1. CHEMISTRY 2600 Topic #6: Reactions of Carboxylic Acid Derivatives Spring 2009 Dr. Susan Lait

2. 2 Representative Carboxylic Acid Derivatives 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 (HCO 2 H) 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.

3. 3 Interconverting Carboxylic Acid Derivatives 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.

4. 4 Interconverting Carboxylic Acid Derivatives Compare what happens when we use methoxide instead: Again, a tetrahedral intermediate is formed as the nucleophile attacks the electrophilic carbon, breaking the weakest bond (the C-O pi bond). The C-O pi bond reforms, regenerating the carbonyl group. We can also see that this reaction would not have worked as well if we replaced the acid chloride with an amide. Why not?

5. 5 Interconverting 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; pK a of HCl is ___) Anhydrides (RCO 2 - leaves; pK a of RCO 2 H is ___) Thioesters (RS - leaves; pK a of RSH is ___) Esters (RO - leaves; pK a of ROH is ___) Amides (R 2 N - leaves; pK a of R 2 NH 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.)

6. 6 Interconverting Carboxylic Acid Derivatives Which of the following reactions would you expect to work well? For those that will, draw the products.

7. 7 Interconverting Carboxylic Acid Derivatives Reaction of an ester with hydroxide is called a saponification (“soap making”) reaction. Acidic work up is necessary if you wish to obtain the carboxylic acid rather than a carboxylate salt. If, on the other hand, you want to make soap, the carboxylate salt is your target: R is an alkyl chain (typically 15-25 carbon atoms long). It may include double bonds (if an unsaturated fat was used).

8. 8 Interconverting Carboxylic Acid Derivatives Amines are good enough nucleophiles that they can attack most carboxylic acid derivatives without being deprotonated first. Reaction of an ester with an amine (or NH 3 ) is termed ammonolysis.

9. 9 Esters from Carboxylic Acids 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: This is known as a Fischer esterification.

10. 10 Esters from Carboxylic Acids Fischer esterifications may look like straightforward substitution reactions, but they still go through a tetrahedral intermediate. Remember that S N 2 reactions can only occur at tetrahedral carbon atoms; they are not an option for carbonyl groups!

11. 11 Esters from Carboxylic Acids If the alcohol and carboxylic acid are both in the same molecule, the product of an esterification will be a lactone (a cyclic ester). What are the products of the following reactions:

12. 12 Esters from Other Esters We can perform transesterification reactions in a similar way: Note that these are equilibrium conditions. How do we favour reaction in the forward direction?

13. 13 Acid Chlorides from Carboxylic Acids 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 (SOCl 2 ): Similarly, thionyl bromide (SOBr 2 ) can be used to make acid bromides, SO 2 & HBr.

14. 14 Acid Chlorides from Carboxylic Acids First, the carboxylic acid attacks the SOCl 2 : Then the chloride ion produced attacks the adduct: Finally, there is a rearrangement, breaking the adduct into the acid chloride and two gases (SO 2 and HCl):

15. 15 Acid Chlorides from Carboxylic Acids Draw the products of each of the following reaction sequences:

16. 16 Acid Chlorides from Carboxylic Acids How would you make the molecule below? You may use benzyl alcohol as well as any inorganic reagents you like (and/or organic reagents that don’t add carbon atoms to the molecule):

17. 17 Amines from Amides We have seen that LiAlH 4 can be used to reduce a variety of carbonyl groups. This includes esters and carboxylic acids (as seen previously). It also includes amines: