carbonyl compounds (short)

In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a carbonyl group is often referred to as a carbonyl compound.

1. Carbonyl Compounds and Nucleophilic Addition Md. Saiful Islam BPharm, MSc North South University Fb Group: Pharmacy Universe

2. Carbonyl compounds Contain at least one carbonyl group. R = R’ or R  R’ C=O : the carbonyl group also known as the oxo group

3. Aldehydes  terminal carbonyl groups propanal butanal pentanal No need to specify the position of the carbonyl group

4. Aldehydes, IUPAC nomenclature: Parent chain = longest continuous carbon chain containing the carbonyl group; alkane, drop –e, add –al. (note: no locant , -CH=O is carbon #1.) CH 3 CH 3 CH 2 CH 2 CH=O CH 3 CHCH=O butanal 2-methylpropanal H 2 C=O CH 3 CH=O methanal ethanal

5. Ketones, common names: Special name : acetone “alkyl alkyl ketone” or “dialkyl ketone”

6. (o)phenones: Derived from common name of carboxylic acid, drop –ic acid, add –(o)phenone.

7. Ketones: IUPAC nomenclature: Parent = longest continuous carbon chain containing the carbonyl group. Alkane, drop –e, add –one. Prefix a locant for the position of the carbonyl using the principle of lower number.

8. pentan-2-one pentan-3-one

9. cyclohexanone cyclohexanecarbaldehyde cyclohexylethanal cyclohexylmethanal

10. benzaldehyde 1-phenylethanone benzophenone diphenylmethanone

11. 4-oxopentanoic acid 5-oxopentanoic acid 4-oxopentanal

12. Physical Properties Most simple aliphatic ketones and aldehydes are liquids at room temperature except methanal ( b.p . = -21 ° C ) and ethanal ( b.p . = 20.8°C) Aliphatic aldehydes have an unpleasant and pungent smell Ketones and aromatic aldehydes have a pleasant and sweet odor

13. Name Molecular formula Boiling point ( o C) Melting point ( o C ) Density at 20 o C (g cm -3 ) Aldehydes: Methanal HCHO -21 -92  Ethanal CH 3 CHO 20.8 -124 0.783 Propanal CH 3 CH 2 CHO 48.8 -81 0.807 Butanal CH 3 (CH 2 ) 2 CHO 75.7 -99 0.817 Methylpropanal (CH 3 ) 2 CHCHO 64.2 -65.9 0.790 Benzaldehyde C 6 H 5 CHO 179 -26 1.046 Physical properties of some aldehydes and ketones

14. Less dense than water except aromatic members Name Molecular formula Boiling point ( o C) Melting point ( o C) Density at 20 o C (g cm -3 ) Ketones: Propanone CH 3 COCH 3 56.2 -95.4 0.791 Butanone CH 3 COCH 2 CH 3 79.6 -86.9 0.806 Pentan-2-one CH 3 CO(CH 2 ) 2 CH 3 102 -77.8 0.811 Pentan-3-one CH 3 CH 2 COCH 2 CH 3 102 -39.9 0.814 3-Methylbutan-2-one CH 3 COCH(CH 3 ) 2 95 -92 0.803 Hexan-2-one Phenylethanone CH 3 CO(CH 2 ) 3 CH 3 C 6 H 5 COCH 3 127 202 -56.9 19.6 0.812 1.028

15. Boiling point : - (similar molecular masses) carboxylic acid > alcohol > aldehyde, ketone > C x H y Presence of polar group Absence of –OH group

16. Solubility Small aldehydes and ketones show appreciable solubilities in water due to the formation of intermolecular hydrogen bonds with water

17. Solubility Ethanal and propanone are miscible with water in all proportions. Propanone(acetone) is volatile and miscible with water  Once used to clean quick-fit apparatus potentially carcinogenic

18. Solubility Methanal gas dissolves readily in water Aqueous solutions of methanal ( Formalin ) are used to preserve biological specimens Methanal(formaldehyde) is highly toxic

