# Organic Chemistry/Carboxylic acid derivatives

The carboxyl group (abbreviated -CO~2~H 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:**\
> CH~3~COOH = *acetic acid*\
> CH~3~CO-R = *acetyl-R*

### Acyl Halides

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

> **EXAMPLE:**\
> CH~3~COOH = *acetic acid*\
> CH~3~COBr = *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:**\
> CH~3~COOH = *acetic acid*\
> CH~3~CO-O-OCCH~3~ = *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 (RCOOR^1^) 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:**\
> CH~3~COOH = *acetic acid*\
> CH~3~COOCH~2~CH~2~CH~2~CH~3~ = *acetyl butanoate*

> cooh 1 cooh 1 2-ethan oic acid

### Amides

Amides which have an amino group (-NH~2~) 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:**\
> CH~3~COOH = *acetic acid*\
> CH~3~CONH~2~ = *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:**\
> CH~3~CH~2~CH~2~CH~2~CN = *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-NR~2~)**

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.

## Reactions of Carboxylic Acids and Their Derivatives

### Carboxylic Acids

1\) As acids:

`  RCO`~`2`~`H + NaOH ----> RCO`~`2`~^`-`^`Na`^`+`^` + H`~`2`~`O`\
`  RCO`~`2`~`H + NaHCO`~`3`~` ----> RCO`~`2`~^`-`^`Na`^`+`^` + H`~`2`~`O + CO`~`2`~

2\) Reduction:

`  RCO`~`2`~`H + LiAlH`~`4`~` --- (1) Et`~`2`~`O -- (2) H`~`2`~`O ----> RCH`~`2`~`OH`

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

3\) Conversion to acyl chlorides:

`  RCO`~`2`~`H -----SOCl`~`2`~` or PCl`~`5`~` ----> RCOCl`

4\) Conversion to esters (Fischer esterfication):

`  RCOOH + R'-OH  <--- HA --->  RCOOR' + H`~`2`~`O`

5\) Conversion to amides:

`  RCO`~`2`~`H -----SOCl`~`2`~` or PCl`~`5`~` ----> RCOCl + NH`~`3`~` <------> RCOO`^`-`^`NH`~`4`~^`+`^` --- heat ---> R-CONH`~`2`~` + H`~`2`~`O`

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`\
`  RCOCH`~`2`~`COOH  --- heat ---> R-COCH`~`3`~` + CO`~`2`~\
`  HOCOCH`~`2`~`COOH --- heat ---> CH`~`3`~`COOH + CO`~`2`~

7)R-COOH + R-OH \-\-\-\-\-\-\-\--R-COOR + H2O

### Acyl Chlorides

1\) Conversion to acids:

`  R-COCl + H`~`2`~`O ----> 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'NH`~`2`~`R"Cl`

R\' and/or R\" may be H

5\) Conversion to ketones:

Friedel-Crafts acylation

`  R-COCl + C`~`6`~`H`~`6`~` --- AlCl`~`3`~` ---> C`~`6`~`H`~`5`~`-COR`

Reaction of Dialkylcuprates (also known as a Gilman reagent)

`  R-COCl + R'`~`2`~`CuLi ----> R-CO-R'`

6\) Conversion to aldehydes:

`  R-COCl + LiAlH[OC(CH`~`3`~`)`~`3`~`]`~`3`~` --- (1) Et`~`2`~`O  (2) H`~`2`~`O ---> R-CHO`

### Acid Anhydrides

1\) Conversion to acids:

`  (R-CO)`~`2`~`-O + H`~`2`~`O ----> 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 + C`~`6`~`H`~`6`~` --- AlCl`~`3`~` C`~`6`~`H`~`5`~`-COR + R-COOH`

### Esters

1\) Hydrolysis:

`   R-COOR' + H`~`2`~`O <--- 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 --- Et`~`2`~`O ---> R-C-R"`~`2`~`OMgX + R'OMgX ---> H`~`3`~`O`^`+`^`  R-C-R"`~`2`~`OH`

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' + LiAlH`~`4`~` --- (1) Et`~`2`~`O (2) H`~`2`~`O ---> R-CH`~`2`~`OH + R'-OH`

### Amides

1\) Hydrolysis:

`  R-CON(R'R") + H`~`3`~`O`^`+`^`  --- H`~`2`~`O ---> R-COOH + R'-N`^`+`^`H`~`2`~`R"`\
`  R-CON(R'R") + OH`^`-`^`  --- H`~`2`~`O ---> R-COO`^`-`^` + R'-NHR"`

R,R\' and/or R\" may be H.

2\) Dehydration (conversion to nitriles):

`  R-CONH`~`2`~`  --- P`~`4`~`O`~`10`~`, heat, (-H`~`2`~`O) ---> R-CN`

### Nitriles

1\) Hydrolysis:

`  R-CN --- H`~`3`~`O`^`+`^`,heat ---> RCOOH`\
`  R-CN --- OH`^`-`^`,H`~`2`~`O,heat ---> RCOO`^`-`^

2\) Reduction to aldehyde:

`  R-CN --- (1) (`*`i`*`-Bu)`~`2`~`AlH (2) H`~`2`~`O ---> R-COH`

(*i*-Bu)~2~AlH = DIBAL-H

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

`  R-CN + R"-M --- (1) Et`~`2`~`O (2) H`~`3`~`O`^`+`^` ---> 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)

