Putting all we have learnt into one diagram:
The simplest method to make a carboxylic acid derivative very electrophillic is to hydrolyze it with water , then convert it to an acid chloride.
Making acid chlorides from carboxylic acids
The use of this should be obvious - Cl- is a much better leaving group than OH-.
1. Thionyl chloride
This is a fun volatile liquid with a choking smell. Industrial production is controlled under the Chemical Weapons Convention, something nearly every country has agreed to. This reagent is probably the first compound of this calibre which you will encounter in an undergrad lab.
It is generally the preferred reagent for converting COOH to COOCl since both its byproducts - HCl and SO2 - are gaseous.
Mechanism:
The reaction is driven by loss of SO2 and HCl gas from the reaction mixture.
2. Phosphorus pentachloride
Oxalyl chloride is the diacid chloride of oxalic acid. It is a colorless liquid with a sharp smell.
Dimethylformamide is also colorless. It has no odor unless some of it has degraded to dimethylamine, which has a fishy smell. It is often used as a solvent - one with a low evaporation rate.
Oxalyl chloride also has gaseous by-products. But it also has a minor byproduct which is a potent carcinogenic, and it is a lot more expensive.
Mechanism:
1. Thionyl chloride
This is a fun volatile liquid with a choking smell. Industrial production is controlled under the Chemical Weapons Convention, something nearly every country has agreed to. This reagent is probably the first compound of this calibre which you will encounter in an undergrad lab.
It is generally the preferred reagent for converting COOH to COOCl since both its byproducts - HCl and SO2 - are gaseous.
Mechanism:
The reaction is driven by loss of SO2 and HCl gas from the reaction mixture.
2. Phosphorus pentachloride
This is a white solid, though many samples are light yellow from HCl contamination.
The mechanism is extremely similar to thionyl chloride. I suggest trying to guess it yourself and see how it compares to the one below:
3. Oxalyl chloride plus dimethylformamide (DMF)
Dimethylformamide is also colorless. It has no odor unless some of it has degraded to dimethylamine, which has a fishy smell. It is often used as a solvent - one with a low evaporation rate.
Oxalyl chloride also has gaseous by-products. But it also has a minor byproduct which is a potent carcinogenic, and it is a lot more expensive.
Mechanism:
Notice how this creates a highly electrophillic intermediate which attacks the carboxylic acid. It is then kicked off by a chloride ion, producing an acid chloride while regenerating the catalyst.
Mandelic acid
Mandelic acid can be made from benzaldehyde.
Using previous posts you should be able to suggest the synthesis. It takes two or three steps.
Solution:
Using previous posts you should be able to suggest the synthesis. It takes two or three steps.
Solution:
Mandelic acid is an antibacterial which can be used orally. It is also used in skin cream to prevent acne and wrinkles.
Hydrolysis of nitriles
Nitriles can be viewed as primary amide which has lost a molecule of water:
Reacting a primary amide with a dehydrating reagent is one way nitriles can be made.
Likewise, nitriles can be made into primary amides by acid-catalysed hydrolysis. Mechanism:
Reacting a primary amide with a dehydrating reagent is one way nitriles can be made.
Likewise, nitriles can be made into primary amides by acid-catalysed hydrolysis. Mechanism:
Of course we also know that if the conditions are vigorous enough, the amide will hydrolyse into a carboxylic acid and ammonia. So overall a long acid reflux can turn a C≡N into a COOH.
Hydrolysing amides
There are two ways of doing this. The first one is protonating the C=O to make it more electrophillic.
The second is brute force by OH-:
The second is brute force by OH-:
Both methods require vigorous conditions - high acid/base concentration, high heat, and long reaction times. Secondary and tertiary amides hydrolyse even more slowly.
A secret weapon to force the hydrolysis of a tertiary amide is to use a very strong base such as Potassium tert-butoxide. This deprotonates the tetrahedral intermediate:
It may be difficult to make an amine anion leave, but something has to, and O2- or a carbanion are much harder to push off.
Using an acid to aid attack on C=O
This has two uses:
1. It can protonate an electrophile, making it more open to attack.
2. It can protonate a leaving group - turning a poor leaving group into a good one
Both of these effects are shown in the most common example of acid catalysts - the formation of an ester:
Alternatively the OR in the tetrahedral intermediate could be protonated instead - which would lead back to the reactant. We drive the formation of product by removing water using distillation or a drying agent.
We can also use an excess of one of the reactants. If we want to fully esterificate an expensive carboxylic acid, we can use an excess of alcohol, and vice versa.
To reverse the reaction, we can use an excess of water.
The same principles can be used to convert the ester of one alcohol into the ester of another. For example, the reaction below can be driven to the right by distilling off methanol:
Another example of transesterifaction is in the commercial production of PET (polyethylene terephthalate) which is the polymer used in plastic drink bottles. It is the ester of terephalic acid and ethylene glycol.
It is produced commercially by transesterifying dimethyl terephthalate, distilling off methanol to drive the reaction.
I don't know why this process is cheaper than making it directly.
1. It can protonate an electrophile, making it more open to attack.
2. It can protonate a leaving group - turning a poor leaving group into a good one
Both of these effects are shown in the most common example of acid catalysts - the formation of an ester:
Alternatively the OR in the tetrahedral intermediate could be protonated instead - which would lead back to the reactant. We drive the formation of product by removing water using distillation or a drying agent.
We can also use an excess of one of the reactants. If we want to fully esterificate an expensive carboxylic acid, we can use an excess of alcohol, and vice versa.
To reverse the reaction, we can use an excess of water.
The same principles can be used to convert the ester of one alcohol into the ester of another. For example, the reaction below can be driven to the right by distilling off methanol:
Another example of transesterifaction is in the commercial production of PET (polyethylene terephthalate) which is the polymer used in plastic drink bottles. It is the ester of terephalic acid and ethylene glycol.
It is produced commercially by transesterifying dimethyl terephthalate, distilling off methanol to drive the reaction.
I don't know why this process is cheaper than making it directly.
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