Amides acyl chloride carbonylation

Many compounds contain more than one functional group Prostaglandin Ei a hormone that regulates the relaxation of smooth muscles con tains two different kinds of carbonyl groups Classify each one (aldehyde ketone carboxylic acid ester amide acyl chloride or acid anhydride) Identify the most acidic proton in prostaglandin Ei and use Table 1 7 to estimate its pK ... 

The chemistry of the carbonyl group is probably the single most important aspect of organic chemical reactivity Classes of compounds that contain the carbonyl group include many derived from carboxylic acids (acyl chlorides acid anhydrides esters and amides) as well as the two related classes discussed m this chapter aldehydes and ketones... 

The negatively charged oxygen substituent is a powerful electron donor to the carbonyl group Resonance m carboxylate anions is more effective than resonance m carboxylic acids acyl chlorides anhydrides thioesters esters and amides... 

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated m Table 20 2 Because a more highly stabilized carbonyl group must result m order for nucleophilic acyl substitution to be effective acid anhydrides are readily converted to carboxylic acids esters and amides but not to acyl chlorides... 

Nitrogen is a better electron parr donor than oxygen and amides have a more stabilized carbonyl group than esters and anhydrides Chlorine is the poorest electron pair donor and acyl chlorides have the least stabi lized carbonyl group and are the most reactive... 

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 mtermedi ate that dissociates to give the product of substitution... 

Section 20 21 Acyl chlorides anhydrides esters and amides all show a strong band for C=0 stretching m the infrared The range extends from about 1820 cm (acyl chlorides) to 1690 cm (amides) Their NMR spectra are characterized by a peak near 8 180 for the carbonyl carbon H NMR spectroscopy is useful for distinguishing between the groups R and R m esters (RCO2R ) The protons on the carbon bonded to O m R appear at lower field (less shielded) than those on the carbon bonded to C=0... 

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. 

FIGURE 20.1 Structure, reactivity, and carbonyl-group stabilization in carboxylic acid derivatives. Acyl chlorides are the most reactive, amides the least reactive. Acyl chlorides have the least stabilized carbonyl group, amides the most. Conversion of one class of compounds to another is feasible only in the direction that leads to a more stabilized carbonyl group that is, from more reactive to less reactive. 

Several new methods for the synthesis of the oxazole nucleus were published. A new consecutive three-component oxazole synthesis by an amidation-coupling-cycloisomerisation sequence was developed. The synthesis started from propargylamine 92 and acyl chlorides. To extend this process, a four component sequence involving a carbonylative arylation by substitution of one acyl chloride with an aryl iodide and a CO atmosphere was also performed <06CC4817>. 

The carbonyl group of an amide is stabilized to a greater extent than that of an acyl chloride, acid anhydride, or ester amides are formed rapidly and in high yield from each of these carboxylic acid derivatives. 

We start with acid derivatives since we almost always choose to disconnect the bond between the heteroatom and the carbonyl group. So we make esters 11 and amides 13 from acid (acyl) chlorides 12 and alcohols or amines. 

Both additions are irreversible, and BuLi attacks the reactive carbonyl group of the aldehyde, but prefers conjugate addition to the less reactive amide. Similarly, ammonia reacts with this acyl chloride to give an amide product that derives (for details see Chapter 12) from direct addition to the carbonyl group, while with the ester it undergoes conjugate addition to give an amine. 

The iminium ion, is of course, more electrophilic than the starting amides (amide carbonyl groups are about the least electrophilic of any ), so it gets reduced to the secondary amine. This reaction can be used to make secondary amines, from primary amines and acyl chlorides. 

The reaction is deceptively simple—formation of an amide in the presence of base—and you would expect the mechanism to follow what we told you in Chapter 12. But the acyl chloride is, in fact, set up for an ElcB elimination—and you should expect this whenever you see an acyl chloride with acidic protons next to the carbonyl group used in the presence of triethylamine. 

Although borane appears superficially similar to borohydride, it is not an ion and that makes all the difference to its reactivity. Whereas borohydride reacts best with the most electrophilic carbonyl groups, borane s reactivity is dominated by its desire to accept an electron pair into its empty p orbital. In the context of carbonyl group reductions, this means that it reduces electron-rich carbonyl groups fastest. The carbonyl groups of acyl chlorides and esters are relatively electron-poor (Cl and OR are very electronegative) borane will not touch acyl chlorides and reduces esters only slowly. But it will reduce amides. 

We established in Chapter 12 a hierarchy for the electrophilic reactivity of acid derivatives that should by now be very familiar to you—acyl chlorides at the top to amides at the bottom. But what about the reactivity of these same derivatives towards enolization at the a position, that is, the CH2 group between R and the carbonyl group in the various structures You might by now be able to work this out. The principle is based on the mechanisms for the two processes, mechanism of nucleophilic attack mechanism of enolate formation... 

Finally, an even more familiar example that you may never have thought about. You are well aware now that amides are planar, with partially double C-N bonds, and that tertiary amides have one alkyl group cis to oxygen and one tram. But what about esters Esters are less reactive than acyl chlorides because of donation from the oxygen p orbital into the carbonyl tt, so we expect them to be planar too, and they are. But there are two possible planar conformations for an ester one with R cis to oxygen and one with R trans. Which is preferred ... 

In the initial studies about the reaction of /V.zV-disubstituted formamides with alkaline metals to give glyoxylic amides, the participation of carbamoyl metal derivatives as intermediates was postulated83. The first preparation of the carbamoyllithium 77 was described two years later by a mercury-lithium transmetallation from compound 76 at —75 °C (Scheme 20)84. The authors proposed also an aminocarbene structure 78 and studied its reactivity with methanol, methyl iodide, carbonyl compounds, esters, acyl chlorides, mercury(II) chloride and tri-n-butyltin chloride providing compounds 79. 

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