Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 328

Brief Organic Chemistry

Summer 2004

Lecture Notes: 6 July

© R. Paselk 2004
 
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Chemistry of the Carboxylic Acid Derivatives, cont.

Esters: Esters can be synthesized from acids, acid chlorides, or acid anhydrides, as we have seen above and previously.

Reduction to Primary Alcohols: Esters may be reduced, like acids, to primary alcohols using lithium aluminum hydride (LiAlH4) in ether, followed by aqueous acids. As with other ester reactions, the hydride attacks as a nucleophile at the carbonyl carbon:

Note that as in carboxylic acids, the reduction is selective, the double bond in this case is untouched.

Hydrolysis (acid synthesis): Water will attack nucleophilically to give acids. The reaction is catalyzed by both acids and bases. Acid catalysis works by first protonating the carboxyl oxygen to make the carbon more electrophilic, and thus more "attractive" to the water nucleophile:

With base catalysis, on the other hand, the base removes a proton from water making hydroxide, which is a better nucleophile. Base catalyzed hydrolysis is also known as saponification. We used saponification in lab to make soap from fats. The example shows tristearin saponification:

Aminolysis (amide synthesis): Amines will substitute for alcohol groups on esters to give amides:

Reaction with Grignard reagents. Recall once again that the effect of a Grignard reagent is to act like a alkyl carbanion. Thus the alkyl group becomes a good nucleophile and can attack the carbonyl carbon of the ester:

Amide Chemistry: Amides are usually synthesized by the reaction of acid chlorides with amines, as seen previously. Note that ammonia, monosubstituted amines, and disubstituted amines all work.

Hydrolysis of amides to give acids: The hydrolysis of amides is catalyzed by both acids in aqueous solutions:

and bases in aqueous solutions:

Reduction of amides to amines: As nitrogen analogs of carboxylic acids, amides are reduced to the nitrogen analog of an alcohol, an amine:

 

Enols and Enolate Chemistry

Keto-Enol Tautomerism: Recall keto-enol tautomers from our discussion of aldehydes and ketones:

As you might expect keto-enol tautomerism is catalyzed by both acids and bases: acids protonate the hydroxyl group, bases pull off the alpha proton (similar to base catalysis of E1 reactions):

Note the regeneration (on the second arrow) of the catalyst (used up on the first arrow) in each case.

Enols generally cannot be isolated due to the low concentrations. However, enolate ions can be isolated since the ionic form can be stable (depends on conditions). Enolate ion formation is possible because the alpha-hydrogens are slightly acidic. Thus they can be abstracted by strong bases to give alpha-carbon carbanions. The basis of this acidity is the stability of the carbanion, as predicted by the possible resonance forms:

Enolate ions are more reactive than enols - they are stronger nucleophiles (more electron density) and they will be in higher concentration.

Lets look at a few acids, and note the factors which contribute to their acidity. Note that the main factor in predicting the acidity of a molecule is the stability of the ionized species. Thus we want to look at the dissociated molecule and ask if it has stabilizing mechanisms such as resonance, electron withdrawing groups etc. Recall also that resonance structures are better when they are of close or identical energies. (Thus carboxylate ions are particularly stable because the two structures are identical, and thus the electrons are equally spread over both oxygens.)

Try to account for the relative acidities of the carbon based molecules in the table below:

 Type of Compound Compound pKa  Ka
 Carboxylic acid CH3COOH 4.75 1.8 x10-5
1,3-Diketone CH2(COR)2  9  10-9

 Phenol

C6H5 OH

9.95

 1.1 x10-10
1,3-Diester CH2(COOR)2  13   10-13
Water  HOH 15.74 1.8 x10-16 
1° Alcohol CH3CH2 OH 16 10-16 
Acid chloride CH3COCl 16 10-16 
Aldehyde CH3CHO 17 10-17 
Ketone CH3COCH3 19 10-19 
Ester CH3COOCH3 25  10-25
Nitrile CH3CN 25  10-25
Dialkylamide CH3CON(CH3)2 30  10-30
Ammonia NH3 35  10-35 

 Alkene

RC=CH2

 44

 10-44 
Alkane CH3CH3   60 10-60  

 

Let's look at the chemistry expected from the enols and enolate ions.

Alpha-Substitution Reactions: Because of the double bonds in enols we should expect alkene type chemistry. That is enols should react as nucleophiles due to the electron-rich double bond. We can think of the enol as attacking via the enol (alkene-like) form or the carbanion resonance form:

Enols can react with halogens in a manner reminiscent of the reaction of alkenes. The reactions of enols differ from alkenes in that the alkene intermediate carbocation reacts with a nucleophile to give an addition product. Enols, on the other hand, tend to lose the intermediate hydroxyl proton to give back a carbonyl compound:

Halogenation: Aldehydes and ketones react with chlorine, bromine, and iodine in acidic solution to make the respective halogenated products. Bromine is the most commonly used halogen, and acetic acid is a frequent solvent:

 

 

Enolate and Carbonyl Condensation Reactions

Enolate Reactions: Last time we looked at the acidity of enols and the resulting formation of enolate ions. The enolate ion is stabilized by resonance between two charged forms which can be considered vinylic alkoxides or alpha-keto carbanions:

Thus the enolate ion can act as a nucleophile by reacting either with the oxygen (alkoxide form) or the alpha carbon (carbanion form). Reactions with the alpha carbon are more common, and the only reactions we will look at.

Alkylation: Enolate ions are good nucleophiles. An enolate carbanion can attack an alkyl halide in an SN2 reaction:

Note that this reaction, like all other SN2 reactions, is only successful with methyl or primary alkyl groups. Secondary and tertiary halides lead to E2 elimination reactions instead.


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Last modified 6 July 2004