Water, acyl addition carbonyls

Dithioacetals are useful in organic synthesis as protective groups for carbonyl compounds, as precursors of acyl carbanion equivalents or as electrophiles under Lewis acidic conditions. The DBSA-catalysed system was also found to be applicable to dithioacetal-ization in water. In addition, easy work-up has been realized without the use of organic solvents when the products are solid and insoluble in water. In fact, the dithioacetaliza-tion of cinnamaldehyde on 10 mmol-scale with 1 mol% of DBSA proceeded smoothly to deposit crystals. The pure product was obtained in excellent yield after the crystals were filtered and washed with water (Equation (8)). This simple procedure is one of the advantages of the present reaction system. 

In Section 18.5, water was a weak nucleophile that reacts with aldehydes or ketones to generate hydrates however, they are unstable and lose water to regenerate the ketone or aldehyde via an enol. Therefore, even if a reaction is devised that will overcome the weak nucleophilic strength of water and force the reaction, the product is unstable. An alcohol is ROH and, from a simple structural point of view, one H of HOH has been replaced by an alkyl group. Chemically, this will cause some differences, but there should be many similarities. The oxygen atom of an alcohol is a nucleophile when it reacts with carbonyls, and there is an obvious structural relationship to water. The nucleophilic strength of an alcohol, the reversibility of acyl addition, and the stability of the expected product lead to differences with the water reaction. 

The reactivity of alcohols and carbonyl compounds will be examined using ethanol as the nucleophile. Initial reaction of ethanol with butanal (20) leads to the acyl addition product—oxonium ion 42—analogous to the reaction of water... 

This premise is easily put to the test. However, when butanal (20) reacts with an excess of ethanol in the presence of an acid catalyst, the isolated product is 46, which is 1,1-diethoxybutane (generically known as an acetal see later discussion), along with water as a second product. Clearly, this is not the product 43 mentioned in the previous section, but must result from acyl addition of two equivalents of ethanol to the acyl carbon. Water is the by-product, and the only source of that oxygen atom is the carbonyl oxygen in 20. 

If this simple analysis is formally applied to butanal (20), both EtO units in 46 must be derived from ethanol therefore, two equivalents of ethanol are used. To understand the reaction, work backward from the products and ask how the starting materials are transformed. Both ethoxy units in 46 must arise from acyl addition of ethanol to that carbon atom. Only one molecule of ethanol may be added at a time, however. The other product is water, and the only source of that oxygen atom is the carbonyl oxygen atom in 20. Conversion of this oxygen atom to H2O requires two acid-base reactions (C=0 + H+ C=OH+ and ROH -i- H" R0H2 ). These transformations require the presence of the acid catalyst. If water is lost during the course of the reaction, it is reasonable that one ethanol molecule reacts and then, after water is lost, the second molecule of ethanol reacts. 

With respect to this sequence of observed reactions, experimental evidence shows that 21 reacts with the base (NaOEt) to form an enolate anion, and the nucleophilic carbon atom of that enolate anion attacks the carbonyl of a second aldehyde to give the alkoxide of 22. This is a normal acyl addition reaction, and the nucleophile is the a-carbon of the enolate anion. Treatment of this initial alkoxide product with aqueous acid under mild conditions simply generates alcohol 22, as with all other acyl addition reactions (see Chapter 18). Product 22 is called an alilol or an aldolate. The reaction of an aldehyde or a ketone with a base generates an aldol product. Vigorous acid hydrolysis led to protonation of the OH unit in 22 by the strong acid (to form an oxonium ion), which eliminated a molecule of water (dehydration) to give the alkene unit in 23. 

The reaction proceeds by acyl addition of the amine to one carbonyl, elimination of water, and attack of the nitrogen on the second carbonyl. Elimination of a second molecule of water gives 116. 

There is no simple, commonly accepted method for the preparation of imidazoles, but rather many different approaches. One approach, somewhat related to chemistry seen in previous chapters, involves the reaction of an a-hydroxy-ketone such as 121 with formamide, 122. The -NH2 unit of forma-mide attacks the carbonyl (acyl addition), and loss of water (elimination) gives an enol that tautomerizes to the ketone. (Keto-enol tautomerism was first discussed in Chapter 10, Section 10.4.5.) A second molecule of formamide reacts with this ketone via acyl addition to give a product, which loses water. An intramolecular attack of the nitrogen atom from this product to one -CHO rmit on the carbonyl of the other CHO unit, followed by loss of water under the reaction conditions, gives imidazole, 123. 

