Nucleophilic alcohols

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

Termination. It can be achieved using nucleophiles (alcohols, ammonia, amines, alkalis, water). 

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

The mechanism for the lipase-catalyzed reaction of an acid derivative with a nucleophile (alcohol, amine, or thiol) is known as a serine hydrolase mechanism (Scheme 7.2). The active site of the enzyme is constituted by a catalytic triad (serine, aspartic, and histidine residues). The serine residue accepts the acyl group of the ester, leading to an acyl-enzyme activated intermediate. This acyl-enzyme intermediate reacts with the nucleophile, an amine or ammonia in this case, to yield the final amide product and leading to the free biocatalyst, which can enter again into the catalytic cycle. A histidine residue, activated by an aspartate side chain, is responsible for the proton transference necessary for the catalysis. Another important factor is that the oxyanion hole, formed by different residues, is able to stabilize the negatively charged oxygen present in both the transition state and the tetrahedral intermediate. 

Another philosophy would be the one-pot resolution of two different nucleophiles, alcohol and amine [39]. An acylated racemic alcohol reacts with a racemic amine in... 

LG = leaving group phosphate, UTP, TDP, etc. NuH = nucleophile alcohol, sulfide, amine, etc. 

C-nucleophile (X = active H-borate, boronate) N-nucleophile (amine, NaN3, tosyl amide, amide, lactam, imine, carbamate, urea) O-nucleophile (alcohol, acid, carbonate) S-nucleophile (PhS02Na)... 

In HO -catalyzed hydrolysis (specific base catalyzed hydrolysis), the tetrahedral intermediate is formed by the addition of a nucleophilic HO ion (Fig. 3.1, Pathway b). This reaction is irreversible for both esters and amides, since the carboxylate ion formed is deprotonated in basic solution and, hence, is not receptive to attack by the nucleophilic alcohol, phenol, or amine. The reactivity of the carboxylic acid derivative toward a particular nucleophile depends on a) the relative electron-donating or -withdrawing power of the substituents on the carbonyl group, and b) the relative ability of the -OR or -NR R" moiety to act as a leaving group. Thus, electronegative substituents accelerate hydrolysis, and esters are more readily hydrolyzed than amides. 

Scheldt and co-workers have also illustrated the oxidation of activated alcohols to esters [132], Oxidations of alcohols such as 260 provide the electrophile (acyl donor) for a nucleophilic alcohol 261. Esters 262 are derived from propargylic, allylic, aromatic, and hetero-aromatic substrates (Table 20). The nucleophilic alcohol scope includes MeOH, n-BuOH, f-BuOH, 2,2,2-trichloroethanol, 2-methoxyethanol, and 2-(trimethylsilyl) ethanol. 

Though reaction with the more nucleophilic alcohol... 

PU formation occurs with attack of the nucleophilic alcohol at the electron-poor isocyanate carbon with a proton shift followed by rearrangement to the urethane structure ... 

Fig. 19 Monomer activation mechanism for the ROP of lactones catalyzed by Bronsted acids and initiated by nucleophilic alcohols...

The rapid S l reaction is attributed to the stability of a C adjacent to —O—. The empty p orbital on the C" can overlap with the p orbital on O, thereby delocalizing the + charge. The positive ion then reacts with the nucleophilic alcohol, giving an ether. 

Mechanism. The nucleophilic alcohol attacks the carbonyl carbon of the acid chloride and displaces the chloride ion. The protonated ester loses a proton to the solvent (pyridine or EtsN) to give the ester. 

The fate of the acyl palladium complex depends on the circumstances. In the presence of a suitable nucleophile (alcohol, amine) it is converted into the corresponding carboxylic acid derivative. The side product, a palladium hydride is converted to the active form of the catalyst in a reductive elimination step, resulting in the formation of an equimolar amount of acid, which is quenched by an added base (in most cases the excess of the nucleophile). 

Acid catalysis of RO—C—OH formation, like ester formation, depends on formation of the conjugate acid of the carbonyl compound. This is expected to enhance the positive (electrophilic) character of the carbonyl carbon so that the nucleophilic alcohol can add readily to it ... 

The course of addition reactions of ROH-XeF2 to alkenes has been elucidated using norbomene, 2-methylpent-2-ene and hex-l-ene as model substrates. It turned out that the alkoxyxenon fluoride intermediates (ROXeF) can react either as oxygen electrophiles (initially adding alkoxy substituent) or as apparent fluorine electrophiles (initially adding fluorine), depending on the reaction conditions. Simple addition of poorly nucleophilic alcohols to norbomene was also observed in certain instances. Selectivity between the various reaction pathways (simple fluorination, alkoxyfluorina-tion, or alcohol addition) proved to be sensitive to various reactions conditions, especially solvent, temperature, and catalyst.27... 

In the stoichiometric oxidation of secondary alcohols to ketones by tetraoxoferr-ate(VI), the second-order rate constant depends on pH. Rate acceleration at high [HO-] is attributed to formation of HOFeO -, proposed to be more susceptible to attack by nucleophiles (alcohols, R2CHOH) than FeO itself, to generate a ferrate ester, H0Fe(0-)4-0CHR2. A second effect accounting for the steep dependence on [HO-] is attributed to ionization of alcohols to generate the more readily oxidized alkoxide ions.88... 

After change of solvent and addition of DMAP, the mixed anhydride is attacked by the nucleophilic alcohol oxygen. 

Given the structure or name of an aldehyde or ketone, write an equation for its reaction with the following nucleophiles alcohol, cyanide ion, Grignard reagent or acetylide, hydroxylamine, hydrazine, phenylhydrazine, 2,4-dinitrophenylhydrazine, primary amine, lithium aluminum hydride, and sodium borohydride. 

The earliest report of a solution-phase combinatorial library of small drug-like molecules was by Smith et al. [2], The reaction of 40 individual acid chlorides with an equimolar mixture of 40 nucleophiles (alcohols or amines) and of the individual nucleophiles with an equimolar mixture of the acid chlorides produced a library of 1600 amides and esters as pools of 40 compounds. The orthogonal design strategy determined that each possible product should appear in a unique pair of samples to allow the rapid identification of lead compounds after screening. 

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