Editing Acyl group (section)

==Reaction mechanisms==
Acyl compounds react with nucleophiles via an addition mechanism: the nucleophile attacks the carbonyl carbon, forming a [[tetrahedral intermediate]]. This reaction can be accelerated by [[acid]]ic conditions, which make the carbonyl more [[electrophile|electrophilic]], or [[base (chemistry)|basic]] conditions, which provide a more [[anion]]ic and therefore more reactive nucleophile. The tetrahedral intermediate itself can be an alcohol or [[alkoxide]], depending on the [[pH]] of the reaction.

The tetrahedral intermediate of an [[acyl]] compound contains a [[substituent]] attached to the central carbon that can act as a [[leaving group]]. After the tetrahedral intermediate forms, it collapses, recreating the carbonyl C=O bond and ejecting the leaving group in an [[elimination reaction]]. As a result of this two-step addition/elimination process, the nucleophile takes the place of the leaving group on the carbonyl compound by way of an intermediate state that does not contain a carbonyl. Both steps are [[reversible reaction|reversible]] and as a result, nucleophilic acyl substitution reactions are equilibrium processes.<ref>Wade 2010, pp. 996–997.</ref>{{Full citation needed|date=June 2017}} Because the equilibrium will favor the product containing the best nucleophile, the leaving group must be a comparatively poor nucleophile in order for a reaction to be practical.

===Acidic conditions===
Under acidic conditions, the carbonyl group of the acyl compound '''1''' is protonated, which activates it towards nucleophilic attack. In the second step, the protonated carbonyl '''2''' is attacked by a nucleophile (H−Z) to give tetrahedral intermediate '''3'''. Proton transfer from the nucleophile (Z) to the leaving group (X) gives '''4''', which then collapses to eject the protonated leaving group (H−X), giving protonated carbonyl compound '''5'''. The loss of a proton gives the substitution product, '''6'''. Because the last step involves the loss of a proton, nucleophilic acyl substitution reactions are considered catalytic in acid. Also note that under acidic conditions, a nucleophile will typically exist in its protonated form (i.e. H−Z instead of Z<sup>−</sup>).

:[[File:General Scheme for Acid Catalyzed Nucleophilic Acyl Substitution.png|A general mechanism for acid catalyzed nucleophilic acyl substitution|800px]]

===Basic conditions===
Under [[base (chemistry)|basic]] conditions, a nucleophile (Nuc) attacks the carbonyl group of the acyl compound '''1''' to give tetrahedral alkoxide intermediate '''2'''. The intermediate collapses and expels the leaving group (X) to give the substitution product '''3'''. While nucleophilic acyl substitution reactions can be base-catalyzed, the reaction will not occur if the leaving group is a stronger base than the nucleophile (i.e. the leaving group must have a higher p''K''<sub>a</sub> than the nucleophile). Unlike acid-catalyzed processes, both the nucleophile and the leaving group exist as anions under basic conditions.

:[[File:General Scheme for Base Catalyzed Nucleophilc Acyl Substitution.png|A general mechanism for base catalyzed nucleophilic acyl substitution|400px]]

This mechanism is supported by [[isotope labeling]] experiments. When [[ethyl propionate]] with an [[oxygen-18]]-labeled ethoxy group is treated with [[sodium hydroxide]] (NaOH), the oxygen-18 label is completely absent from [[propionic acid]] and is found exclusively in the [[ethanol]].<ref name=mcmurry>{{cite book|last=McMurry|first=John|title=Organic Chemistry|year=1996|publisher=Brooks/Cole Publishing Company|location=Pacific Grove, CA|isbn=0534238327|pages=[https://archive.org/details/organicchemistry00mcmu/page/820 820–821]|edition=4th|url=https://archive.org/details/organicchemistry00mcmu/page/820}}</ref>

:[[File:Nucleophilic Acyl Substitution with a Labeled Oxygen.png|Reacting isotopically labeled ethyl propionate with sodium hydroxide proves the proposed mechanism for nucleophilic acyl substitution.|600px]]