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Home , Alkyl, Carboxylate, Carboxylic acid, Deprotonation, Hunsdiecker reaction, Ketone

Carboxylic

A carbonyl with one OH attached is called a carboxylic

One important property of carboxylic acids is the acidity

O O pKa ~4-5 B B H H3C OH H3C O

Upon a carboxylate is formed Carboxylic Acids

Nomenclature

There are two important guidelines to know about carboxylic acids:

1) The has the highest priority in naming

2) In common names, the point of substitution is labeled by the Greek letter counting from the carbonyl

" O

OH # !

This naming is common practice amongst organic chemists, e,g, substitution at α- Carboxylic Acids

Examples

O Br O

OH OH

(E)-2-pentenoic acid 3-bromo-2-methylpentanoic acid Or β-bromo-α-methylpentanoic acid (common)

CO2H

Cl

Trans-2-chlorocyclohexanecarboxylic acid Carboxylic Acids

Many carboxylic acids have a common name

Aromatic rings have a number of these common names

CO2H CO2H

CO2H

Benzoic acid

-As do many dicarboxylic acids

O O

HO OH

Malonic acid (IUPAC: Propanediodic acid) Carboxylic Acids

Due to the ability to resonate a lone pair of electrons on with the carbonyl, the structure of an acid has two preferred conformations

O O H O O H s-cis s-trans

The s-cis conformer also allows an acid to form a dimer in solution with two bonds

O H O

O H O

This hydrogen bonding causes a higher melting point and compared to compounds of similar molecular weight Carboxylic Acids

As noted in the name, carboxylic acids are relatively acidic organic compounds

The acidity is rationalized by the ability to resonate the anion after deprotonation between the two oxygen

O O O

H3C OH H3C O H3C O

The large dipole of the carbonyl though also stabilizes the anion formed after deprotonation

O O!- O!- ≅ !+ !+ H C O H3C OH H3C OH 3 Anion stabilized by adjacent partial positive charge Carboxylic Acids

In addition to being acidic, however, carboxylic acids can also be protonated to act as a Lewis

H O O O H+ H H3C OH H3C OH H3C O H

The question is which oxygen becomes protonated preferentially

When the carbonyl oxygen is protonated, the charge can be delocalized through

H H H O O O O O!- H ≅ !+ H H H C O H C O H3C OH H3C OH H3C O 3 3 H H

When the hydroxyl oxygen is protonated, however, resonance cannot occur (already have 8 electrons in outer shell) and the cation is destabilized by adjacent partial charge

Therefore carbonyl oxygen is protonated preferentially Synthesis of Carboxylic Acids

Oxidative Routes Other Routes

H CrO O 2 4 H O O OH 2 H2SO4 OH CN H+, ! OH

O 1) O3 2) H O OH 2 2 O 1) Mg Br OH 2) CO2

O H2O2 O

H OH Thus a variety of , , halides, alkyl substituted aromatic rings, can be

CO2H converted into carboxylic acids KMnO4 Reactions of Acyl Compounds

There is a commonality amongst carbonyl reactions, they have a react at the carbonyl carbon

O NUC O O X H C X H3C X 3 NUC H3C NUC

Generate a tetrahedral intermediate that can expel a

O NUC O With and aldehydes, H however, there was no suitable H C H H3C 3 NUC leaving group present

In acidic conditions, have same mechanism but first protonate carbonyl to make a more electrophilic carbon H H O H+ O NUC O O X H C X H C X H C X 3 3 3 NUC H3C NUC Fischer Esterification

One common reaction is to convert a carboxylic acid into an (called Fischer esterification)

H H O O O H+ ROH H C OH H C OH H C OH 3 3 3 OR H Protonate carbonyl

-H+

H H H H O O O -H2O H+ H C OR H C OH H C OH 3 3 OR 3 OR

-H+ O Overall converted (1852-1919) acid into ester, each Also invented H C OR 3 step is an equilibrium “Fischer Projections” Esterification

Other methods to synthesize an ester from a carboxylic acid include:

SN2 reaction with carboxylate nucleophile

O base O CH3Br O

H3C OH H3C O H3C OCH3

Diazomethane

O H2C N N O H3C N N O

H3C OH H3C O H3C OCH3

Yields are quite high, but reaction is potentially dangerous for most lab-scale reactions a different route to is preferred

Direct acid to interconversion

An amide can also be formed directly from carboxylic acid by combining the two reagents

O O O ! RNH2 H2O H3C OH H3C O RNH3 H3C NHR

The first step is merely an acid/base reaction as the base abstracts the acidic hydrogen

