Applications of reaction chemoinformatics to reaction chemistry problems.ppt

Applications of reaction chemoinformatics to reaction chemistry problems

1. Chemical Reactions

2. 2
Overview
•Reactions in organic chemistry, review
•Problems in reaction chemistry
•Chemoinformatics methods
•Applications of reaction chemoinformatics
to reaction chemistry problems
•Review questions

3. 3
Overview
•Reactions in organic chemistry, review
•Problems in reaction chemistry
•Chemoinformatics methods
•Applications of reaction chemoinformatics
to reaction chemistry problems
•Review questions
–Chemicals – Reactions Relationship
–Reaction Specification
–Reaction Mechanisms
–Reactivity Principles
–Reaction Favorability
–Reaction Classification

4. 4
Chemicals – Rxns Relationship
•Chemical Space
–Chemicals are points in the space
–Reactions are “vectors” describing how to reach new
points from existing ones
•Reactant Chemicals  Product Chemicals
•Transformation that forms and breaks bonds
–Rearrangement of electron configuration
CH
3
CH
2
CH
3
Br
CH
3
HBr+

5. 5
Reaction Specification
•Simplest reaction specification is a chemical
equation indicating starting reactants and
resultant products
•For practical use and reproducibility, additional
information is required:
–Catalyst or other reagents
–Reaction conditions (temperature, solvent, etc.)
–Yield %, etc.
Br
+ HBr
C
2H
5O
-
Na
+
C
2
H
5
OH
70
o
C

6. 6
Reaction Mechanisms
•Reactions are fundamentally
rearrangements of electron configurations
•Mechanisms describe the specific flow of
electrons, the transient intermediates, and
the final products

7. 7
Mechanistic Principles
•Curved arrow diagrams
–Depict flow of electrons, NOT atoms
–Source must be electrons (bond, lone pair, radical)
–Targets should be atoms / nuclei
O
Cl
N C
- N
O
-
Cl
N
O
Cl
-
+

8. 8
Reactivity Principles
•Broadly speaking, reactions are the
transfer of electrons from
–Electron-dense groups (nucleophiles) to
–Electron-deficient ones (electrophiles)

9. 9
H
N C
H
H
. .
. .
..
.
.
.
.
.
. .
.



n
Reactivity Principles
•Molecular orbitals
–Distinct spaces around atoms that electrons
reside in (high electron probability density)
–Up to 2 electrons per orbital
–Relative order of reactivity:
•radicals (1e) >
• n-orbital: Lone pairs >
• -orbital: Double / triple bonds >
• -orbital: Single bonds
N
H
H
H

10. 10
Reaction Favorability
•Thermodynamics
–Eventually reactions will proceed to thermodynamic
equilibrium, maintaining a steady state ratio of products
: reactants
–K
eq
: Equilibrium constant defining the stable ratio of
products : reactants for a reaction under standard
conditions (1 atmosphere, room temperature)
–Larger value of K
eq
thus indicates greater favorability
for a reaction
–Given competing products, K
eq
can indicate major ones

11. 11
Reaction Favorability
•Gibbs Free Energy
–K
eq
is a function of G
o
(and temperature)
– G: Difference between product and
reactant (Gibbs) free energy
•Negative G is thus favorable
•State function, measuring thermodynamic stability
• G
o
: G under standard conditions
K
eq =
e-G
o
/RT
G
o
= -RT ln K
eq
R = Universal gas constant
T = Absolute temperature

12. 12
Reaction Favorability
•Enthalpy and Entropy contributors
–G = H – TS
–H: Enthalpy, primarily determined by strength of
bonds broken and formed in a reaction
–S: Entropy, measuring “randomness” of a system,
with greater randomness being favorable
•For most reactions, S is small (esp. when n = 0), thus
•Unless at very high temperatures, H dominates TS, thus
•Calculating H provides a good estimate for G

13. 13
Reaction Favorability Scoring
•Thermodynamics
– G = H – TS(Enthalpy & Entropy contribute)
–Hess’ Law simplification
– H
reaction = (BDE
broken) – (BDE
formed)
–BDE: Bond Dissociation Energy
•Standard lookup values (kcal/mol)
C-C : 83 C=O : 178
C=C : 146 C≡N : 213
C=N : 147 etc.
•Kinetics
–Much less data available
http://www.cem.msu.edu/~reusch/OrgPage/bndenrgy.htm
O
N
83 + 178 + 83 + 213
557

