Chapter 21. Carboxylic Acid Derivatives. and Nucleophilic Acyl Substitution. Reactions. - many carboxylic acid derivatives are known:

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1 hapter 21 arboxylic Acid Derivatives and ucleophilic Acyl Substitution eactions - many carboxylic acid derivatives are known: X ' carboxylic acid acid halide (X = F, l, Br, I) acid anhydride ' 2 ester amide nitrile - chemistry of carboxylic acid derivatives is dominated by a single reaction - nucleophilic acyl substitution reaction: :u - Y u 1

2 Acid alides aming arboxylic Acid Derivatives and itriles - first identify the acyl group, then identify the halide - acyl group name is derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the -carboxylic acid ending with -carbonyl 3 l Br l acetyl chloride (from acetic acid) benzoyl bromide (from benzoic acid) cyclohexanecarbonyl chloride (from cyclohexanecarboxylic acid) Acid Anhydrides - anhydrides are named by replacing the word acid with anhydride 3 3 acetic anhydride benzoic anhydride succinic anhydride l 2 2 l 3 bis(chloroacetic) anhydride acetic benzoic anhydride Amides - amides with an unsubstituted - 2 group are named by replacing the -oic acid or -ic acid ending with -amide, or by replacing the -carboxylic acid ending with -carboxamide ( 2 ) acetamide (from acetic acid) hexanamide (from hexanoic acid) cyclopentanecarboxamide (from cyclopentanecarboxylic acid) - compound is also named by identifying substituents and parent amide (2 3 ) methylpropanamide,-cyclohexanecarboxamide 2

3 Esters - first identify the alkyl group attached to the oxygen and then the carboxylic acid, with the -ic acid ending being replaced by -ate ethyl acetate (ethyl ester of acetic acid) dimethyl malonate (dimethyl ester of malonic acid) ( 3 ) 3 tert-butylcyclohexanecarboxylate (tert-butyl ester of cyclohexanecarboxylic acid) itriles - open-chain nitriles are named by adding -nitrile as a suffix to the alkane name, with the - carbon being methylpentanenitrile - more complex nitriles are named as derivatives of carboxylic acids by using the ending -onitrile or -carbonitrile where the - carbon is not part of the numbering system 3 acetonitrile (from acetic acid) benzonitrile (from benzoic acid) 3 3 2,2-dimethylcyclohexanecarbonitrile (from 2,2-dimethylcyclohexane carboxylic acid) ucleophilic Acyl Substitution eactions - carboxylic acid derivatives have an acyl carbon bonded to a potential leaving group -Y - as soon as the tetrahedral intermediate is formed, the leaving group is expelled good leaving group not a good leaving group Y carboxylic acid derivative aldehyde ' ketone - such a leaving group is not present in aldehydes and ketones 3

4 elative eactivity of arboxylic Acid Derivatives - of the addition and elimination steps of a nucleophilic acyl substitution reaction, the first-step is generally rate-limiting - factors that can effect the first-step arise from steric and electronic considerations - sterically, unhindered carbonyl groups react with nucleophiles more readily that do hindered groups - electronically, strongly polarized acid derivatives react more readily that less polar ones < < < Less reactive More reactive 2 < < < ' ' l Less reactive More reactive 4

5 onsequences of bserved eactivity 1) It is usually possible to transform a more reactive acid derivative into a less reactive one (downhill process in terms of energy) 2) nly esters and amides are commonly found in nature. Acid halides and acid anhydrides undergo nucleophilic attack by water such that they cannot exist in living organisms. Acid Derivative 5

6 ucleophilic Acyl Substitution eactions of arboxylic Acids arboxylic Acids Acid hlorides - carboxylic acids are converted into acid chlorides using thionyl chloride (Sl 2 ) l 3 3 Sl l 3 l S ,4,6-trimethylbenzoic acid 2,4,6-trimethylbenzoyl chloride (90%) Mechanism l carboxylic acid S l S l l Base S l chlorosulfite S l l S l l acid chloride arboxylic Acids Acid Anhydrides - acid anhydrides are derived from two carboxylic functionalities by heating to remove 1 equivalent of water - reaction typically requires very harsh conditions 2 2 succinic acid 200 o succinic anhydride 6

7 Proximity Effects 40 o Et 2 1,8-naphthalenedicarboxylic acid 1,8-naphthalene anhydride arboxylic Acids Esters 1) S 2 reaction of a carboxylate anion with a primary alkyl halide S 2 3 I 322 a reaction sodium butanoate 2) Fischer esterification reaction ai methyl butanoate (ester) (97%) 3 2 ethanol l 23 2 mandelic acid ethyl mandelate (86%) - commerical constraints limit reaction to methyl, ethyl, propyl esters Mechanism 7

8 Evidence omes from 18 -Labeling Experiments * 3 l * 3 catalyst arboxylic Acids Amides - acid-base reaction occurs and reaction to form an an amide does not occur readily : 3 4 carboxylic acid ammonium salt hemistry of Acid alides - there are two general methods to prepare acid halides: Sl 2 l PBr 3 ether Br 8