To form the amide bond, the ionic needs to be heated

This procedure is not as mild as a Fischer esterification, need to heat the reaction (usually >100 ˚C) to drive off -Loss of water as steam shifts equilibrium to products Amides

Since the direct conversion of an acid and amine to an amide requires high heat, a more efficient method to convert the reagents was developed

The key is activating the acid into a better leaving group that doesn’t have a labile hydrogen

Because of diimide, carbon is very electrophilic R O O O NHR N C N H3C H3C R RNH R H C OH R O 2 O 3 N C N C NHR NHR

The amine can react at activated carbonyl with a There are many variants of stable leaving group O diimide coupling reagents

by changing R group H3C NHR

The leaving group is O R O R R protonated to form a stable N N N C complex H H NHR Acid Chlorides

Carboxylic acid can be converted into acid chlorides by reaction with

O SOCl2 O

H3C OH H3C Cl

The mechanism once again involves converting the acid into a better leaving group

O O O O O O S S S HCl H3C OH Cl Cl H C O Cl H3C O Cl 3 Cl H SOCl2

H O HO Cl O O O -SO2 HCl S S Cl H3C Cl H3C O Cl H3C O Cl After deprotonation obtain acid chloride Anhydrides

Acid anhydrides (often just shortened to anhydrides) literally means loss of water from acid

O O O O H2O H3C OH H3C OH H3C O CH3

Typically need to again make acid a better leaving group for reaction to proceed

Use acid chlorides O O O O O O O SOCl2 H3C OH HCl H C OH H C Cl H C O CH H3C O CH3 3 3 3 Cl 3 H

Or DCC coupling

O O DCC O O urea H3C OH H3C OH H3C O CH3 Ketones

While a Fischer esterification is an example of reacting a carboxylic acid in acidic conditions by first protonating the carbonyl, most basic will simply deprotonate the carboxylic acid

O NUC O NUC H H3C OH H3C O

The carboxylate is less electrophilic that either a or and thus it is more difficult to react with nucleophiles and often this is the final product before work-up

Organolithiums, however, are much stronger nucleophiles and are able to react

O O O O O RLi RLi H+ HO OH -H2O

H3C OH H3C O H3C R H3C R H3C R The dianion has no After , leaving group the equilibrates to ketone Overall acids can be converted to ketones with two equivalents of organolithium Alcohols

Another nucleophilic reaction that can occur with carboxylate anions is reaction with LAH

AlH2 O O H Al H Li O O LAH 3 O AlH2 H C OH H C O H C H 3 H3C O 3 H 3

1) LAH 2) H2O Initially an aldehyde is generated, but it H H occurs in the presence of LAH and thus it reacts a second time to yield an H3C OH

NaBH4 is not a strong enough source for reaction, need to use LAH

O 1) LAH 2) H2O OH OH Alcohols

In addition to using the metal as a , carboxylic acids have also been found to be reduced to an alcohol using borane

1) BH3•THF O H H 2) H2O

H3C OH H3C OH

What is unique about this reduction compared to lithium aluminum hydride is that the carboxylic acid is reduced faster than other carbonyls

This leads to selectivity differences in compounds with multiple carbonyls

1) LAH O O OH LAH is 2) H2O unselective H3C OH H3C OH OH O NaBH does not NaBH4 4 H3C OH reduce acids

1) BH3•THF O Borane reduces 2) H2O acids first H3C OH

If a carboxylic acid is β to another carbonyl, then the acid will decarboxylate readily under gentle heating

rotate carbon-carbon H H O O O O O O bond ! C

H3C OH H3C O H3C O

The formed after losing O equilibrates to a ketone H3C CH3

Anytime a carboxylic acid is β to any type of carbonyl, a decarboxylation can occur

O O O O ! C HO OH HO CH3 O Decarboxylation

A similar decarboxylation occurs with and derivatives

O O ROH H C RO O ROH2 RO O Monoester of carbonic acid

O O H C NH H N O 3 2 O Carbamic acid

If the acid functionality is protected as an ester, then the decarboxylation cannot occur

O O O

RO OR H2N OR H2N NH2 Carbonates Urea Hunsdiecker

Another type of decarboxylation involves an electrochemical oxidation of a carboxylate to a carboxyl which subsequently loses carbon dioxide

O O O electrochemical H R O H3C O M R O

-CO2

Called Kolbe electrolysis R R R

A similar decarboxylation occurs with “Hunsdiecker” reaction where an alkyl bromide is formed from carboxylic acids

O O O Br O Br2 -CO2 O R AgBr R R Br H3C O Ag R O R O

Generates an alkyl bromide from carboxylic acid, carboxyl radical propagates reaction