14. 14
Reaction Favorability
•Reaction Kinetics
–Thermodynamics: How “far” a reaction will proceed
–Kinetics: How “fast” a reaction will proceed
2 H
2 + O
2  2 H
2O
•Highly favorable G, but without a catalyst or flame, reaction
proceeds so slowly as to essentially not occur
–Measured by rate constants, but much less data
exists
–Based on relative stability of transition states…

15. 15
Reaction Favorability
•Given infinite time, all reactions
will reach thermodynamic
equilibrium, but
•Intervening, unstable
intermediates in the pathway
impose an activation energy
(E
a
) barrier
•Given limited time and input
energy, a reactions may only
achieve kinetic equilibrium,
settling into an energy local
minimum between large E
a

barriers
Reaction Coordinate
R
e
la
t
iv
e

E
n
e
r
g
y
E
a
G
G
o
= 1.4 kcal / mol ~ 10x K
eq
E
a
< 22 kcal / mol ~ Room temperature reaction
OH
H
H
H
Cl
-
+
OH
-
Cl
H
H
H
C
-
Cl
H
H
H
OH

16. 16
Overview
•Reactions in organic chemistry, review
–Reaction Classification
•Specific chemicals
•Compatible functional groups
•Reactant counts
•Bond rearrangement patterns
•Functional classification
•Mechanism based
M
o
r
e

G
e
n
e
r
a
l
More Informative

17. 17
Reaction
Classification/Organization
•Specific chemicals
–acetic acid + methanamine  N-methylacetamide
•Compatible functional groups
–carboxylic acid + primary amine  amide + water
NH
2
R
2 R
1
NH
O
R
2
R
1
OH
O
OH
2
+
+
NH
2
NH
O
OH
O
OH
2+ +

18. 18
Reaction Classification
•Reactant counts
–Substitution
n = 0
–Addition
n < 0
–Elimination
n > 0
CH
3
CH
2
CH
3
Br
CH
3
HBr+
NH
2
NH
O
OH
O
OH
2+ +
OH
H
OH
2+

19. 19
Reaction Classification
•Bond rearrangement patterns
–4 atom bond swap covers ~50% of organic reactions
C
O
Cl
HNH
C
O
NH
Cl
H
NH
O
C
A B
C D
A B
C D
A B
C D

20. 20
Reaction Classification
•Bond rearrangement patterns
–6 atom cyclic rearrangement covers ~25%
A
F B
E C
D
A
F B
E C
D
O
O
O
O
O
O
+

21. 21
Reaction Classification
•Functional classification
–Acid-catalyzed,
Electrophilic
–Base-catalyzed,
Nucleophilic
–Oxidation-
Reduction
–Free-radical
–Etc.
NH
2
NH
O
OH
O
OH
2+ +
NO
2
+ HNO
3
H
2
SO
4
Heat
+ H
2O
O
OH
OH
Na
2
Cr
2
O
7
H
2
SO
4

22. 22
Reaction Classification
•Mechanism-based
–Sn1
–Sn2
–E1
–E2
–etc.
–Most informative classification patterns, but
•Reaction mechanisms often unknown
•Mechanisms cannot be directly observed, can only
be proposed and supported with exp. evidence
OH
-
OH
H
H
H
Cl
-
Cl
H
H
H
+
OH
OH
-
Cl
Cl
-

23. 23
•Reactions in organic chemistry, review
•Problems in reaction chemistry
•Chemoinformatics methods
•Applications of reaction chemoinformatics to
reaction chemistry problems
•Review questions
Overview
•Reactions in organic chemistry, review
•Problems in reaction chemistry
–Storing / retrieving reaction information
–Combinatorial chemistry / virtual chemical space
–Reaction prediction / discovery
–Chemical Synthesis
•Reaction planning
•Synthesis design (retrosynthesis)

24. 24
Storing / Retrieving Reactions
•DB: Record and classify all reactions, including:
–Reactants and products
–Reaction conditions, catalysts, solvents, etc.
–Literature references, lab notes, etc.
•Search: Ability to query for information on all
reactions that
•Use an epoxide reactant
•Produce an aromatic ring
•Follow the Sn2 reaction mechanism
•Use copper as a catalyst
•Can be run at room temperature in aqueous solution

25. 25
Combi Chem + Virtual Space
•Combinatorial Chemistry
–Given a collection of “building block” chemicals,
combine them with reactions to produce a diverse set
of new products
•Virtual Chemical Space
–Systems like ChemDB catalog all chemicals available
for purchase from different vendors
–“RChemDB” would store or allow on-the-fly searching
of all chemicals indirectly (but easily) available by
applying reactions to directly available chemicals

26. 26
Reaction Prediction / Discovery
•Given a mixture of reactants and reaction
conditions, predict the major products
O
O
O
O
N
N
NH
2
NH
+ ?
NaOMe


27. 27
Knowledge vs. Principle-based
•Knowledge-based
–If a reaction database was available, predicting the
course of a reaction could just be a matter of finding it (or
an analog) in the database
•Knowledge-based limitations
–Requires construction of the database of many different
known reaction profiles to achieve any degree of
generalization
–DB driven approach would be unlikely to discern
competing cases. For example,
•carboxylic acid + amine  amide
•carboxylic acid + alcohol  ester
•carboxylic acid + amino-alcohol  ?

28. 28
Knowledge vs. Principle-based
•Principle-based
–Predict or derive reactions based on general
principles of reactivity
–Much more flexible and powerful
–Entails the ability to discover new reaction profiles
that may not be in known in any DB
•Principle-based limitations
–Complex reactivity can be very difficult to predict
–Confounding factors of solvent effects, catalysts, etc.

29. 29
Chemical Synthesis
•Series of reactions from starting reactants
to form a pathway to the final product
CH
3
CH
CH
3
CH
2
CH
3
Br
CH
3
C
-
NNa
+
CH
3
CH
3
N
H
2
Pd
CaCO
3 Quinolone
HBr

30. 30
Reaction Planning
•Derive synthesis pathway given
–Starting reactant
–Target product
–Available reagents / reactions
?
?
?
O
N
O
Cl
O
N
O

31. 31
Retrosynthesis
•Derive synthesis pathway given
–Starting reactant pool
–Target product
–Available reagents / reactions
O
N
H
N
O
S
O
O
N
N
N
N
?
?
?
Chemical
Vendor
Catalog

32. 32
Overview
•Reactions in organic chemistry, review
•Problems in reaction chemistry
•Chemoinformatics methods
•Applications of reaction chemoinformatics to
reaction chemistry problems
•Review questions
•Problems in reaction chemistry
•Chemoinformatics methods
–SMILES Extensions
•Reaction SMILES
•SMARTS
•SMIRKS
–Quantum Mechanics

33. 33
SMILES Extensions
•Reaction SMILES
–Reaction equation denoted with delimiters
•“.” separates distinct molecules
•“>>” separates reactants from products
CCC(Br)(C)C>>CC=C(C)C.Br
Br
+ HBr

34. 34
SMILES Extensions
•Reaction SMILES
–Catalyst, solvent or other chemicals may be
added between the “>>” delimiters
–No natural space to specify non-molecular
info such as temperature, yield %, etc.
CCC(Br)(C)C>CC[O-].[Na+].CCO>CC=C(C)C.Br
Br
+ HBr
C
2
H
5
O
-
Na
+
C
2H
5OH
70
o
C

35. 35
SMILES Extensions
•SMARTS
–“Regular expressions” for molecules
–SMILES are SMARTS strings, but
–SMARTS strings can describe more general
matching criteria, such as
•Atom types
•Bond types
•Logical operators (and, or, not)
http://www.daylight.com/dayhtml_tutorials/languages/smarts/

36. 36
SMILES Extensions
http://www.daylight.com/dayhtml_tutorials/languages/smarts/
for complete rule list
SMARTS Description
* Wildcard atom. Matches any atom
[C] Aliphatic (non-aromatic) carbons
[c] Aromatic carbons
[#6] Any carbons (aliphatic or aromatic)
[CH3] Terminal carbons (having exactly 3 hydrogens)
[+1] Any atom with a formal charge of +1
[OX2] Oxygen with degree 2 (exactly 2 neighbors)
[!#1] Any atom that is NOT hydrogen
[N,O,C-1]Nitrogen OR oxygen OR (carbon with –1 charge)
[N,O;+1](Nitrogen OR oxygen) AND +1 charge

37. 37
SMILES Extensions
SMARTS Description
[CH3]C(=O)[OH]Acetic acid
*C(=O)[OH] Any carboxylic acid
C(=O)O Any carboxylic acid or ester
C(=O)[F,Cl,Br,I]Any acid halide
[C+,B;X3] Carbocation or neutral boron

38. 38
SMILES Extensions
•SMIRKS
–Reaction profile describing reactants and how
to transform them into respective products
–Combination of
•Reaction SMILES
•SMARTS
•Atom Mapping
–Generally must be manually specified.
Limited work done to automatically derive
reaction profile from specific examples
http://www.daylight.com/dayhtml_tutorials/languages/smirks/

39. 39
SMILES Extensions
•Atom Mapping
–Necessary to map reactant to product atoms
–Proper transform requires balanced stoichiometry
•Hydrogens generally must be explicitly specified
Carboxylic acid + [O:1]=[C:2]([*:9])[O:3][H:7].
Primary amine  [H:8][N:4]([*:10])[H:5]>>
Amide + [O:1]=[C:2]([*:9])[N:4]([*:10])[H:5].
Water [H:7][O:3][H:8]
R
1
O
OH
NH-R
2
H
+
R
1
O
+ H
2
O
NH-R
2
1
2
9 3 7
8 4 5 10
1
2
7,8 3
9 4 5 10

40. 40
SMILES Extensions
•Atom mapping implies mechanism
–Two feasible mechanisms for reaction below
–Ambiguity without at least atom mapping
•Atom mapping still lacks a complete mechanistic
description analogous to “curved arrow” diagram
Br
OH
-
OH
Br
-
+
OH
Br
-
+

41. 41
Quantum Mechanics
•Capable of accurate predictions for
–Chemical reactivity
–Chemical stability  Reaction favorability
•Requires significant computational power,
unfeasible for large scale processing

42. 42
Overview
•Reactions in organic chemistry, review
•Problems in reaction chemistry
•Chemoinformatics methods
•Applications of reaction chemoinformatics to
organic chemistry problems
•Review questions
–Reaction databases (storing / retrieving info)
–Combinatorial chemistry / virtual chemical space
–Reaction prediction / discovery
–Synthesis design (retrosynthesis)
•Chemoinformatics methods
•Applications of reaction chemoinformatics
to organic chemistry problems

43. 43
Reaction Databases
•Storage
–Specific reactions can be recorded with
reaction SMILES
–More general mechanistic reaction profiles can
be stored with SMIRKS
•Retrieval
–Search by reactant or product is same as
usual chemical structure search
–Search by bonds that change focuses on
reaction centers to find similar classes

44. 44
Reaction Databases
•Most repositories with thousands of records,
some may have millions
- CASREACT - Beilstein
- ChemInform RX - ChemReact
•Generally poor consistency and completion of
–Balanced reaction stoichiometry
–Atom mapping / mechanistic description
–Reaction conditions, etc.
•Not publicly available or difficult to access

45. 45
Reaction Prediction / Discovery
•Algorithm features needed
–Hypothesis generating scheme
–Thermodynamic scoring system
–Kinetic scoring system
–Known reactions database
O
O
O
O
N
N
NH
2
NH
+
?
NaOMe


46. 46
Reaction Prediction Approximation
•Find electron donors (nucleophile) and
electron acceptors (electrophile) using
rules and rank them
•Compute all possible intermediates
•Rank by Enthalpy (+Enthropy)
•Recurse
•Stopping rule (drop in delta G)

47. 47
Reaction Prediction Example
Blue: HOMOs / Nucleophiles
Red: LUMOs / Electrophiles
H O
-
CH
3
C
Cl
O
0
CH
3
C
Cl
O
-
OH
+7
CH
3
C
OH
O
Cl
-
-17.5

