Oxygen nucleophiles,

Various nucleophiles that can attack a carbonyl group. 

Once equihbrium has been achieved, the mixture consists primarily of the ketone, and only small quantities of the addition product. 

The remainder of the chapter will be a methodical survey of the reactions that occur between 

When an aldehyde or ketone is treated with water, the carbonyl group can be converted into a hydrate  

The position of equilibrium generally favors the carbonyl group rather than the hydrate, except 

Oxygen nucleophiles usually attack a ring carbon atom rather than the sulfur atom of a thiirane, and those cases in which desulfurization is observed on treatment of a thiirane with oxygen bases probably involve the extrusion of sulfur by mechanisms other than a nucleophilic attack on sulfur, e.g. thermal. Desulfurization of thiirane intermediate (43) 

The oxygen nucleophiles that are of primary interest in synthesis are the hydroxide ion (or water), alkoxide ions, and carboxylate anions, which lead, respectively, to alcohols, ethers, and esters. Since each of these nucleophiles can also act as a base, reaction conditions are selected to favor substitution over elimination. Usually, a given alcohol is more easily obtained than the corresponding halide so the halide-to-alcohol transformation is not used extensively for synthesis. The hydrolysis of benzyl halides to the corresponding alcohols proceeds in good yield. This can be a useful synthetic transformation because benzyl halides are available either by side chain halogenation or by the chloromethylation reaction (Section 11.1.3). 

Two methods for converting carboxylic acids to esters fall into the mechanistic group under discussion the reaction of carboxylic acids with diazo compounds, especially diazomethane and alkylation of carboxylate anions by halides or sulfonates. The esterification of carboxylic acids with diazomethane is a very fast and clean reaction.41 The alkylating agent is the extremely reactive methyldiazonium ion, which is generated by proton transfer from the carboxylic acid to diazomethane. The collapse of the resulting ion pair with loss of nitrogen is extremely rapid. 

Introduction of Functional Groups by Nucleophilic Substitution at Saturated Carbon 

The main drawback to this reaction is the toxicity of diazomethane and some of its precursors. Diazomethane is also potentially explosive. Trimethylsilyldia-zomethane is an alternative reagent,42 which is safer and frequently used in preparation of methyl esters from carboxylic acids.43 Trimethylsilyldiazomethane also O-methylates alcohols.44 The latter reactions occur in the presence of fluoroboric acid in dichloromethane. 

Especially for large-scale work, esters may be more safely and efficiently prepared by reaction of carboxylate salts with alkyl halides or tosylates. Carboxylate anions are not very reactive nucleophiles so the best results are obtained in polar aprotic solvents45 or with crown ether catalysts.46 The reactivity order for carboxylate salts is Na+ K+ Rb+ Cs+. Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due to both high solubility and minimal ion pairing with the anion 47 Acetone is a good solvent for reaction of carboxylate anions with alkyl iodides48 Cesium fluoride in DMF is another useful 

The oxygen nucleophiles that are of primary interest in synthesis are the hydroxide ion (or water), alkoxide ions, and carboxylate anions, which lead, respectively, to alcohols, ethers, and esters. Because each of these nucleophiles can also act as a base, reaction conditions must be selected to favor substitution over elimination. 

2 provide some typical examples of ether preparations. 

Mizuno andT. Shiori,./ Chem. Soc., Chem. Commun. 1997 2165. 

Lopez-Calahorra, B. Ballart, F. Hombrados, and J. Marti, Synth. Commun. 28 795 (1998). 

SECTION 3.2. INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON 

FUNCTIONAL GROUP D. Hydrolysis of Alkyl Halides INTERCONVERSION BY NUCLFOPHILIC  

Esterification by Nucleophilic Substitution with Carboxylate Salts 

Frequently, a given alcohol is more easily obtained than the corresponding halide so the halide-to-alcohol transformations are not extensively used for synthesis. 

