CHEMISTRY 2600. Topic #6: Reactions of Carboxylic Acid Derivatives Spring 2009 Dr. Susan Lait. Representative Carboxylic Acid Derivatives.
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Carboxylic acid derivatives are frequently grouped together because the carbonyl carbon has the same oxidation state (+3 if R-group is carbon-based; +2 for formic acid (HCO2H) derivatives) so they can be interconverted via substitution reactions.
The most common carboxylic acid derivatives include:
For these examples, note that
R groups shown in the same molecule are not necessarily the same.
R groups may be carbon-based or hydrogen.
R’ groups must be carbon-based. If they were hydrogen, that would change the functional group.
When have seen what happens when a nucleophile attacks a carbonyl compound:
A tetrahedral intermediate is formed as the nucleophile attacks the electrophilic carbon, breaking the weakest bond (the C-O pi bond). If a leaving group is present, the C-O pi bond reforms (as shown above), regenerating the carbonyl group.
This type of reaction can also be used to interconvert carboxylic acid derivatives.
We can use the leaving group’s basicity as a measure of how reactive a carboxylic acid group is to this type of substitution:
Acid Chlorides (Cl- leaves; pKa of HCl is ___)
Anhydrides (RCO2- leaves; pKa of RCO2H is ___)
Thioesters (RS- leaves; pKa of RSH is ___)
Esters (RO- leaves; pKa of ROH is ___)
Amides (R2N- leaves; pKa of R2NH is ___)
Carboxylic Acids cannot undergo this type of reaction directly.
They are deprotonated instead.
As a general rule, we can only displace a better leaving group with a poorer leaving group (and better nucleophile). So, you can make an ester by reacting an acid chloride with RO- but you cannot make an acid chloride by reacting an ester with Cl-. (The nucleophilicity of HO- is similar to that of RO-but if you add a lot of hydroxide and heat, you can use Le Châtelier’s principle to push the reaction forward slowly – even with amides.)
If we wish to use a weaker nucleophile, we need to activate the carbonyl group first. We saw how this can be done when we learned about acetals. How did we make ketones/aldehydes electrophilic enough that they could react with alcohols (which are only weakly nucleophilic)?
We can do the same thing if we wish to perform a reaction between an alcohol and a carboxylic acid, for example:
Fischer esterifications may look like straightforward substitution reactions, but they still go through a tetrahedral intermediate. Remember that SN2 reactions can only occur at tetrahedral carbon atoms; they are not an option for carbonyl groups!
While esters can be prepared directly from carboxylic acids or other esters, it’s generally easier to control the reaction when one of the more electrophilic carboxylic acid derivatives is used as the electrophile. For this reason, acid chlorides are widely used. They can be readily prepared from carboxylic acids and react with a much wider variety of nucleophiles.
To make an acid chloride from a carboxylic acid, just add thionyl chloride (SOCl2):
Similarly, thionyl bromide (SOBr2) can be used to make acid bromides, SO2 & HBr.