48. 48
CH
CH
Br
-
O
+
H
H
H
+300
Reaction Prediction Example
CH
CH
Blue: HOMOs / Nucleophiles
Red: LUMOs / Electrophiles
O H
H
H Br
CH
CH
0
Br
O H
H
-30
CH
-
CH
Br
O
+
H
H
H+415
CH
2
CH
+
O H
HBr
-
+315
Br
-
O
+
H
H
+300
OH
H Br
-25

49. 49
Retro-Synthesis Tree
•Apply retro reactions towards available starting reactants
OH
OH
Starting
Material
OH
OH
O
O
OH
OH
Br
Dead End
Dead End
O
O
Starting Material
OH OH

50. 50
Existing Approaches
•Retrosynthetic
–Interactive: LHASA, SECS
–Non-Interactive: SYNCHEM
•Forward: SST, CHIRON
•Formal: IGOR, WODCA, SYNGEN
•Reaction Prediction: CAMEO, EROS
Todd, M. H. (2004). "Computer-Aided Organic
Synthesis." Chemical Society Reviews(34): 247-266.

51. 51 Virtual Chemical Space
Target Structure
Nothing directly similar in DB
NH
N
O
N
H
O
O
N
N
H
O
NH
2
N
O
O
O
O
N
O
O
N
N
O
O
N
O
O
N
O
O NH
N
N
N
NN
NN
N
N
N
N
N
N
N
N
2. Search DB for items similar to components
1. Apply retro reaction to find possible components
Retro Diels-Alder
+
N
ONH

52. 52
N
H
O
O
N
N
H
O
NH
2
N
O
O
O
O
N
O
O
N
N
O
O
N
O
O
N
O
O NH
N
N
N
NN
NN
N
N
N
N
N
N
N
N
Forward Diels-Alder
+
O
NH N
O
N O
N
O
O
NH N
O
O
N N
O
O
N N
O
Target Structure
NH
N
O
3. Reapply forward reaction to
components to generate theoretical
products that should be similar to the
original target
4. 160 unique products resulted with
similarity scores ranging in [0.247,
0.860],
14 with similarity score > 0.80

53. 53
Reaction Discovery and
Retrosynthesis
•Synergy between:
1.Chemical DB
2.Reaction DB
3.Reaction mechanism
4.Search algorithms (chemical and reactions)
–Address combinatorial challenges

54. 54
Docking and Drug Discovery

55. 55
Reaction Prediction / Discovery
•Discover reaction profiles by general principles
•Generic 4 atom reaction profile covers about
50% of all known organic reactions
C
O
Cl
HNH
C
O
NH
Cl
H
NH
O
C
A B
C D
A B
C D
A B
C D

56. 56
Generic Reaction Profile Issues
•Still, a screening or ranking method is needed to
filter many unrealistic reactions proposed
•More sophisticated profiles are not covered
without more knowledge based profiles
O Cl
NH
2
O
Cl
NH
CH
4
O
NH Cl
C
O
Cl
HNH
+

Diels-Alder
N N
+
N
-
N N
N
+

Azide + Alkyne
aromatic cyclization

57. 57
Reaction Favorability Scoring
•Thermodynamics
– G = H – TS(Enthalpy & Entropy contribute)
–Hess’ Law simplification
– H
reaction = (BDE
broken) – (BDE
formed)
–BDE: Bond Dissociation Energy
•Standard lookup values (kcal/mol)
C-C : 83 C=O : 178
C=C : 146 C≡N : 213
C=N : 147 etc.
•Kinetics
–Much less data available
http://www.cem.msu.edu/~reusch/OrgPage/bndenrgy.htm
O
N
83 + 178 + 83 + 213
557

58. 58
Pseudo-Mechanistic Reactions
•More generalized, pseudo-mechanistic reaction
modeling with the introduction of “intermediates”
•Model breaking a bond by separating charge,
representing bond electrons moving to one atom
•Closing the intermediates is then just a matter of
matching + and - charges
A B
C D
A
+
B
-
C
-
D
+
A B
C D

59. 59
Pseudo-Mechanistic Reactions
•Applying general electron-shifting rules on
the intermediates provides significant
power and chemically intuitive results
O
-
H
+
O H
O
-
H
+
O

