Reactions of Carbonyl Groups

Nucleophilic Addition Reactions

The nucleophilic addition reaction involves the addition of a nucleophile to the electrophilic carbon of the carbonyl group. The nucleophile employs its electron pair to attack the carbonyl carbon and thus the two electrons that form the carbon-oxygen double bond move onto the electronegative oxygen atom – in this manner a stabilised oxyanion ion is formed. The nucleophile approaches the carbonyl carbon in the p-plane at an angle of 109º (the Bürgi-Dunitz angle) above or below the plane formed by the substituents on the carbonyl group. During the reaction, the carbon is rehybridised from sp² to sp³ and thus the initial product has a tetrahedral geometry. The equilibrium reaction will be displaced to the right hand side in favour of the tetrahedral intermediate and the overall result is 1,2-addition across the carbonyl group. The tetrahedral intermediate thus formed can then undergo either of two reactions: be protonated to form the corresponding alcohol or expel oxygen in either the form of hydroxide anion or water to form a system that features a new double bond

Nucleophilic Acyl Substitution Reactions

Nucleophilic acyl substitution reactions are similar to nucleophilic addition reactions in that the first step of the mechanism involves nucleophilic attack at the electrophilic carbonyl carbon centre. However, if the carbonyl carbon has a substituent that can act as a leaving group (i.e. amides, esters, acid chlorides, acid anhydrides) a different reaction path is followed. The tetrahedral intermediate is just an intermediate which reacts further by expulsion of the leaving group and formation of a new carbonyl compound is formed. The overall effect is the substitution of the leaving group by the attacking nucleophile (similar in nature to an S_N2 reaction but involving a different substitution mechanism).

Y = NH₂ (Amide), OCOR’ (Anhydride), Cl (Chloride), OR’ (Ester)

Substituent Effects

1. Influence of the carbonyl group on rate of nucleophilic acyl substitution reactions

• Oxygen is more electronegative than chlorine and has a greater inductive electron withdrawing effect than chlorine. However, this inductive electron withdrawing effect is overruled by the mesomeric electron donating effect of oxygen.

• Nitrogen is less electronegative than oxygen and also has greater mesomeric electron donation. Thus esters are more reactive than amides.
• Mesomeric electron donation by -NR₂' is greater than -NH₂ due to inductive electron donation by R'.
• Step 1 (addition) is generally the rate determining step and the above effects of Y control the rate. However, in some cases, Step 2 (elimination) is important in the rate determination and the overall reaction rate is affected by the relative leaving group ability of Y. In this case resonance stabilisation and ready solvation of Y^– will affect the rate of the reaction.
• The carbonyl substituent ‘R’ affects the addition-elimination process via:
  • Electronic effects: the electron withdrawing ability of R increases the d+ve charge on the carbonyl carbon and therefore enhances the rate of reaction.
  • Steric effects: an increase in the bulk of the carbonyl substituent ‘R’ decreases the rate of reaction as the electrophilic carbonyl group will be less accessible

2. Influence of the nucleophile on rate of nucleophilic acyl substitution reactions

• Nucleophilicity
• Size of the nucleophilic species (reduction of steric strain)

As a result of the factors listed above the following reactions involving carbonyl groups occur very readily.

• Hydrolysis of Acid Chlorides: RCOCl Acid chlorides are readily hydrolysed in aqueous solution.
• Hydrolysis of Carboxylic Esters: RCOOR' Typically carboxylic esters are hydrolysed using aqueous acid or aqueous base (referred to as saponification)

  Base catalysis: B_AC2(bimolecular base–catalysed acyl cleavage)

The ¹⁸O isotope label shows up entirely in R'OH proving that elimination occurs via C-OR' bond fission. NOT O-R'. (Consistent with the general mechanism of addition-elimination)

Acid catalysis: A_AC2 (Bimolecular acid–catalysed acyl cleavage)

Base catalysis is usually better for ester saponification as the reverse reaction as the corresponding acid product is effectively totally deprotonated to RCO₂^–. Therefore it will not react with R'OH as it is far less susceptible to nucleophilic attack. Hydrolysis of Amides: RCONH₂ The hydrolysis of amides requires much more vigorous conditions – commonly heating in acidic or bas ic solution is necessary to achieve effective conversion.