Chapter 10 + acetylcholine Clayden Organics 大学有机化学

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Nucleophilic Substitution at the Carbonyl (C=O) Group
Based on Clayden’s Organic Chemistry, Chapter 10
The aims of this chapter are to learn …..
• What makes a good nucleophile? • What makes a good leaving group ?
the unstable intermediate formed is known as tetrahedral intermediate, because the trigonal (sp2) C atom of the carbonyl group has become a tetrahedral (sp3) C atom
How do we know that the tetrahedral intermediate exists?
This result cannot be explained by direct substitution of X by H2O, but is consistent with the existence of an intermediate in which the unlabelled 16O and labelled 18O can ‘change places’.
Acetyl chloride and acid anhydride react with alcohol in the presence of a base to give an acetate ester
Hale Waihona Puke addition of the nucleophilic alcohol to the electrophilic C=O
- amines react with acetic anhydride quite rapidly at room temperature (reaction complete in a few hours); - alcohols react extremely slowly in the absence of a base. - alkoxide anion reacts with acetic anhydride extremely rapidly - the reactions are often complete within seconds at 0 °C. There is no need to deprotonate an alcohol completely to increase its reactivity: just a catalytic quantity of a weak base can do this job by removing the alcohol’s proton as it adds to the carbonyl group.
In Chapters 6 and 9:
Nu = -CN, H- (NaBH4, LiAlH4),
RMgX, RLi (carbon nucleophile), H2O, ROH (oxygen nucleophile)
Nucleophilic Addition to a Carbonyl Group
Pyridine acts as a nucleophile to speed up the reaction, yet is unchanged by the reaction a nucleophilic catalyst.
How do we know that the tetrahedral intermediate exists?
pKa is a Useful Guide to Leaving Group Ability
the stability of the tetrahedral intermediate depends on how good the groups attached to the new tetrahedral carbon atom are at leaving with the negative charge.
Amines react with acyl chlorides to give amides
react with amines (such as ammonia) to give amides
Factors other than leaving group ability can be important
Groups that can be expelled from molecules, usually taking with them a negative charge, leaving groups.
Does not go back to starting materials. A new compound (a ketone) is made substitution reaction
pKaH is a guide to nucleophilicity
- good nucleophiles are bad leaving groups
- bases with high pKaH are bad leaving groups and they are, in general, good nucleophiles towards the carbonyl group
Carboxylic Acid Derivatives
Leaving groups are anions such as Cl–, RO–, and RCO2– that can be expelled from molecules taking their negative charge with them most of the starting materials for, and products of, these substitutions will be carboxylic acid derivatives, with the general formula RCOX.
The lone pairs of a carbonyl group may be protonated by strong acid: pKa of protonated acetone is –7, so, 1M HCl (pH 0) would protonate only 1 in 107 molecules of acetone.
Addition of a Grignard reagent to an aldehyde or ketone gives a stable alkoxide, which can be protonated with acid to produce an alcohol. The same is not true for addition of an alcohol to a carbonyl group in the presence of base because RO– is easily expelled from the molecule. The energy released in forming the C=O bond
removes the proton from the alcohol
With an acyl chloride, the alkoxide intermediate is also unstable. It collapses by an elimination reaction, losing chloride ion, and forming the ester. Chloride is the leaving group here - it leaves with its negative charge.
Amides are the least reactive towards nucleophiles because they exhibit the greatest degree of delocalization.
In an amide, the lone pair on the nitrogen atom can be stabilized by overlap with the p* orbital of the carbonyl group—this overlap is best when the lone pair occupies a p orbital
Reactivities of carboxylic acid derivatives
Recap: hierarchy is (i) due to how good the leaving group is (the ones at the top are best), and (ii) due to how good the nucleophile needed to make the derivative is
Pyridine is more nucleophilic than alcohol, and it attacks the acyl chloride rapidly,
forming a highly electrophilic intermediate which subsequently reacts with the alcohol to give the ester.
•Tetrahedral intermediate
• How to make acid derivatives • Reactivity of acid derivatives • How to make ketones from acids • How to reduce acids to alcohols