Organic Chemistry/Carboxylic acid derivatives

The carboxyl group (abbreviated -CO2H or -COOH) is one of the most widely occurring functional groups in chemistry as well as biochemistry. The carboxyl group of a large family of related compounds called Acyl compounds or Carboxylic Acid Derivatives.

All the reactions and compounds covered in this section will yield Carboxylic Acids on hydrolysis, and thus are known as Carboxylic Acid Derivatives. Hydrolysis is one example of Nucleophilic Acyl Substitution, which is a very important two step mechanism that is common in all reactions that will be covered here.

Structure
This group of compounds also contains a carbonyl group, but now there is an electronegative atom (oxygen, nitrogen, or a halogen) attached to the carbonyl carbon. This difference in structure leads to a major change in reactivity.

Nomenclature
The systematic IUPAC nomenclature for carboxylic acid derivatives is different for the various compounds which are in this vast category, but each is based upon the name of the carboxylic acid closest to the derivative in structure. Each type is discussed individually below.

Acyl Groups
Acyl groups are named by stripping the -ic acid of the corresponding carboxylic acid and replacing it with -yl.

EXAMPLE: CH3COOH = acetic acid CH3CO-R = acetyl-R

Acyl Halides
Simply add the name of the attached halide to the end of the acyl group.

EXAMPLE: CH3COOH = acetic acid CH3COBr = acetyl bromide

Carboxylic Acid Anhydrides
A carboxylic acid anhydride ([RC=O]O[O=CR]) is a carboxylic acid (COOH) that has an acyl group (RC=O) attached to its oxygen instead of a hydrogen. If both acyl groups are the same, then it is simply the name of the carboxylic acid with the word acid replaced with anhydride. If the acyl groups are different, then they are named in alphabetical order in the same way, with anhydride replacing acid.

EXAMPLE: CH3COOH = acetic acid CH3CO-O-OCCH3 = Ethanoic Anhydride

Esters
Esters are created when the hydrogen on a carboxylic acid is replaced by an alkyl group. Esters are known for their pleseant, fruity smell and taste, and they are often found in both natural and artificial flavors. Esters (RCOOR1) are named as alkyl alkanoates. The alkyl group directly attached to the oxygen is named first, followed by the acyl group, with -ate replacing -yl of the acyl group.

EXAMPLE: CH3COOH = acetic acid CH3COOCH2CH2CH2CH3 = acetyl butanoate cooh 1 cooh 1 2-ethan oic acid

Amides
Amides which have an amino group (-NH2) attached to a carbonyl group (RC=O) are named by replacing the -oic acid or -ic acid of the corresponding carboxylic acid with -amide. EXAMPLE: CH3COOH = acetic acid CH3CONH2 = acetamide

Nitriles
Nitriles (RCN) can be viewed a nitrogen analogue of a carbonyl and are known for their strong electron withdrawing nature and toxicity. Nitriles are named by adding the suffix -nitrile to the longest hydrocarbon chain (including the carbon of the cyano group). It can also be named by replacing the -ic acid or -oic acid of their corresponding carboxylic acids with -onitrile. Functional class IUPAC nomenclature may also be used in the form of alkyl cyanides.

EXAMPLE: CH3CH2CH2CH2CN = pentanenitrile or butyl cyanide

Structure and Reactivity
Stability and reactivity have an inverse relationship, which means that the more stable a compound, generally the less reactive - and vice versa. Since acyl halides are the least stable group listed above, it makes sense that they can be chemically changed to the other types. Since the amides are the most stable type listed above, it should logically follow that they cannot easily changed into the other molecule types, and this is indeed the case.

The stability of any type of carboxylic acid derivative is generally determined by the ability of its functional group to donate electrons to the rest of the molecule. In essence, the more electronegative the atom or group attached to carbonyl group, the less stable the molecule. This readily explains the fact that the acyl halides are the most reactive, because halides are generally quite electronegative. It also explains why acid anhydrides are unstable; with two carbonyl groups so close together the oxygen in between them cannot stabilize both by resonance - it can't loan electrons to both carbonyls.

The following derivative types are ordered in decreasing reactivity (the first is the most reactive):

Acyl Halides (CO-X) > Acyl Anhydrides (-CO-O-OCR) > Acyl Thioester (-CO-SR) > Acyl Esters (-CO-OR) > Acyl Amides (-CO-NR2)

As mentioned before, any substance in the preceding list can be readily transformed into a substance to its right; that is, the more reactive derivative types (acyl halides) can be directly transformed into less reactive derivative types (esters and amides). Every type can be made directly from carboxylic acid (hence the name of this subsection) but carboxylic acid can also be made from any of these types.

