Tetrahedral intermediate acyl chlorides

In the conversion of an acyl chloride into an ester, the nucleophilic alcohol attacks the carbonyl carbon of the acyl chloride. Because the protonated ether group is a strong acid (Section 1.17), the tetrahedral intermediate loses a proton. Chloride ion is expelled from the deprotonated tetrahedral intermediate because chloride ion is a weaker base than the alkoxide ion. 

FIGURE 20 2 Hydrolysis of an acyl chloride proceeds by way of a tetrahedral intermediate For mationofthe tetrahedral intermediate is rate determining... 

The sp hybridized carbon of an acyl chloride is less sterically hindered than the sp hybridized carbon of an alkyl chloride making an acyl chloride more open toward nude ophilic attack Also unlike the 8 2 transition state or a carbocation intermediate m an Stvfl reaction the tetrahedral intermediate m nucleophilic acyl substitution has a stable arrangement of bonds and can be formed via a lower energy transition state... 

There are large differences in reactivity among the various carboxylic acid derivatives, such as amides, esters, and acyl chlorides. One important factor is the resonance stabilization provided by the heteroatom. This decreases in the order N > O > Cl. Electron donation reduces the electrophilicity of the carbonyl group, and the corresponding stabilization is lost in the tetrahedral intermediate. 

The characteristic reaction of acyl chlorides, acid anhydrides, esters, and amides is nucleophilic acyl substitution. Addition of a nucleophilic reagent Nu—H to the carbonyl group leads to a tetrahedral intermediate that dissociates to give the product of substitution ... 

Conversion of Acid Halides into Acids Hydrolysis Acid chlorides react with water to yield carboxylic acids. This hydrolysis reaction is a typical nucleophilic acyl substitution process and is initiated by attack of water on the acid chloride carbonyl group. The tetrahedral intermediate undergoes elimination of Cl and loss of H+ fo give the product carboxylic acid plus HC1. 

Conversion of Acid Chlorides into Alcohols Reduction Acid chlorides are reduced by LiAJH4 to yield primary alcohols. The reaction is of little practical value, however, because the parent carboxylic acids are generally more readily available and can themselves be reduced by L1AIH4 to yield alcohols. Reduction occurs via a typical nucleophilic acyl substitution mechanism in which a hydride ion (H -) adds to the carbonyl group, yielding a tetrahedral intermediate that expels Cl-. The net effect is a substitution of -Cl by -H to yield an aldehyde, which is then immediately reduced by UAIH4 in a second step to yield the primary alcohol. 

Acid chlorides, RCOCl, undergo ready attack by weaker nucleophiles, e.g. H2O, ROH. The question then arises whether, with the better potential leaving group Cl , the reactions of acid chlorides could proceed either via a single step 8 2 type pathway (cf. p. 78) involving a T.S., in which attack by and loss of Q are essentially synchronous or via an 8 1 type pathway (cf. p. 79) in which the slow step is RCOCl RCO Cl , followed by fast attack by Y on the acyl cation, RCO . In fact, most reactions of acid chlorides probably proceed via the now familiar tetrahedral intermediate pathway, though there may be some exceptions. 

This follows, since, if step C is slow, step B must also be slow and thus the addition intermediate would accumulate. Satchell found no spectrophoto-metric or kinetic evidence for this with either chloracetyl or /3-chloropropionyl chlorides. This conclusion is obviously of wide potential significance in the hydrolyses of acyl derivatives and even the observation of oxygen exchange during solvolysis (one of the main supports of the tetrahedral intermediate postulate) does not rule reaction (26) out, since the acylation could remain synchronous in part. 

Primary or secondary amine Acyl chloride Tetrahedral intermediate Amide... 

A key intermediate of the esterification in Figure 9.16 is the iminium ion F. It is identical to the iminium ion B in Figure 6.11, which represents the activated carboxylic acid in the DMF-catalyzed conversion of carboxylic acids into acid chlorides. Thus, the iminium ion F in Figure 9.16 is a potent acylating agent. As such, it reacts with the methoxide ion, a stoichiometric by-product of its formation reaction, via the tetrahedral intermediate C to furnish the corresponding carboxylic acid methyl ester and DMF. 

A complementary access to alkoxy- and aminocarbene complexes ( Semmelhack-Hegedus route ) involves the addition of the pentacarbonylchromate dianion 18 (obtained from the reduction of hexacarbonylchromium with C8K) to carboxylic acid chlorides and amides [27] (Scheme 10). While alkylation of acyl chromate 19 leads to alkoxycarbene complexes 12, addition of chromate dianion 18 to carboxylic amides generates the tetrahedral intermediates 20, which are deoxygenated by trimethylsilyl chloride to give amino carbene complexes 14. 

Propose a mechanism for the reaction of benzoic acid with oxalyl chloride. This mechanism begins like the thionyl chloride reaction, to give a reactive mixed anhydride. Nucleophilic acyl substitution by chloride ion gives a tetrahedral intermediate that eliminates a leaving group, which then fragments into carbon dioxide, carbon monoxide, and chloride ion. 

We can use pKa to predict what happens if we react an acyl chloride with a carboxylate salt. We expect the carboxylate salt (here, sodium formate, or sodium methanoate, HCC Na) to act as the nucleophile to form a tetrahedral intermediate, which could collapse in any one of three ways. 

Protonation of the unstable intermediate (by the HC1 just produced) gives an electrophile powerful enough to react even with the weak nucleophile Cl" (low pi Hi poor nucleophilicity). The tetrahedral intermediate that results can collapse to the acyl chloride, sulfur dioxide, and hydrogen chloride. This step is irreversible because SC)2 and HCl are gases that are lost from the reaction mixture. 

Similar experiments have indicated the reversible formation of tetrahedral intermediates in hydrolysis of other esters, amides, anhydrides, and acid chlorides, and are the basis of the general mechanism we have shown for nucleophilic acyl substitution. 

AnoAer procedure which was thought to pass through a mixed phosphoms anhydride was the acylation of Grignard reagents with an adduct formed between lithium carboxylates and triphenylphosphine dichloride (Scheme 26). The betaine (70) was the proposed tetrahedral intermediate however, since no evidence is provided, the reaction may have also proceeded by way of the acid chloride. Surprisingly, good yields of ketone are preserved even in the presence of excess nucleophile and no tertiary alcohol formation was observed. Triethylamine can be used for prior deprotonation of the carboxylic acid how-... 

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