Water, acyl addition

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. 

When the enzyme is used to catalyse the synthesis of a peptide bond, the solvent is either non-aqueous or contains only a low concentration of water. In addition, of course, an amino component such as an amino acid or peptide ester replaces the water in the second step. Obviously, the amino component must be unprotonated for reaction to succeed. Synthesis is favoured over hydrolysis of the resultant peptide because an amide is kinetically a much worse substrate for a proteinase than is an ester. The rapid acylation of a proteinase by an TV-protected amino acid or peptide aryl ester can be demonstrated experimentally using a stopped-flow apparatus with spectrophotometric facilities. A rapid burst of phenol is followed by steady-state release, showing that acylation of the enzyme is faster than hydrolysis of the acy-lated enzyme. No such burst is detectable if, for example, an TV-acylated amino acid anilide is used as substrate. In fact, acylation is the rate-determining step with amide substrates. 

If the solvent is water, or contains water, the bimolecular (collision) processes between a neutral substrate and a charged nucleophile (such as nucleophilic acyl addition reactions and nucleophilic displacement with alkyl halides) are generally slow due to solvation effects and unimolecular processes may be competitive. A H unimolecular process involves ionization of the substrate, usually to a carbocation (sec. 2.7.B.1). If the solvent is anything but water, the faster bimolecular processes probably dominates., which is obviously an assumption. 

For the acylation, additional amounts (50% molar excess) of pyridine and acid chloride are beneficial. The reaction takes from hours to days at room temperature. The triacylglycerol product can be crystallized with good purity in some cases but in others it is necessary to use an alumina column in addition. Jensen and Pitas (1976) emphasize that, for the latter to be used efficiently, the triacylglycerol must be soluble in hexane-anhydrous diethyl ether (9 1) at room temperature. Many saturated triacylglycerols are not thus soluble and, so, have to be purified by crystallization alone. When the latter is used then ethanol is included in the crystallization solvent so that excess acid chloride is converted to the ester which remains in solution. When alumina columns are employed, care must be taken to eliminate all traces of alcohol, chloroform or water from the eluting solvents, since these can ruin the separation. Alumina columns can be run rapidly and recoveries are 80-90% (Jensen etaL, 1966). 

If the solvent is water or if it contains water, the bimolecular (collision) processes between a neutral substrate and a charged nucleophile (such as nucleophilic acyl addition reactions and nucleophilic displacement with alkyl hahdes) are slower due to solvation effects. On the other hand, water is an excellent solvent for the solvation and separation of ions, so unimolecular processes (which involve ionization to carbocations see Chapter 11, Section 11.6) may be competitive. If the solvent is protic (ethanol, acetic acid, methanol), ionization is possible, but much slower than in water. However, ionization can occiu- if the reaction is given sufficient time to react. In other words, ionization is slow, but not impossible. An example of this statement is the solvolysis of alcohols presented in Chapter 6 (Section 6.4.2). Based on this observation, assume that ionization (unimolecular reactions) will be competitive in water, but not in other solvents, leading to the assumption that bimolecular reactions should be dominant in solvents other than water. This statement is clearly an assumption, and it is not entirely correct because ionization can occur in ethanol, acetic acid, and so on however, the assumption is remarkably accurate in many simple reactions and it allows one to begin making predictions about nucleophilic reactions. 

In Chapter 15, Grignard reagents react as bases, but they are poor nucleophiles with alkyl halides. Grignard reagents are good nucleophiles with ketones or aldehydes, however, and these reactions will be discussed in more detail in Chapter 18. For the moment, the point of this example is to see that nucleophiles react with ketones and aldehydes by acyl addition. In each example, the alkoxide products 30-32 are converted to an alcohol via an acid-base reaction where the alkoxide is the base and aqueous acid (H+) is used. The alcohol product is the conjugate acid of this reaction and, because the hydronium ion is used as an acid, water is the conjugate base in this second reaction. This second chemical reaction is necessary in order to isolate a neutral product. 

Water A Weak Nucleophile That Gives Reversible Acyl Addition... 