Nucleophilic acyl addition of water (hydration) to a carbonyl group of an aldehyde or a ketone forms a geminal diol, commonly abbreviated gem-diol. 

Mechanism of esterification of carboxylic acids The esterification of carboxylic acids with alcohols is a kind of nncleophilic acyl snbstitntion. Protonation of the carbonyl ojq gen activates the carbonyl gronp towards nncleophilic addition of the alcohol. Proton transfer in the tetrahedral intermediate converts the hydrojq l group into - 0H2 group, which, being a better leaving group, is eliminated as neutml water molecule. The protonated ester so formed finally loses a proton to give the ester. 

Stoichiometry (28) is followed under neutral or in alkaline aqueous conditions and (29) in concentrated mineral acids. In acid solution reaction (28) is powerfully inhibited and in the absence of general acids or bases the rate of hydrolysis is a function of pH. At pH >5.0 the reaction is first-order in OH but below this value there is a region where the rate of hydrolysis is largely independent of pH followed by a region where the rate falls as [H30+] increases. The kinetic data at various temperatures both with pure water and buffer solutions, the solvent isotope effect and the rate increase of the 4-chloro derivative ( 2-fold) are compatible with the interpretation of the hydrolysis in terms of two mechanisms. These are a dominant bimolecular reaction between hydroxide ion and acyl cyanide at pH >5.0 and a dominant water reaction at lower pH, the latter susceptible to general base catalysis and inhibition by acids. The data at pH <5.0 can be rationalised by a carbonyl addition intermediate and are compatible with a two-step, but not one-step, cyclic mechanism for hydration. Benzoyl cyanide is more reactive towards water than benzoyl fluoride, but less reactive than benzoyl chloride and anhydride, an unexpected result since HCN has a smaller dissociation constant than HF or RC02H. There are no grounds, however, to suspect that an ionisation mechanism is involved. 

Catalytic hydrogenation of the nitro group of 21 with Raney nickel under hydrogen atmosphere followed by catalyst removal and recrystallization from methanol-water then furnished aniline 22 and set the stage for the ultimate installation of costly biphenyl-2-carbonyl chloride. Selective acylation of the aniline moiety of 22 was readily achieved by treatment with biphenyl-2-carbonyl chloride in a refluxing mixture of pyridine and acetonitrile. Subsequent addition of a solution of hydrogen chloride in ethyl acetate to the cooled reaction mixture resulted in the precipitation of conivaptan HCl (1), which was isolated in 74% yield. 

When the derivatives are required to convert to the parent 5-FU in vivo, appropriate substituents were introduced across the carbonyl groups in the chemical modification [20-25]. Though the first synthesis of acryloyl derivatives of 5-FU, which is the simplest polymerizable derivative, was done by Gebelein, the monomer has not been purified and collected [23]. In the present case, as shown in Scheme 2, silylated 5-FU was used instead of just 5-FU so as to give selectivity to the 1 TV-acylation similar to that of the acryloyl derivatives of thymine [9]. For the preparation of acryloyl-5-FU (AFU), methacryloyl-5-FU (MAFU) and / -vinylbenzoyl-5FU (VBFU), trimethylsilylated 5-FU (1) was allowed to react with acryloyl chloride, methacryloyl chloride and vinyl-benzoyl-chloride, respectively. The reaction was carried out in water-free acetonitrile solution after the addition of acid chloride at room temperature the solution was stirred for 30 min. This procedure afforded AFU in 16%, MAFU in 56%, and VBFU in 63% yield. 

Ethynyl carbinols (propargylic alcohols) such as 134 (Scheme 2.58) represent another important group of oxidation level 3 compounds. Their preparation involves nucleophilic addition of acetylides to the carbonyl group, a reaction that is nearly universal in its scope. Elimination of water from 134 followed by hydration of the triple bond is used as a convenient protocol for the preparation of various conjugated enones 135. Easily prepared O-acylated derivatives are extremely useful electrophiles in reactions with organocuprates, which proceed with propargyl-allenyl rearrangements to furnish allene derivatives 136. 

---