Organic Chemistry - Carboxylic Acid Derivatives

Front 1

What are some carboxylic acid derivatives?

Back 1

Acid Halide

Acid anhydride

Ester

Amide

Thioester

Acyl Phosphate

Front 2

What is the order of polarity of the derivatives?

Back 2

amide < ester < thioester < acid anhydride < acid chloride

more reactive acid derivatives are easier to convert

acid halides and acid anhydrides do not persist in living organisms because they react too rapidly with water

Front 3

What are 4 common reactions for carboxylic acid derivatives?

Back 3

Hydrolysis:
conversion of acid halides into acids:
-reaction with water to yield tetrahedral intermediate, tetrahedral intermediate expels Cl- and lose H+ to give carboxylic acid and HCl
conversion of acid halides into anhydrides:
-acid chloride + carboxylate anion = acid anhydride

Alcoholysis:
converstion of acid halides into esters:
-reaction with alcohol to yield ester
-most common method for preparing esters in lab
-carried out in presence of pyridine or NaOH
-strongly affected by steric hinderance (prefers NON bulky groups)

Aminolysis:
converstion of acid halides into amines:
-reaction with ammonia or amine to yield amide
-trisubstituted amines cannot be used
-because HCl is formed, 2 equivalent amines must be used
-first reacts with acid chloride, 2nd with HCl by product

Reduction:
-reaction with hydride reducing agent to yield aldehyde or alcohol

Front 4

How are Carboxylic Acids converted to Acid Chlorides?

Back 4

SOCl2

chlorosulfite intermediate, replacing OH with a better leaving group

Front 5

How are carboxylic acids converted to Acid Anhydrides?

Back 5

2 molecules of carboxylic acid lose 1 equivalent water by heating

prep is uncommon due to high temperatures required

Front 6

How are Carboxylic acids converted to Esters?

Back 6

most useful reaction of carboxylic acids

Sn2 reaction with carboxylate anion with primary alkyl halide

Fischer Esterification reaction:
-acid catalyzed substitution of carboxylic acid with alcohol
-excess liquid alcohol limits reaction to methyl, ethyl, propyl, and butyl esters
-evidence provided by isotopic labeling experiment

Front 7

How are Carboxylic Acids converted to Amides?

Back 7

-difficult by direction reaction of carboxylic acid with amines because amines are bases that convert acidic carboxyl groups into their unreactive carboxylate anions

-amides first activated by DCC
-intermediate then treated with amine
-key step in synthesis of small proteins

Front 8

How are Carboxylic Acids converted into Alcohols?

Back 8

reduced by LiAlH4 to give primary alcohols

reaction proceeds through aldehyde intermediate

hydride ion is a base and a nucleophile:
-reaction involves carboxylate anion and gives high energy dianion intermediate complexed to a lewis acidic aluminum species

Front 9

What are some Biological conversions of Carboxylic Acids?

Back 9

acid must first be activated

acid reactions with ATP to give acycl adenosyl phosphate or acyl adenylate

acyl adenylate is a mixed anhydride between carboxylic and AMP known as adenylic acid

occurs in biosynthesis of fats

acyl adenylate undergoes nucleophilic acyl substitution with -SH group on CoA

Front 10

What is a naturally occurring ester?

Back 10

Dibutyl phthalate is a common plasticizer

all reactions of esters are equally applicable to acyclic and cyclic esters called lactones

Front 11

What is a Saponification reaction?

Back 11

Basic ester hydrolysis to yield a carboxylic acid

means soap which is made from boiling animal fat with base

occurs by cleavage of C-OR' rather than CO-R'

Front 12

How does acid-catalyzed hydrolysis occur for esters?

Back 12

Reverse of Fischer Esterification reaction (most common):
-protonation of carboxyl oxygen activates ester towards nucleophilic attack
-nucleophilic addition of water occurs
-alcohol is eliminated forming the carboxylic acid

ester hydrolysis is common in digestion of fats and oils involved in two sequential acyl substitution reactions

Front 13

What is the Aminolysis reaction for esters?

Back 13

Conversion of esters into amides:
-esters react with ammonia and amines to yield amides
-not as common as with acid chlorides

Front 14

How are esters converted to alcohols?

Back 14

Reduction and Grignard reaction:
-esters reduced by treatment with LiAlH4 to yield primary alcohols
-proceeds through aldehyde intermediate
-aldehyde intermediate can be isolated by DIBAH

Esters and lactones react with 2 equivalents of grignard reagent to yield tertiary alcohols:
-ketone intermediate

Front 15

What are characteristics of Amides?

Back 15

abundant in proteins, NA, and many pharmaceuticals

least reactive of carboxylic acid derivatives

Front 16

How are amides converted into Carboxylic Acids?

Back 16

Hydrolysis

acidic hydrolysis:
-nucleophilic addition of water to protonated amide followed by loss of water

basic hydrolysis:
-nucleophilic addition of -OH followed by deprotonation of -OH group and elimination of -NH2

Amide hydrolysis is the initial step in digestion of dietary proteins:
-reaction is catalyzed by protease enzmes and occurs by mechanism almost identical to fat hydrolysis

Front 17

How are Amides converted to Amines?

Back 17

Reduction:
-reduced by LiAlH4 to amines
-reduction of amide carbonyl into a methylene (C=O --> CH2)
-gives iminium ion intermediate which is further reduced by LiAlH4

Front 18

How are cyclic amines prepared?

Back 18

aminolysis of acyclic and cyclic amides called lactams

lactam reacts with LiAlH4, ehter to yield a cyclic amine

Front 19

What are some biological Carboxylic Acid Derivatives?

Back 19

usually Thioesters or Acyl Phosphates:
-not as reactive as acid chlorides or acid anhydrides

Acetyl CoA is most common thioester in nature

N-acteylglucosamine is synthesized by an aminolysis reaction between glucosamine and acetyl CoA; component of cartilage and other CT

R-Mevaldehyde is an intermediate in terpenoid synthesis; formed by hydride donation from NADPH

Front 20

What are Step-Growth Polymers?

Back 20

Polymers are produced by chain reactions:
-amide polymers formed from reaction of diamines with diacid chlorides (ex. Nylon 66)
-ester polymers are formed from reaction of diols with diacids (Dacron or Mylar)
-Lexan is a polymer of diphenyl carbonate with bisphenol A, used in bicycle helmets and computer cases

Biodegradable polymers:
-rapidly broken down by soil microorganisms
-PGA (polyglycolic acid), PLA (polylactic acid), and PHB
-90/10 copolymer of PGA with PLA used to make absorbable sutures which are absorbed by body within 90 days after surgery