9 Acid hloride ydrolysis: onversion of Acid alides into Acids l acid chloride 2 l Base carboxylic acid - since l is generated during hydrolysis, the reaction is often carried out in the presence of a base (e.g. pyridine, a) Alcoholysis: onversion of Acid alides into Esters - reaction is analogous to hydrolysis and is strongly affected by steric hindrance l pyridine benzoyl chloride cyclohexanol cyclohexyl benzoate (97%) - reactivity order among alcohols: primary > secondary > tertiary 9

10 Illustration of Alcohol eactivity primary alcohol (less hindered and more reactive) 2 3 l pyridine 3 secondary alcohol (more hindered and less reactive) Aminolysis: onversion of Acid alides into Amides - reaction is analogous to hydrolysis and alcoholysis; in a similar way to alcoholysis, the reaction is sensitive to steric hindrance such that primary and secondary amine react, while tertiary amines do not 2 3 ( 3) 2 l ( 3) methylpropanoyl chloride 2-methylpropanamide (83%) l 2 ( 3) 2 (3)2 benzoyl chloride,-dimethylbenzamide 3 3 l a ,4,5-trimethoxybenzoyl chloride morpholine 3 trimetozine eduction: onversion of Acid alides into Alcohols - acid chlorides are reduced by LiAl 4, by way of an aldehyde intermediate which can be trapped using lithium tri-tertbutoxyaluminum hydride as the reducing agent l 1) LiAl 4, ether 2) 3 2 benzoyl chloride benzyl alcohol (96%) l acid chloride LiAl 4 ether l aldehyde (not isolated) 1) LiAl 4 2) 3 primary alcohol 10

11 - lithium tri-tert-butoxyaluminum hydride is effective for achieving partial reduction of acid chlorides to aldehydes 3 ( 3 ) 3 LiAl 4 Li - Al[( 3 ) 3 ] lithium tri-tert-butoxyaluminum 2 l 1) LiAl[( 3 ) 3 ] 3, ether 2) 3 2 p-nitrobenzoyl chloride p-nitrobenzaldehyde (81%) eaction of Acid alides with rganometallic eagents - Grignard reagents react with acid chlorides to give tertiary alcohols with two identical substituents that originate from the organometallic reagent l 2 MgX 1) Ether ' ' 2) 3 acid chloride 3 o alcohol - reaction proceeds through a ketone intermediate l 1) 3 MgBr 2) Ether 3 1) 3 MgBr 2) Ether 3 3 benzoyl chloride acetophenone 2-phenyl-2-propanol - ketone intermediate can be isolated using a Gilman reagent l 2 u - ether Li solvent ' acid chloride ketone 32 l 3 ( 3 2 ) 2 uli ether, -78 o ,4-dimethyl-2-hexenoyl chloride manicone (92%) 11

12 hemistry of Acid Anhydrides Preparation of Acid Anhydrides - most general method is nucleophilic acyl substitution involving a carboxylate anion a ether l 3 25 o 3 sodium formate acetyl chloride acetyl formic anhydride (64%) Acid Anhydride eactions of Acid Anhydrides - acid anhydrides and acid chlorides undergo the same reactions salicyclic acid 3 3 acetic anhydride a 2 3 aspirin a p-hydroxyaniline acetic anhydride acetominophen 12

13 hemistry of Esters - esters are among the most widespread of all types of molecules methyl butanoate (from pineapples) isopentyl acetate (from bananas) dibutyl phthalate (a plasticizer) Preparation of Esters - methods that we have previously discussed: Sl 2 l 1) a 2) X l pyridine ' ' ' limited to primary alkyl halides limited to simple alcohols very general eactions of Esters - reactions similar to acid chlorides and acid anhydrides, yet are less reactive since the alkoxide ion is a relatively poor leaving group Ester 13

14 ydrolysis of Esters - hydrolysis of an ester can be achieved in two ways: 1) base-catalyzed mechanism (saponification) 2) acid-catalyzed mechanism ' 2, a or 3 Base-Induced Ester ydrolysis Mechanism Acid-Induced Ester ydrolysis 14

15 Support for Mechanism of Base-atalysis 1) a, 2 * * ) bond broken labeling experiments Aminolysis and eduction 3 3 ether 2 3 methyl benzoate benzamide 1) LiAl 4, ether ) 3 ethyl 2-pentenoate 2-penten-1-ol (91%) 3 lactone 1) LiAl 4, ether 2) ,4-pentanediol (86%) - mechanism of reduction is similar to that of acid chloride: ' LiAl 4 ether ' 1) LiAl 4 2) 3 - the intermediate aldehyde involved in the reduction reaction can be isolated using diisobutylaluminum hydride (DIBA) 1) DIBA in toluene 3 ( 2 ) ( 2 ) 10 2) 3 ethyl dodecanoate dodecanal (88%) - where DIBA = [( 3 ) 2 2 ] 2 Al 15

