Puan Rozaini Abdullah School of Bioprocess Engineering ERT 102 ORGANIC CHEMISTRY SEM 1 2012/2013 chapter 2 BIOPROCESS ENGINEERING Puan Rozaini Abdullah School of Bioprocess Engineering

Carboxylic Acid Carboxylic acids (RCO2H) are a common and important functional group (e.g. amino acids, fatty acids etc.) and provide the point of access to the carboxylic acids derivatives (acyl chlorides, acid anhydrides, esters, amides etc.). Carboxylic acids are the most acidic of the common organic functional groups. Structure: The CO2H unit is planar and consistent with sp2 hydridization and a resonance interaction of the lone pairs of the hydroxyl oxygen with the p system of the carbonyl.

Example of Carboxylic Acid:

Physical Properties: The polar nature of both the O-H and C=O bonds (due to the electonegativity difference of  the atoms) results in the formation of strong hydrogen bonds with other carboxylic acid molecules or other H-bonding systems (e.g. water). The implications are: higher melting and boiling points compared to analogous alcohols high solubility in aqueous media hydrogen bonded dimers in gas phase and dimers or aggregates in pure liquid

Reaction of Carboxylic Acid: Conversion carboxylic acid to : 1. Ester 2. Acyl halide 3. Acid Anhydrides 4. Amides. Reduction to alcohol Hell-Volhard-Zelinsky reaction Decarboxylation reaction

Relative reactivity of carboxylic acid: The image shows the electrostatic potential for acetic acid (ethanoic acid). The more red an area is, the higher the electron density and the more blue an area is, the lower the electron density.  There is low electron density (blue) on H atom of the -CO2H group alcohol, i.e. H+ character.  The H atom of the RCO2H is acidic (pKa ~ 5). The most important reactions of carboxylic acids converts them into carboxylic acid derivatives such as acyl halides, esters and amides via nucleophilic acyl substitution reactions.

Relative reactivity of carboxylic acid: The image shows the electrostatic potential for the acetate ion (ethanoate ion) The more red an area is, the higher the electron density and the more blue an area is, the lower the electron density.  There is high electron density (red) on both O atoms of the -CO2- group alcohol, i.e. resonance and basic or nucleophilic behavior

Relative reactivity of carboxylic acid derivatives: Carboxylic acid derivatives react tend to react via Nucleophilic Acyl substitution where the group on the acyl unit, R-C=O undergoes substitution:

The observed reactivity order is shown below: It is useful to view the carboxylic acid derivatives as an acyl group, R-C=O,  with a different substituent attached.  The important features of the carboxylic acid derivatives that influence their reactivity are governed by this substituent in the following ways:  the effect the substituent has on the electrophilicity of the carbonyl C? if the substituent is electron donating, then the electrophilicity is reduced, \ less reactive if the substituent is electron withdrawing, the electrophilicity is increased, \ more reactive the ability of the substituent to function as a leaving group.

Leaving Group Availbility Derivative Substituent Electronic effect Leaving Group Availbility Relative Reactivity Acyl chloride -Cl withdrawing group (inductive) very good 1 (most) Anhydride -OC=OR donating good 2 Ester -OR strongly donating poor =3 Acid -OH Amide -NH2 very strongly donating very poor 4 Carboxylate -O- very, very strongly donating appalling ! 5 (least)

Preparation of Acyl Chlorides Reaction type:  Nucleophilic Acyl Substiution Acyl chlorides are prepared by treating the carboxylic acid with thionyl chloride, SOCl2, in the presence of a base. Acyl chlorides are by far the most commonly encountered of the acyl halides.

Esterification Reaction: Reaction type:  Nucleophilic Acyl Substitution This reaction is also known as the Fischer esterification. Esters are obtained by refluxing the parent carboxylic acid with the appropriate alcohol with an acid catalyst. The equilibrium can be driven to completion by using an excess of either the alcohol or the carboxylic acid, or by removing the water as it forms. Alcohol reactivity order :  CH3OH > 1o > 2o > 3o (steric effects) If a compound contains both hydroxy- and carboxylic acid groups, then cyclic esters or lactones can form via an intramolecular reaction. Reactions that form 5- or 6-membered rings are particularly favorable.

Step 1: An acid/base reaction Step 1: An acid/base reaction. Protonation of the carbonyl makes it more electrophilic. Step 2: The alcohol O functions as the nucleophile attacking the electrophilic C in the C=O, with the electrons moving towards the oxonium ion, creating the tetrahedral intermediate. Step 3: An acid/base reaction. Deprotonate the alcoholic oxygen. Step 4: An acid/base reaction. Need to make an -OH leave, it doesn't matter which one, so convert it into a good leaving group by protonation. Step 5: Use the electrons of an adjacent oxygen to help "push out" the leaving group, a neutral water molecule. Step 6: An acid/base reaction. Deprotonation of the oxonium ion reveals the carbonyl in the ester product.

Hell-Volhard-Zelinsky Reaction Reaction type: Substitution Reagents most commonly : Br2 and either PCl3, PBr3 or red phosphorous in catalytic amounts. Carboxylic acids can be halogenated at the C adjacent to the carboxyl group. This reaction depends on the enol type character of carbonyl compounds. The product of the reaction, an a-bromocarboxylic acid can be converted via substitution reaction to a-hydroxy- or a-amino carboxylic acids.

Synthesis of Paracetamol & Aspirin: Acetic Anhydride Salicylic acid Acetyl salicylic acid, aspirin Acetic Acid

Synthesis of Paracetamol & Aspirin: Para-nitrophenol Orto-nitrophenol 4-aminophenol Paracetamol N-(4-hydroxyphenyl)ethanamide