In Section 18.2, the chloride ion was shown to be a weak nucleophile, and there is no acyl addition product at all. In Section 18.3.1, the cyanide anion was classified as a weak nucleophile because the non-acid-catalyzed acyl addition is reversible and the yield of product is low. With an acid catalyst, formation of an oxocarbenium ion allowed the acyl addition product to be isolated in good yield. Other weak nucleophiles give reversible acyl addition, and it is reasonable to ask if those equilibria may be shifted to give an acyl addition product via formation of an oxocarbenium ion. The answer is yes. This statement is demonstrated by the reaction of very weak nucleophiles in acyl addition, water. 

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... 

From the previous section, it is clear that the reaction of an alcohol with an aldehyde or a ketone does not give a stable product—or at least the equilibrium for the reaction favors the aldehyde or ketone starting material rather than the acyl addition product. A reaction does occur, and the reversible reaction is completely analogous to the reaction with water. Intermediate 10 via the acyl addition of cyanide ion, intermediate 36 via the acyl addition of water, or intermediate 42 via the acyl addition of ethanol all show a common problem. An alkoxide is present that allows facile donation of electrons to the electrophilic carbon, which also has a good leaving group. 

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. 

The nitrogen atom in an amine (71) is a good electron donor and a better nucleophile than water or alcohols. Indeed, amines react with aldehydes and ketones by acyl addition, but the acyl addition is reversible and the initially formed products can react further. The flnal product of the reaction with a primary amine is an imine (72), but secondary amines react to give an enamine (see 73). 

Anhydrides may be prepared by coupling two carboxylic acids under acidic conditions. If ethanoic acid (acetic acid, 21) is heated with HCl, protonation to give an oxocarbenium ion is followed by reaction with a second equivalent of acetic acid to give a tetrahedral intermediate. This reaction is the usual acid-catalyzed acyl addition mechanism. Protonation of the OH unit leads to loss of water and formation of the anhydride. Each step in this process is reversible and steps must be taken to drive the equilibrium (see Chapter 7, Section 7.10, for a discussion of equilibria) toward the anhydride product by removing the water by-product (see Chapter 18, Section 18.6.3). Remember that such techniques are an application of Le Chatelier s principle (discussed in Section 18.3). Even when this is done, isolation of pure anhydrides by this method can be difficult. Unreacted acid may contaminate the product and atternpts to remove the acid with aqueous base may induce hydrolysis of the anhydride. 

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. 

The second example involves an acyl transfer from chloride to water. The addition and elimination reactions are combined into one step. Although the arrows do keep track of the electrons involved in the reaction, such steps are known not to occur simultaneously, and thus the electron-pushing notation does not reflect what is known about the mechanism. 

Addition of one mole of P,P -dipheny1methy1enediphosphinic acid to tetraisopropyl titanate gives a chelated product, the solutions of which can be used as a primer coat for metals to enhance the adhesion of topcoats, eg, alkyds, polyalkyl acylates, and other polymeric surface coating products, and improve the corrosion resistance of the metal to salt water (102). 

Schollenberger added 2% of a polycarbodiimide additive to the same poly(tetra-methylene adipate) urethane with the high level of acid (AN = 3.66). After 9 weeks of 70°C water immersion, the urethane was reported to retain 84% of its original strength. Carbodiimides react quickly with residual acid to form an acyl urea, removing the acid catalysis contributing to the hydrolysis. New carbodiimides have been developed to prevent hydrolysis of polyester thermoplastics. Carbodiimides are also reported to react with residual water, which may contribute to hydrolysis when the urethane is exposed to high temperatures in an extruder [90]. 

The reaction of 1,2,4-triazine 4-oxides 55 with water in the presence of benzoyl chloride affords 3-hydroxy-1,2,4-triazines 78. The mechanism suggested for this reaction includes acylation of the substrate at the oxygen of the iV-oxide group, followed by the addition of water to the 1,2,4-tiiazinium cation and the autoaromatization of the (T -adducts with the elimination of benzoic acid. 

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