This can be a useful synthetic transformation, since benzyl halides are available 

FUNCTIONAL GROUP either by side-chain halogenation or by the chloromethylation reaction (Section INTERCONVERSION i i i 

The reaction of alkoxide ions with alkynyliodonium salts is unproductive, leading to only decomposition products rather than the desired alkoxyacetylenes. Similarly, reaction of R3SiO does not lead to any siloxyalkynes. In contrast the softer sulfonate, carboxylate, and phosphate nucleophiles all readily react with alkynyliodonium salts leading to the corresponding alkynyl sulfonate, carboxylate and phosphate esters [4]. 

Reaction of alkynyliodonium sulfonates, 9, in dry acetonitrile in the presence of catalytic amounts of AgOTs or CuOTf leads to the formation of alkynyl sulfonates, 70, in reasonable yields [Eq. (30)] [18], In a similar manner bis(alkynyliodonium) tosylates, 36, give modest yields of bisalkynyl tosylates, 71, accompanied by some monotosylates, 72 [Eq. (31)] [41]. 

Alkynyl carboxylate esters, 75, are obtained in the reaction of lithium acetylides with bis(acyloxy)iodobenzene, 73 [Eq. (32)] [59], These reactions are likely to proceed through the intermediacy of the respective alkynyliodonium carboxylates (74), although no such salts have been isolated to date as they spontaneously decompose, via loss of iodobenzene, to the alkynyl carboxylates, 75. Only benzoate esters (75 R = CgHj) are sufficiently stable to isolate and store pure for longer periods. Simple alkylcarboxylates such as acetates are not stable although the hindered pivaloate ester (65 R = t-Bu, R = t-Bu) has been isolated in low yield [59]. Among the reasons for the instability of these esters is their sensitivity to moisture they both readily add water and undergo subsequent hydrolyses [60]. Because of the sensitivity to moisture, the isolated yield [41] of bisalkynyl benzoates, 76, from the bisalkynyliodonium triflates, 35, is only 6-15% [Eq. (33)]. 

In contrast, alkynyl dialkyl phosphate esters, 78, are formed in good isolated yields by either the treatment of alkynyliodonium triflates with (R0)2P02Na or the reaction of terminal alkynes with [hydroxy(phosphoryloxy)iodo]benzene, 77 [Eq. (34)], or the sequential treatment of alkynylsilanes with PhIO Et20Bp3 followed by aqueous (R0)2P02Na [Eq. (35)) [61]. These new, alkynyliodonium-derived, acetylenic esters have potent biological activity [4] in particular, the alkynyl benzoates are protease inhibitors [62], whereas the alkynyl dialkylphos-phates, 78, are inhibitors of a bacterial phosphotriesterase [63]. 

Phenoxide ion, unlike alkoxides, interacts favorably with alkynyliodonium species. Reaction of two equivalents of lithium phenoxide with the [bis(phenyliodonium)ethyne, 30, results in diphenoxyacetylene, 79 [24] [Eq. (36)]. Benzofurans, 81, are obtained in the reaction of 23 with PhONa in methanol [Eq. (37)] [64]. As indicated, these products arise via insertion of the intermediate carbene, 80, into the ortho-C-H bond. 

Barbier-type reactions of alkyl iodides with ketones can be performed with Sml2 when Fe(III) compounds are used as catalysts [22]. Particularly efficient for the intramolecular reaction of co-iodo ketones such as compound 16 turned out to be Fe(dbm)3 (dbm = l,3-diphenyl-l,3-propanedionato). The latter is an air-stable, THF-soluble, non-hygroscopic complex that can be very easily prepared from 

A very interesting example of the synthetic utility of the selenoetherifica-tion reactions was reported by Metha [71] who described a very simple and 

Electrophilic 5-endo-trig cyclizations continue to be the subject of considerable research efforts by several groups. Interest has been focused on the stereoselectivity of the ring closure reactions of homoallylic alcohols to substituted 

in which the carbon-nitrogen double bond is exocychc, reacts with sodium borohydride to afford the M-benzyl 1,2-oxazine 132. On the contrary, treatment with methanol gives the 1,2-oxazine 133 and PhCH(OMe)2 as the result of the methanolysis of the iminium salt. Compounds 132 and 133 were formed as a mixture of two stereoisomers in the ratio of 2 1 and 4 1, respectively. In both cases the major isomers were those in which the methyl group occupies an equatorial position. On the other hand, with intermediate 135, in which the carbon-nitrogen double bond is endocyclic, the only reaction observed is the addition of the nucleophile at the positive carbon atom to afford compounds 136 and 137 which were formed as single stereoisomers. 

