Posted by: Mark Foreman | February 4, 2016

Attack on carbonyl groups

Dear Reader,

The attack of a nueclophile on a carbonyl group is an important reaction, organic chemistry is littered with examples of carbonyl groups reacting with nucelophiles. It even pops up in interesting places such as the chemistry of the pyridines. The reaction of a nucleophile such as an amide ion with pyridine can be viewed as being like the reaction of a carbonyl. Here is the first stage of the Chichibabin reaction of pyridine and sodium amide.

The first stage of a Chichibabin reaction

The first stage of a Chichibabin reaction

Now to get us going we need to look at the list of groups, I have put the normal carboxylic acid derivatives in order of reactivity with a nucleophile. Here is the list.

List of carbonyl compounds in desending order of reactivity

List of carbonyl compounds in descending order of reactivity

Now the important thing to understand is that the pKa of the “leaving group” is increasing as we go down the list. At the top we have chloride which relates to the very strong acid hydrochloric acid while at the bottom we have an oxide group which corresponds to a very weak acid (hydroxide anion). In general if the nucelophile is the conjugate base of an acid with a higher pKa than the acid corresponding to the leaving group then the reaction is easy. If the reverse of this is true then the reaction is very hard or impossible. If the two pKas are the same then sometimes it is possible to do the reaction.

If by some miracle a chloride was to attack an ester on the carbonyl carbon then we would have the following tetrahedral intermediate.

Tetrahedral intermediate

Tetrahedral intermediate

When the negative charge on the oxygen is used to recreate the pi bond between the oxygen and the carbon (remaking the double bond) it will be much more likely that the chloride will be lost rather than the ethoxide as the chloride is far better leaving group. In general good leaving groups are the conjugate bases of strong acids, which makes them weak bases.

For example an acid chloride can react with an amine to form an amide with ease, but an amide can not react with hydrochloric acid to form an acid chloride. A second thing which contributes to the reduced reactivity of the compounds which are towards the bottom of the list is that the partial positive charge on the carbonyl carbon is very small. This small degree of positive charge on the carbonyl reduces the ability of the nucelophile to attack.

This change in the partial positive charge on the carbon explains the following reactivity series with nucleophiles such as borohydride and Grignard reagents.

Chart of carbonyl groups listed in order of reactivity

Chart of carbonyl groups listed in order of reactivity

In the near future I hope to post some more on this topic

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Categories

%d bloggers like this: