
and inevitable. The high and lofty qualities which, in other
scenes and for other purposes, characterize and adorn our
Southern brethren, are fatal to the enduring patience, the
corporal exertion, and the painstaking simplicity, by which only a
successful yeomanry can be formed. When, in fact, sir, the
senator from South Carolina asserts that 'slaves are too
improvident, too incapable of that minute, constant, delicate
attention, and that persevering industry which is essential to the
success of manufacturing establishments,' he himself admits the
defect in the condition of Southern labor, by which the progress
of his favorite section must be retarded. He admits an inability
to keep pace with the rest of the world. He admits an inherent
weakness; a weakness neither engendered nor aggravated by
the tariff—which, as societies are now constituted and directed,
must drag in the rear, and be distanced in the common race."
Thus spoke Mr. Dallas, senator from Pennsylvania; and thus
speaking, gave offence to no Southern man; and seemed to be well
justified in what he said, from the historical fact that the loss of
ground, in the race of prosperity, had commenced in the South
before the protective system began—before that epoch year, 1816,
when it was first installed as a system, and so installed by the power

of the South Carolina vote and talent. But the levy and expenditure
of the federal government was, doubtless, the main cause of this
Southern decadence—so unnatural in the midst of her rich staples—
and which had commenced before 1816.
It so happened, that while the advocates of the American system
were calling so earnestly for government protection, to enable them
to sustain themselves at home, that the custom-house books were
showing that a great many species of our manufactures, and
especially the cotton, were going abroad to far distant countries; and
sustaining themselves on remote theatres against all competition,
and beyond the range of any help from our laws. Mr. Clay, himself,
spoke of this exportation, to show the excellence of our fabrics, and
that they were worth protection; I used the same fact to show that
they were independent of protection; and said:
"And here I would ask, how many and which are the articles
that require the present high rate of protection? Certainly not
the cotton manufacture; for, the senator from Kentucky [Mr.
Clay], who appears on this floor as the leading champion of
domestic manufactures, and whose admissions of fact must be
conclusive against his arguments of theory! this senator tells
you, and dwells upon the disclosure with triumphant exultation,
that American cottons are now exported to Asia, and sold at a
profit in the cotton markets of Canton and Calcutta! Surely, sir,
our tariff laws of 1824 and 1828 are not in force in Bengal and
China. And I appeal to all mankind for the truth of the
inference, that, if our cottons can go to these countries, and be
sold at a profit without any protection at all, they can stay at
home, and be sold to our own citizens, without loss, under a
less protection than fifty and two hundred and fifty per centum!
One fact, Mr. President, is said to be worth a thousand theories;
I will add that it is worth a hundred thousand speeches; and
this fact that the American cottons now traverse the one-half of
the circumference of this globe—cross the equinoctial line;
descend to the antipodes; seek foreign markets on the double

theatre of British and Asiatic competition, and come off
victorious from the contest—is a full and overwhelming answer
to all the speeches that have been made, or ever can be made,
in favor of high protecting duties on these cottons at home. The
only effect of such duties is to cut off importations—to create
monopoly at home—to enable our manufacturers to sell their
goods higher to their own christian fellow-citizens than to the
pagan worshippers of Fo and of Brahma! to enable the
inhabitants of the Ganges and the Burrampooter to wear
American cottons upon cheaper terms than the inhabitants of
the Ohio and Mississippi. And every Western citizen knows the
fact, that when these shipments of American cottons were
making to the extremities of Asia, the price of these same
cottons was actually raised twenty and twenty-five per cent., in
all the towns of the West; with this further difference to our
prejudice, that we can only pay for them in money, while the
inhabitants of Asia make payment in the products of their own
country.
"This is what the gentleman's admission proved; but I do not
come here to argue upon admissions, whether candid or
unguarded, of the adversary speakers. I bring my own facts and
proofs; and, really, sir, I have a mind to complain that the
gentleman's admission about cottons has crippled the force of
my argument; that it has weakened its effect by letting out half
at a time, and destroyed its novelty, by an anticipated
revelation. The truth is, I have this fact (that we exported
domestic cottons) treasured up in my magazine of material! and
intended to produce it, at the proper time, to show that we
exported this article, not to Canton and Calcutta alone, but to all
quarters of the globe; not a few cargoes only, by way of
experiment, but in great quantities, as a regular trade, to the
amount of a million and a quarter of dollars, annually; and that,
of this amount, no less than forty thousand dollars' worth, in the
year 1880, had done what the combined fleets and armies of
the world could not do; it had scaled the rock of Gibraltar,