16 eaction of Esters with Grignard eagents - esters react with two equivalents of Grignard reagent to yield a tertiary alcohol with two identical substituents 3 1) 2 MgBr, ether 2) 3 methyl benzoate triphenylmethanol (96%) 1) 2 3 MgBr, ether 2) valerolactone 5-methyl-1,5-hexanediol hemistry of Amides - amides are much less reactive than acid chlorides, acid anhydrides, and esters Preparation - usually prepared by reaction of acid chloride with an amine 3 l ' 2 ' ydrolysis of Amides - owing to lesser reactivity, more severe conditions are required to hydrolyze an amide (i.e. aqueous acid or base) Acid ydrolysis Base ydrolysis

17 - the stability of amides makes the structure one of the essential blocks of life; specifically, amides linkages are the building units of proteins ' '' 2 amino acid protein (polyamide) eduction: onversion of Amides to Amines - amides are reduced, similar to carboxylic acids, using LiAl 4 - the product is an amine (instead of an alcohol), with conversion of an amide carbonyl group to a methylene group (= 2 ) 1) LiAl 4, ether 3( 2) ( 2) ) 2 -methyldodecanamide dodecylmethylamine (95%) ) LiAl 4, ether 2) 2 3 lactam cyclic amine (80%) - specific to amides and not other carboxylic acid derivatives Mechanism Al 3 1) LiAl 4 2) amide iminium ion 2 17

18 hemistry of itriles - nitriles are analogous to carboxylic acids in terms of structure and reactivity - both nitriles and carboxylic acids have a carbon atom with three bonds to an electronegative atoms and a π bond :u - u products :u - u products - both nitriles and carboxylic acids undergo nucleophilic addition Preparation of itriles 1) S 2 reaction with - with a primary alkyl halide Br a - S 2 2 reaction 2 abr 2) dehydration of a primary amide Sl 2, benzene 80 o S 2 l ethylpentanamide 2-ethylpentanenitrile (90%) Mechanism of Dehydration S l l 2 S l :Base S l :Base S 2 - dehydration is more general since the reaction is not limited by steric hindrance 18

19 itrile ydrolysis of itriles - nitriles are hydrolyzed in either acidic or base aqueous solution to give carboxylic acids plus ammonia or an amine 3 or a, the mechanism involves the generation of an amide intermediate - reaction conditions are quite severe (K, 200 o ), meaning that the amide in some instances can be isolated using milder conditions Amide 19

20 eduction: onversion of itriles into Amines and Aldehydes - nitriles are reduced using either LiAl 4 or DIBA 2 2 1) LiAl 4, ether 2) o-methylbenzonitrile o-methylbenzylamine (88%) - with the less powerful reducing agent DIBA, the second addition of the hydride does not occur and the intermediate imine anion is hydrolyzed to give an aldehyde imine anion 1) LiAl 4 2) 2 2 primary amine 2 imine anion aldehyde ) DIBA, toluene, -78 o 2 2 2) eaction of itriles with rganometallic eagents - in a similar way to the reduction mechanism, Grignard reagents add to nitriles to produce an imine anion that can be hydrolyzed by addition of water to yield a ketone : - MgX ' 2 3 ' - the nucleophile is a carbanion (: - ) rather than a hydride 1) 3 2 MgBr, ether 2 3 2) 3 benzonitrile propiophenone (89%) 20

21 Thiol Esters - ature carboxylic acid derivatives are in the form of thiol esters S' - acetyl coenzyme A (acetyl oa) is one such ester, serving as an acylating agent in nucleophilic acyl substitution reactions S () 2P 3 P 2 acetyl oa P Synthesis of -acetylglucosamine 3 SoA :u - 3 u SoA 2 3 glucosamine -acetylglucosamine Polyamides and Polyesters - reaction of a diamine and a diacid chloride produces a polyamide 2 ( 2 ) n 2 l ( 2 ) m l ( 2 ) n ( 2 ) m diamine diacid chloride polyamide - similarly, reaction of a diol and a diacid produces a polyester ( 2 ) n ( 2 ) m ( 2 ) n ( 2 ) m diol diacid polyester - polymers are known as step-growth polymers 21

22 Synthesis of ylon ( 2 ) 4 2 ( 2 ) 6 2 adipic acid hexamethylenediamine ( 2 ) 4 ( 2 ) 6 ylon 66 Synthesis of Dacron n 2n dimethylterephthalate 200 o 22 n Dacron; Mylar 2n ethylene glycol Spectroscopy of arboxylic Acid Derivatives and itriles Infrared Spectroscopy - carbonyl-containing compounds have intense I absorptions in the range cm -1 - position provides information about the kind of carbonyl group M Spectroscopy - hydrogens on carbon next to carbonyl group are slightly deshielded and absorb near 2 δ in the 1 M spectrum - carbon carbon atoms absorb near 200 δ in the 13 M spectrum 1 M Spectrum of Ethyl Acetate hemical Shift (δ) 22