19. Industrial preparation By dehyd rogenation (oxidation) of al cohols Out-dated Further oxidation is prohibited

20. Laboratory preparation Oxidation of alcohols 1° alcohol – aldehyde - carboxylic acid 2° alcohol - ketone Further oxidation of aldehyde to carboxylic acid is prohibited by (i) using a milder O.A., e.g. H + / Cr 2 O 7 2

21. Laboratory preparation Oxidation of alcohols 1 alcohol  aldehyde  carboxylic acid 2 alcohol  ketone Further oxidation of aldehyde to carboxylic acid is prohibited by (i) using a milder O.A., e.g. H + / Cr 2 O 7 2 (ii) distilling off the product as it is formed

22. 70C > T > 21C

23. Heating under reflux Ethanol  ethanoic acid

24. 2 alcohol  ketone Further oxidation of ketone to carboxylic acid has not synthetic application since carboxylic acid High T 1. it requires more drastic reaction conditions 2. it results in a mixture of organic products

25. The catalyst Pd or BaSO 4 is poisoned with S to prevent further reduction to alcohol 2. Reduction of acid chlorides

26. Carboxylic acid or acyl chloride Aldehyde Alcohol oxidation reduction  Preparation must be well controlled.  Intermediate oxidation state Aldehydes

27. Friedel-Crafts acylation (Preparation of aromatic ketones)

28. 4. Decarboxylation of calcium salts Symmetrical ketones can be obtained by heating a single calcium carboxylate

29. 4. Decarboxylation of calcium salts Aldehydes can be obtained by heating a mixture of two calcium carboxylates Cross decarboxylation is preferred

30. Decarboxylation of sodium salts gives methane or benzene.(p.30 and p.49) Na O H(s) from soda lime fusion CH 3 COO Na(s) CH 4 + Na 2 CO 3 Na O H(s) from soda lime fusion + Na 2 CO 3

31. 5. Catalytic hydration of alkynes Keto-enol tautomerism enol ketone

32. 5. Catalytic hydration of alkynes Keto-enol tautomerism enol aldehyde

33. 6. Ozonolysis of symmetrical alkenes

34. Unsymmetrical alkenes give a mixture of two carbonyl compounds making subsequent purification more difficult. 1. O 3 2. Zn dust / H 2 O

35. Bonding in the Carbonyl Group The carbonyl carbon atom is sp 2 -hybridized sp 2 – 2 p head-on overlap   bond 2 p – 2 p side-way overlap   bond The  and  bonds in the C = O bond

36. Reactions of Aldehydes and Ketones

37. The most common reaction of aldehydes and ketones is nucleophilic addition.  This is usually the addition of a nucleophile and a proton across the C=O double bond.  As the nucleophile attacks the carbonyl group, the carbon atom changes from sp 2 to sp 3 .   The electrons of the  bond are pushed out onto the oxygen, generating an alkoxide anion.  Protonation of this anion gives the final product. Reactions of Aldehydes and ketones

38. We have already encountered (at least) two examples of this: Grignards and ketones  tertiary alcohols

39. Sodium Borohydride Reduction Of Aldehydes and Ketones H BH 3 - workup step alcohol aldehyde and ketones workup step

40. LITHIUM ALUMINUM HYDRIDE REDUCTIONS

41. LiAlH 4 reduces anything with a polar multiple bond! aldehyde ketone LiAlH 4 (LAH) IS NOT SELECTIVE As with NaBH 4 these compounds give alcohols: C=Y: d+ d- or C Y: d+ d- ..

42. Under acidic conditions, weaker nucleophiles such as water and alcohols can add. The carbonyl group is a weak base, and in acidic solution it can become protonated.

43. This makes the carbon very electrophilic (see resonance structures), and so it will react with poor nucleophiles . E.g. the acid catalyzed nucleophilic addition of water to acetone to produce the acetone hydrate.

44. Summary The base catalyzed addition reactions to carbonyl compounds result from initial attack of a strong nucleophile, whereas the acid catalyzed reactions begin with the protonation of the oxygen, followed by attack of the weaker nucleophile.

