Chapter 7. REACTIONS OF CARBONYL COMPOUNDS

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1 hapter 7. REATINS F ARBNYL MPUNDS In most reactions at carbonyl groups, a key step is addition of a nucleophile, generating a tetracoordinate carbon atom. - R R Nu : R R 7.1 HYDRATIN AND ADDITIN F ALHLS T ALDEHYDES AND KETNES R R H 2 R R The trend of decreasing K in the order : H 2 > RH > R 2 H 2 = K (in H 2, 25 o ) 2280 H= 1.06 ( ) 3 H= 0.23 F 3 H= F 3 35 H H Nu Is unfavorable process for simple carbonyl compounds except formaldehyde and aldehydes and ketones with highly electronegative group. High exchange rate is detected R 2 = H 2 * R 2 H H R 2 = * H 2 Base-atalyzed Hydration H H 2 H R H 2 B: B RH - RH H Acid-atalyzed Hydration H 2 H δ δ- 2 R HA RH HA RH A - RH HA H Associate Prof. Surin Laosooksathit, Ph.D. 5/31/2009 1

2 Alcohols also undergo reversible addition reactions with aldehyde and ketones. H H 2 R 2 = R H R 2 R R 2 R can be acid or base catalyzed reaction Second step must be acid catalysis and the product is stable in alkali solution Hemiacetal (from aldehyde) hemiketal (from ketone) -H 2 R 2 = R R H R HR - R 2 R R 2 R The equilibrium constants for addition of alcohols to carbonyl compounds to give hemiacetals or hemiketals show the same response to structural features as do those for hydration reactions, but slightly in magnitude. e.g. H 2 K = 1.06 Acetal H 0.75 M M -2 H 2 H 0.50 M M -2 Some special structural feature of acetals that show general acid catalysis in hydrolysis are given below: Et Acetal or ketal (from aldehyde or ketone) Et Et Et - N 2 N ADDITIN - ELIMINATIN REATINS F KETNES AND ALDEHYDES 1. R 2 = R NH 2 R 2 =NR imine (also called Schiff base, especially when the amine is an aniline derivative) 2. R 2 = H 2 NH R 2 =NH (oxime) 3. R 2 = R NHNH 2 R 2 =NNHR (hydrazone) 4. R 2 = H 2 NNHNH 2 R 2 =NNHNH 2 (semicarbazone) Associate Prof. Surin Laosooksathit, Ph.D. 5/31/2009 2

3 The completion of the reactions can be driven by removing water as it is formed by azeotropic distillation or by use of dehydration agents. Formation of imine systems in categories 2-4 are facile even in aqueous solution and the reverse reactions are retarded by the electron stabilizing groups on the nitrogen =N H - N= H =N NH 2 - N=N H 2 H B: R 2 = R NH 2 R 2 NHR R 2 =NR H A - R 2 NHR R 2 =N HR R 2 = R 2 NH H R R N R R = N R R H H R--NR REATIVITY F ARBNYL MPUNDS TWARD ADDITIN The hydride reducing agents, in particular sodium borohydride, provide a convenient system for studying the reaction rates. - BH H 3 H - RR BH 4 R R RHR H Rate = k[rr ][BH - 4 ] PhH 12,400 k 10 4 (M -1 sec -1 ) Ph haracteristics of these reactions Ph low enthalpy of activation 15.1 (8-13 kcal) 264 (angle strain) - large enthalpy of activation ( eu), as expected for a bimolecular reaction. 7 (torsional strain in transition state) 161 (torsional strain is relieved due to puckered to chair conformation) Associate Prof. Surin Laosooksathit, Ph.D. 5/31/2009 3

4 R R Nu : R R Sp 2 sp 3 Nu - Nu R R R R Nu - or R N or R N Nu Ground state stabilized by or N atom 7.4 ESTER HYDRLYSIS AND RELATED REATINS Esters can be hydrolyzed in either basic or acidic solution. A A 2 - MEHANISM (reversible process) Increase steric stabilization from R group from starting to transition state H 2 H R--R R--R R--R A = acid catalysis H 2 A = acyl-oxygen fission 2 = bimolecular nature of the H rate-determining step R-- HR R- R H B A 2 MEHANISM - R--R H - R--R R-- - R R-- - HR B = base catalysis Prove of acyl-oxygen fission H H R--R H 2 * R--R R-- H 2 *H Akyl-oxygen cleavage R--R 3 R--R 3 R-- R 3 * Alkene R 3 H Associate Prof. Surin Laosooksathit, Ph.D. 5/31/2009 4

5 A A 1 MEHANISM (IN VERY STRNG AIDI SLUTIN) This is a useful method of hydrolyzing esters that are very severely sterically hindered. R : R conc. H 2 S H 4 3 H H 2 - RH NULEPHILE-ATALYZED ESTER HYDRLYSIS H 2 R--Ar HN N R N R-- HN N R - ArH N H 2 Ar - R----R R-- R --H Transesterification can be catalyzed by either acid or base - - R--- -N 2 R-- N 2 R N 2 Aminolysis of esters R--R R NH 2 R--R R--R H 2 NR - - R--NHR - R R R HNR - H HNR - Associate Prof. Surin Laosooksathit, Ph.D. 5/31/2009 5

6 7.5 AMIDE HYDRLYSIS The hydrolysis of amides to carboxylic acids and amines requires considerably more vigorous conditions than ester hydrolysis. - R--N R-=N B A 2 mechanism is believed to operate in basic solution. R--NHR H - R--NHR R-- R NH - H 2 R NH 2 H - - H H - - slow R NH - R-- - R--NHR A A 2 mechanism is believed to operate in acidic solution - arbonyl oxygen exchange with H 2 is observed. H H 2 H :H R--NHR R--NHR R--NHR R- NHR H 2 R-- - R NH 2 H H H R--NHR R-=NHR R-- R NH 3 R-- R NH 2 There is almost no exchange of oxygen with water during acid-catalyzed hydrolysis of amides. 7.6 AYLATIN F NULEPHILI XYGEN AND NITRGEN GRUPS Esterification ( -acylation ) R-- R H R--R H 2 Amide formation - R-- NH 3 R-- NH 4 R--NH 2 H 2 R NH 2 R H R--NHR Hl R--l R--R Hl Associate Prof. Surin Laosooksathit, Ph.D. 5/31/2009 6

7 R H R NH 2 R--R R--H R----R R--NHR R--H Nucleophilic catalyst of acylation - l - Pyr l - R H R--l R--Pyr R--Pyr R--R Pyr l - R H Et 3 N D l 67% D 33% D Et 3 N l - == R NH 2 R-- R N==NR R--=NR NHR - R NH 2 NHR R---=NR R--NHR R NHNHR H H H 3 H (F 3 ) H H 3 H 94 % 7.7 INTRAMLEULAR ATALYSIS K 1 Ph Ph Ph H H - H - - K 2 The maximum rate, 2.7x10 9, is at ph 6 Ph H - Associate Prof. Surin Laosooksathit, Ph.D. 5/31/2009 7

8 2 N - -- general base -- fast H -H catalysis H H - - H -H - - nucleophilic catalysis H 2 fast N 2 N H N 2 - N N 2 H H 2 HN N: N N N N N NH Ar - Ar slow H Ph.. : Ph H. RNH 3 R-NH 2 H-NH RHN--H RHN- - - R PhH Bifunctional catalysts (tautomeric catalysts-2-pyridone) R-NH -Ar RN--Ar RHN- ArH H H H :H H N H N N Associate Prof. Surin Laosooksathit, Ph.D. 5/31/2009 8