Carboxylic Acids
1) As acids:

RCO2H + NaOH > RCO2-Na+ + H2O RCO2H + NaHCO3 > RCO2-Na+ + H2O + CO2

2) Reduction:  RCO2H + LiAlH4 --- (1) Et2O -- (2) H2O > RCH2OH

2a) Fukyama reduction: Pd and Et3SiH COOH->CHO

3) Conversion to acyl chlorides:

RCO2H -SOCl2 or PCl5 > RCOCl

4) Conversion to esters (Fischer esterfication):

RCOOH + R'-OH <--- HA --->  RCOOR' + H2O

5) Conversion to amides:

RCO2H -SOCl2 or PCl5 > RCOCl + NH3 <--> RCOO-NH4+ --- heat ---> R-CONH2 + H2O

6) Decarboxylation: (Note: you need a doubly-bonded oxygen (carbonyl) two carbons away or two carboxylic acid groups attached to a same carbon atom for this reaction to work)   Note: Decarboxylation by heating can only occur for ẞ-keto acids or 1,1-dicarboxylic acids   RCOCH2COOH  --- heat ---> R-COCH3 + CO2   HOCOCH2COOH --- heat ---> CH3COOH + CO2 7)R-COOH + R-OH -R-COOR + H2O

Acyl Chlorides
1) Conversion to acids:

R-COCl + H2O > R-COOH + HCl

2) Conversion to anhydrides:

R-COCl + R'COO- > R-CO-O-COR' + Cl-

3) Conversion to esters:

R-COCl + R'-OH --- pyridine ---> R-COOR' + Cl- + pyr-H+

4) Conversion to amides:

R-COCl + R'NHR" (excess) ---> R-CONR'R" + R'NH2R"Cl R' and/or R" may be H

5) Conversion to ketones:

Friedel-Crafts acylation R-COCl + C6H6 --- AlCl3 ---> C6H5-COR

Reaction of Dialkylcuprates (also known as a Gilman reagent) R-COCl + R'2CuLi > R-CO-R'

6) Conversion to aldehydes:

R-COCl + LiAlH[OC(CH3)3]3 --- (1) Et2O (2) H2O ---> R-CHO

Acid Anhydrides
1) Conversion to acids:

(R-CO)2-O + H2O > 2 R-COOH

2) Conversion to esters:

(R-CO)2-O + R'OH > R-COOR' + R-COOH

3) Conversion to amides:

(R-CO)2-O + H-N-(R'R") > R-CON-(R'R") + R-COOH R' and/or R" may be H.

4) Conversion to aryl ketones (Friedel-Crafts acylation):

(R-CO)2-O + C6H6 --- AlCl3 C6H5-COR + R-COOH

Esters
1) Hydrolysis:

R-COOR' + H2O <--- HA ---> R-COOH + R'-OH R-COOR' + OH- > RCOO- + R'-OH

2) Transesterification (conversion to other esters):

R-COOR' + R"-OH <--- HA ---> R-COO-R" + R'-OH

3) Conversion to amides:

R-COOR' + HN-(R"R"') > R-CON-(R"R"') + R'-OH R" and/or R"' may be H

4) Reaction with Grignard reagents:

R-COOR' + 2 R"MgX --- Et2O ---> R-C-R"2OMgX + R'OMgX ---> H3O+ R-C-R"2OH The intermediate and final product is a tetrahedral carbon with two R" attached directly to the carbon along with R and OH/OMgX

X = halogen.

5) Reduction:

R-COOR' + LiAlH4 --- (1) Et2O (2) H2O ---> R-CH2OH + R'-OH

Amides
1) Hydrolysis:

R-CON(R'R") + H3O+ --- H2O ---> R-COOH + R'-N+H2R" R-CON(R'R") + OH- --- H2O ---> R-COO- + R'-NHR" R,R' and/or R" may be H.

2) Dehydration (conversion to nitriles):

R-CONH2 --- P4O10, heat, (-H2O) ---> R-CN

Nitriles
1) Hydrolysis:

R-CN --- H3O+,heat ---> RCOOH R-CN --- OH-,H2O,heat ---> RCOO-

2) Reduction to aldehyde:

R-CN --- (1) (i-Bu)2AlH (2) H2O ---> R-COH (i-Bu)2AlH = DIBAL-H

3) Conversion to ketone (by Grignard or organolithium reagents):

R-CN + R"-M --- (1) Et2O (2) H3O+ ---> R-COR" M = MgBr (Grignard reagent) or Li (organolithium reagent)

Mechanisms
A common motif in reactions dealing with carboxylic acid derivatives is the tetrahedral intermediate. The carbonyl group is highly polar, with the carbon having a low electron density, and the oxygen having a high electron density. With an acid catalyst, a H+ is added to the oxygen of the carbonyl group, increasing the positive charge at the carbon atom. A nucleophile can then attack the carbonyl, creating a tetrahedral intermediate.

For example, in Fischer esterification, the mechanism can be outlined thus: 1) H+ is added to carbonyl oxygen 2) Oxygen atom of the alcohol adds to the carbonyl carbon 3) Proton transfer from alcohol oxygen to carboxyl oxygen 4) Water molecule ejected from tetrahedral intermediate, double bond forms, recreating the carbonyl 5) H+ is removed from carbonyl oxygen(very important for the base reduction of acids)