45. Aldehydes are more reactive than ketones.  This (like all things) stems from two factors: (1) electronics (2) sterics Relative Reactivity

46. Electronic Effect Ketones have two alkyl substituents whereas aldehydes only have one. Carbonyl compounds undergo reaction with nucleophiles because of the polarization of the C=O bond.

47. Alkyl groups are electron donating, and so ketones have their effective partial positive charge reduced more than aldehydes (two alkyl substituents vs. one alkyl substituent).   ( Aldehydes more reactive than ketones)

48. The electrophilic carbon is the site that the nucleophile must approach for reaction to occur. In ketones the two alkyl substituents create more steric hindrance than the single substituent that aldehydes have. Therefore ketones offer more steric resistance to nucleophilic attack.  ( Aldehydes more reactive than ketones).  Therefore both factors make aldehydes more reactive than ketones. Steric Reason

49. Nucleophilic Addition of Water (Hydration) In aqueous solution, ketones (and aldehydes) are in equilibrium with their hydrates (gem diols ).

50. Most ketones have the equilibrium in favor of the unhydrated form. Hydration proceeds through the two classic nucleophilic addition mechanisms with water (in acid) or hydroxide (in base) acting as the nucleophile.

51. (Acid)

52. (Base)

53. Aldehydes are more likely to form hydrates since they have the larger partial positive charge on the carbonyl carbon (larger charge = less stable = more reactive).  This is borne out by the following equilibrium constants .

54. Nucleophilic Addition of Hydrogen Cyanide (Cyanohydrins) Hydrogen cyanide is toxic volatile liquid (b.p.26°C) H-CN + H 2 O  H 3 O + + - CN pK a = 9.2 Cyanide is a strong base (HCN weak acid) and a good nucleophile. Cyanide reacts rapidly with carbonyl compounds producing cyanohydrins, via the base catalyzed nucleophilic addition mechanism.

55. Like hydrate formation, cyanohydrin formation is an equilibrium governed reaction (i.e. reversible reaction), and accordingly aldehydes are more reactive than ketones.

56. Formation of Imines (Condensation Reactions) Under appropriate conditions, primary amines (and ammonia) react with ketones or aldehydes to generate imines.

57. The mechanism of imine formation starts with the basic addition of the amine to the carbonyl group. Protonation of the oxyanion and deprotonation of the nitrogen cation generates an unstable intermediate called a carbinolamine.

58. The carbinolamine has its oxygen protonated, and then water acts as the good leaving group.

59. This acid catalyzed dehydration creates the double bond, and the last step is the removal of the proton to produce the neutral amine product. The pH of the reaction mixture is crucial to successful formation of imines. The pH must be acidic to promote the dehydration step, yet if the mixture is too acidic , then the reacting amine will be protonated, and therefore un- nucleophilic , and this should inhibit the first step.  The rate of reaction varies with the pH as follows: The best pH for imine formation is around 4.5.

60. Condensations with Hydroxylamines and Hydrazines Aldehydes and ketones also condense with other ammonia derivatives, such as hydroxylamine and hydrazines . Generally these reactions are better than the analogous amine reactions (i.e. give superior yields ). .

61. Oximes are produced when hydroxylamines are reacted with aldehydes and ketones Hydrazones are produced through reaction of hydrazines with aldehydes and ketones.

62. Oxidation Unlike ketones, aldehydes can be oxidized easily to carboxylic acids (Chromic acid, permanganate etc). Even weak oxidants like silver (I) oxide can perform this reaction, and this is a good, mild selective way to prepare carboxylic acids in the presence of other (oxidizable) functionalities. E.g.

63. Oxidation

64. Silver Mirror Test (Tollen's Test) This type of oxidation reaction is the basis of the most common chemical test for aldehydes - the Silver Mirror Test. Tollen's reagent is added to an unknown compound, and if an aldehyde is present, it is oxidized. R-CHO+2Ag(NH 3 ) 2 + + 3OH -  2Ag+RCO 2 - + 4NH 3 +2H 2 O   This process reduces the Ag + to Ag, and the Ag precipitates - it sticks to the flask wall, and forms a 'silver mirror'.