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.

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
CH₃COO-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

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 = butonitrile 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 be 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.

Reactions of Carboxylic Acids and Their Derivatives

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 

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 for this reaction to work)

     RCOCH2COOH   --- heat --->  R-COCH3  +  CO2      HOCOCH2COOH  --- heat --->  CH3COOH  +  CO2 

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 

[edit] 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

Dicarboxylic acid

Dicarboxylic acids are organic compounds that contain two carboxylic acid functional groups. In molecular formulae for dicarboxylic acids, these groups are often written as HOOC-R-COOH, where R may be an alkyl, alkenyl, alkynyl, or aryl group. Dicarboxylic acids can be used to prepare copolymers such as polyamides and polyesters.

In general, dicarboxylic acids show the same chemical behaviour and reactivity as monocarboxylic acids. The ionization of the second carboxyl group occurs less readily than the first one. This is because more energy is required to separate a positive hydrogen ion from the anion than from the neutral molecule.

A mnemonic to aid in remembering the order of the common nomenclature for the first six dicarboxylic acids is "Oh my, such great apple pie!" (oxalic, malonic, succinic, glutaric, adipic, pimelic). A variant adds "Sweet as sugar!" (suberic, azelaic, sebacic) to the end of the mnemonic. An additional way of remembering the first six dicarboxylic acids is by simply recalling the acronym OMSGAP, which is a simplification of the previously described mnemonic device.

When one of the carboxy groups is replaced with an aldehyde group, the resulting structure is called a "aldehydic acid".

Simple forms of dicarboxylic acids

Short-chain dicarboxylic acids are of great importance in the general metabolism and up to n=3 they cannot be considered as lipids since their water solubility is important. The simplest of these intermediates is oxalic acid (n=0), the others are malonic (n=1), succinic (n=2) and glutaric (n=3) acids.

The other lipid members of the group found in natural products or from synthesis have a "n" value from 4 up to 21.
Adipic acid (n=4) : Despite its name (in Latin adipis is fat), this acid (hexanedioic acid) is not a normal constituent of natural lipids but is a product of oxidative rancidity (lipid peroxidation). It was obtained [1] by oxidation of castor oil with nitric acid (splitting of the carbon chain close to the OH group). Synthesized in 1902 from tetramethylene bromide, it is now obtained by oxidation of cyclohexanol or cyclohexane. It has several industrial uses in the production of adhesives, plasticizers, gelatinizing agents, hydraulic fluids, lubricants, emollients, as an additive in the manufacture of some form of nylon (nylon-6,6), polyurethane foams, leather tanning, urethane and also as an acidulant in foods. Adipic acid is used after esterification with various groups such as dicapryl, di(ethylhexyl), diisobutyl, and diisodecyl.
Pimelic acid (n=5) : this acid (heptanedioic acid), from the Greek pimelh (pimele fat), as adipic acid, was isolated from oxidized fats. It was obtained in 1884 by Ganttner F et al.[2] as a product of ricinoleic acid (hydroxylated oleic acid) from castor oil.
Suberic acid (n=6) : it was firstly produced by nitric acid oxidation of cork (Latin suber) material and then from castor oil [3]. The oxidation of ricinoleic acid produces, by splitting at the level of the double bond and at the level of the OH group, at the same time, suberic acid (octanedioic acid) and the next homologue azelaic acid. Suberic acid was used in the manufacture of alkyd resins and in the synthesis of polyamides leading to nylon.
Azelaic acid (n=7) : nonanedioic acid is the best known dicarboxylic acid. Its name stems from the action of nitric acid (azote, nitrogen, or azotic, nitric) oxidation of oleic or elaidic acid. It was detected among products of rancid fats [4]. Its origin explains for its presence in poorly preserved samples of linseed oil and in specimens of ointment removed from Egyptian tombs 5000 years old [5]. Azelaic acid was prepared by oxidation of oleic acid with potassium permanganate [6], but now by oxidative cleavage of oleic acid with chromic acid or by ozonolysis. Azelaic acid is used, as simple esters or branched-chain esters) in the manufacture of plasticizers (for vinyl chloride resins, rubber), lubricants and greases. Azelaic acid is now used in cosmetics (treatment of acne). It displays bacteriostatic and bactericidal properties against a variety of aerobic and anaerobic micro-organisms present on acne-bearing skin. . Azelaic acid was identified as a molecule that accumulated at elevated levels in some parts of plants and was shown to be able to enhance the resistance of plants to infections [7].
Sebacic acid (n=8) : decanedioic acid was named by Thenard LJ (1802) from the Latin sebaceus(tallow candle) or sebum (tallow) in reference to its use in the manufacture of candles. Thenard LJ isolated this compound from distillation products of beef tallow. In 1954, it was reported that it was produced in excess of 10,000 tons annually by alkali fission of castor oil [8]. Sebacic acid and its derivatives, as azelaic acid, have a variety of industrial uses as plasticizers, lubricants, diffusion pump oils, cosmetics, candles, etc. It is also used in the synthesis of polyamide, as nylon, and of alkyd resins. An isomer, isosebacic acid, has several applications in the manufacture of vinyl resin plasticizers, extrusion plastics, adhesives, ester lubricants, polyesters, polyurethane resins and synthetic rubber.
Dodecanedioic acid (n=10) : that acid is used in the production of nylon (nylon-6,12), polyamides, coatings, adhesives, greases, polyesters, dyestuffs, detergents, flame retardants, and fragrances. It is now produced by fermentation of long-chain alkanes with a specific strain of Candida tropicalis [9]. Its monounsaturated analogue (traumatic acid) is described below.