60. 60
Azide + Alkyne Example
R
1
N N
+
N
-
R
2
C C R
3
R
1
N
+
N N
-
R
2
C
-
C
+
R
3
R
1
N
N N

C C
R
2
R
3
-38.9 kcal / mol

61. 61
Diels-Alder Example
C C
C C

C C
C
-
C
C
+
C

C
-
C
+
C C
C
+
C
-

C
-
C
+
-40 kcal / mol

62. 62
Reactivity Principles
•Rather than trying all possible bond
rearrangement combinations, can use
reactivity principles to predict
•For example, frontier molecular orbital
theory can find the
–Highest Occupied Molecular Orbital (HOMO)
–Lowest Unoccupied Molecular Orbital (LUMO)

63. 63
Synthesis Design (Retrosynth)

Components

Starting Reactants

Reagents w/
Reaction Profiles

Synthesis Problem

64. 64
Synthesis Design (Retrosynth)
•Synthesis problem generator
–Tutorial for students
–Test base for retro-synthesis algorithm
•Algorithm features needed
–Knowledge base of reactions
–Retro-reaction application
–Heuristic to guide search

65. 65
Overview
•Reactions in organic chemistry, review
•Problems in reaction chemistry
•Chemoinformatics methods
•Applications of reaction chemoinformatics
to organic chemistry problems
•Review questions
•Applications of reaction chemoinformatics to
organic chemistry problems
•Review questions

66. 66
Review: Reactivity Principles
•For each molecule, what is the most
reactive (lone or bond) pair of electrons?
NH
3
+O....
O
....
Recall the relative order of molecular orbital reactivity
• n-orbitals (lone pairs) >
• -orbitals (double / triple bonds) >
• -orbitals (single bonds)
Lone pairs win in general, though no lone pair is available in the last
molecule (the nitrogen has already been protonated). In that case, the
-orbital (double bond) supercedes the -orbitals of all the single bonds

67. 67
Review: Reaction Favorability
•For the reaction energy diagram,
suppose A = B = 2.8 kcal / mol
•Would you expect the reaction to
proceed at room temperature?
•At thermodynamic equilibrium, what
ratio of products : reactants would
you expect?
•Which of the following would shift the
equilibrium closer to 50:50 ratio?Reactant Intermediate Product
Reaction Coordinate
R
e
la
t
iv
e

E
n
e
r
g
y
A
B
a.Adding a catalyst
b.Heating the reaction mixture
c.Raising the universal gas constant
d.None of the above

68. 68
Review: Reaction Favorability
•For the reaction energy diagram,
suppose A = B = 2.8 kcal / mol
•Yes, expect the reaction to proceed
at room temperature because
E
a
= A < 22 kcal /mol
•At equilibrium, expect products :
reactants ratio = Keq ~ 100:1
10x Keq ~ 1.4 kcal / mol G =
B
•Shifting the equilibrium ratio…
Reactant Intermediate Product
Reaction Coordinate
R
e
la
t
iv
e

E
n
e
r
g
y
A
B
a.Adding a catalyst: No, this lowers E
a
, but G is unchanged.
Free energy is a state function. Catalyst only accelerates reaction
b.Heating the reaction mixture: Yes, K
eq
depends on G and temperature.
Higher temperature provides more energy to maintain less stable state
K
eq
=
e
-G
o
/RT

69. 69
Review: Reaction Prediction
•Using the provided bond dissociation energies
(BDE), which of the products do you predict is
most likely for a reaction between the reactants?
OH
OH
BondBDE
H—H 104
C—C 83
C=C 146
C—O 85
C—H 99
O—H 111
O—O 35
OH OH
2+
OH
O
H
2+
OH
OH
+

70. 70
Review: Reaction Prediction
•Using the provided bond dissociation energies
(BDE), which of the products do you predict is
most likely for a reaction between the reactants?
OH
OH
BondBDE
H—H 104
C—C 83
C=C 146
C—O 85
C—H 99
O—H 111
O—O 35
OH OH
2+
OH
O
H
2+
OH
OH
+
(O—H + O—H) –
(O—O + H—H) =
(111 + 111) –
(35 + 104) =
+83
(O—H + C—C) –
(C—O + C—H) =
(111 + 83) –
(85 + 99) =
+10
(O—H + C=C) –
(C—O + C—H + C—C) =
(111 + 146) –
(85 + 99 + 83) =
-10