penetrated to the heart of the British garrison, taken possession
of his Britannic Majesty's soldiers, bound their arms, legs, and
bodies, and strutted in triumph over the ramparts and batteries
of that unattackable fortress. And now, sir, I will use no more of
the gentleman's admissions; I will draw upon my own
resources; and will show nearly the whole list of our domestic
manufacture to be in the same flourishing condition with
cottons, actually going abroad to seek competition, without
protection, in every foreign clime, and contending victoriously
with foreign manufactures wherever they can encounter them. I
read from the custom-house returns, of 1830—the last that has
been printed. Listen to it:
"This is the list of domestic manufactures exported to foreign
countries. It comprehends the whole, or nearly the whole, of
that long catalogue of items which the senator from Kentucky
[Mr. Clay] read to us, on the second day of his discourse; and
shows the whole to be going abroad, without a shadow of
protection, to seek competition, in foreign markets, with the
foreign goods of all the world. The list of articles I have read,
contains near fifty varieties of manufactures (and I have omitted
many minor articles) amounting, in value, to near six millions of
dollars! And now behold the diversity of human reasoning! The
senator from Kentucky exhibits a list of articles manufactured in
the United States, and argues that the slightest diminution in
the enormous protection they now enjoy, will overwhelm the
whole in ruin, and cover the country with distress; I read the
same identical list, to show that all these articles go abroad and
contend victoriously with their foreign rivals in all foreign
markets."

Mr. Clay had attributed to the tariffs of 1824 and 1828 the reviving
and returning prosperity of the country, while in fact it was the mere
effect of recovery from prostration, and in spite of these tariffs,
instead of by their help. Business had been brought to a stand
during the disastrous period which ensued the establishment of the
Bank of the United States. It was a period of stagnation, of
settlement, of paying up, of getting clear of loads of debt; and
starting afresh. It was the strong man, freed from the burthen under
which he had long been prostrate, and getting on his feet again. In
the West I knew that this was the process, and that our revived
prosperity was entirely the result of our own resources, independent
of, and in spite of federal legislation; and so declared it in my
speech. I said:
"The fine effects of the high tariff upon the prosperity of the
West have been celebrated on this floor: with how much reason,
let facts respond, and the people judge! I do not think we are
indebted to the high tariff for our fertile lands and our navigable
rivers; and I am certain we are indebted to these blessings for
the prosperity we enjoy. In all that comes from the soil, the
people of the West are rich. They have an abundant supply of
food for man and beast, and a large surplus to send abroad.
They have the comfortable living which industry creates for
itself in a rich soil; but, beyond this, they are poor. They have
none of the splendid works which imply the presence of the
moneyed power! No Appian or Flaminian ways; no roads paved
or McAdamized; no canals, except what are made upon
borrowed means; no aqueducts; no bridges of stone across our
innumerable streams; no edifices dedicated to eternity; no
schools for the fine arts: not a public library for which an
ordinary scholar would not apologize. And why none of those
things? Have the people of the West no taste for public
improvements, for the useful and the fine arts, and for
literature? Certainly they have a very strong taste for them; but
they have no money! not enough for private and current uses,

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Molecular Architectonics And Nanoarchitectonics Thimmaiah Govindaraju

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Molecular Architectonics And Nanoarchitectonics Thimmaiah Govindaraju

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