71. 71
Review: Reaction Classification
•Which reactions can NOT be classified into the 4
atom bond rearrangement pattern?
A—B + C—D  A—C + B—D
CH
3
CH
2
CH
3
Br
CH
3
+ HBr
Br
+ HBr
C
2
H
5
O
-
Na
+
C
2
H
5
OH
70
o
C
NH
2
NH
O
OH
O
OH
2+ +
NO
2
+ HONO
2
H
2SO
4
Heat
+ H
2
O
+
O
OH
OH
Na
2
Cr
2
O
7
H
2SO
4

72. 72
Review: Reaction Classification
•Which reactions can NOT be classified into the 4
atom bond rearrangement pattern?
A—B + C—D  A—C + B—D
CH
3
CH
2
CH
3
Br
CH
3
+ HBr
Br
+ HBr
C
2
H
5
O
-
Na
+
C
2
H
5
OH
70
o
C
NH
2
NH
O
OH
O
OH
2+ +
NO
2
+ HONO
2
H
2SO
4
Heat
+ H
2
O
+
O
OH
OH
Na
2
Cr
2
O
7
H
2SO
4

73. 73
Review: Reaction SMILES
•What features in the reaction below can
NOT be specified with reaction SMILES?
O
OOH
2
(50% yield)
10% NaOH, H
2
O
5
o
C
CC=O.CC=O>[Na]O.O>CC(O)CC=O
Could not specify “10%,” reaction temperature or yield

74. 74
Review: SMARTS
•For each SMARTS pattern, indicate which
molecules it will find at least one match in.
OH
OH
O
O
Cl
O
O
O
OH
O
N
O
-
Cl
# SMARTS
1 C#C
2 C(=O)O
3*C(=O)[OH]
4C(=O)[F,Cl,Br,I]
5 [#8X1]
6 [X3]=[!O]
7 [c]

75. 75
Review: SMARTS
•For each SMARTS pattern, indicate which
molecules it will find at least one match in.
OH
OH
O
O
Cl
O
O
O
OH
O
N
O
-
Cl
# SMARTS
1 C#C
2 C(=O)O
3*C(=O)[OH]
4C(=O)[F,Cl,Br,I]
5 [#8X1]
6 [X3]=[!O]
7 [c]
2
3
5
6
7 4
5
2
5
6
5
1
5

76. 76
Review: SMIRKS
•Apply each SMIRKS string to the respective
starting reactants below to generate a product
[C:1]=[C:2].[H:3][Br:4]>>[H:3][C:1][C:2][Br:4]
OH OH
Br
OH
+ HBr
Br
+ H
2
OH
+ H
2
X
No reaction! Reactant does not match the SMIRKS
reactant pattern. No [H:3] attached to [C:1]
Br
[C:1]#[C:2].[H:3][H:4]>>[H:3][C:1]=[C:2][H:4]
[C:1]=[C:2].[H:3][H:4]>>[H:3][C:1][C:2][H:4]
[H:3][C:1][C:2][O:4][H:5]>>[C:1]=[C:2].[H:3][O:4][H:5]
Hydrobromination, Alkene
Hydrogenation, Alkyne
Hydrogenation, Alkene
Dehydration
+ H
2
O

77. 77
Review: Retrosynthesis
•Using the SMIRKS defined reactions and
starting materials in this and the previous slide,
come up with a synthesis pathway for the boxed
target molecule
Br
Br
OH
OH
OH

78. 78
Review: Retrosynthesis
Br
Br
OH
+ 2 HBr
Halogenation
Dehydration
Hydrogenation, Alkyne
+ H
2
O
OH
+ H
2
Available Starting Material

79. 79
Reaction Favorability
•Enthalpy determination
– H
f: “Heat of formation.” State function indicating
the heat / energy produced accompanying formation
of a substance from its constituent elements in
standard states (room t, 1 atmosphere)
Formation equation for carbon dioxide:
C(solid, graphite) + O
2(gas)  CO
2(gas)
–Only relative values have meaning, “constituent
elements in standard state” is an arbitrary zero point