An examination of the data reported in the table indicates that excellent results can be obtained in most cases and that the nature of the nucleophile and the ring size of the formed heterocyclic compound have httle influence on the facial selectivity observed. The last example reported in Table 4 refers to the interesting case of a 1,1-disubstituted alkene. The cychzation reaction proceeds with a good asymmetric induction to give a tetrasubstituted chiral carbon atom, which is not easily accessible by other methods [80]. 

Enantiomerically enriched MBH alcohols 321 have been prepared in 25-42% yields with optical purities of 54-92% ee by using the combined concept of kinetic resolution during salt formation of racemic MBH acetates 

Ar = 4-MeOPh, S.A-OCHsOPh, 4-MePh, Ph, 3-MeOPh, 4-BrPh, 4-CH3C02Ph 

FIGURE 15.9 Reactions of acid chlorides with alcohols or carboxylic acids. 

FIGURE 15.10 Reactions of anhydrides with aicohois or carboxylic acids. 

FIGURE 15.12 Reactions with acid chlorides are sensitive to steric hindrance. 

Most esters have a pleasant scent, and many are constituents of the scent and flavor of fruits. True natural flavors are very complex, with many components artificial fruit flavorings may have several components but are much less complex. Our perception of taste depends not only on the taste receptors on the tongue (which are limited to salt, sweet, bitter, sour, and umami) but to a great extent on the aroma of the food. This is why food does not taste good, or indeed much at all, when you have a bad cold. Some examples are given in Table 15.3— you did not think that the rum flavor in Rum ri Raisin ice cream actually involved the use of the spirit, did you  

Although esters are quite commonly used in scratch and sniff adverts (they are micro-encapsulated, and your fingernail breaks open the capsules) and air fresheners, they are not widely used in perfumery. The moisture in human skin results in hydrolysis of the esters the alcohol portion may largely evaporate, but the acids remain, and many have a most unpleasant scent butanoic acid is the main scent from rancid butter. 

---

Reactions with Carbon and Oxygen Nucleophiles, and Other Reactions... 

Difluoropyridines. 2,4-Difluoropyridine can be prepared (26% yield) from 2,4-dichloropyridine and potassium fluoride in sulfolane and ethylene glycol initiator (403). The 4-fluorine is preferentially replaced by oxygen nucleophiles to give 2-fluoro-4-hydroxypyridine derivatives for herbicidal apphcations (404). 

Displacement reactions with oxygen nucleophiles are of potential commercial interest. Alkaline hydrolysis provides 2-fluoro-6-hydroxypyridine [55758-32-2], a precursor to 6-fluoropyridyl phosphoms ester insecticides (410—412). Other oxygen nucleophiles such as bisphenol A and hydroquinone have been used to form aryl—pyridine copolymers (413). 

Reaction with Oxygen Nucleophiles. In the presence of strong acids, eg, H2SO4, HBF, or BF, aziridines react with alcohols to form P-amino ethers (93) ... 

The reaction of a hydroperoxide with 2-methylaziridine [75-55-8] has been described (94). The reaction of ethyleneknine with phenols (95) and carboxyHc acids (96,97) produces ethylamine ethers and esters, respectively. However, these reactions frequentiy yield product mixtures which contain polyaminoalkylated oxygen nucleophiles and polymers, in addition to the desked products (1). The selectivity of the reaction can often be improved by using less than the stoichiometric amount of the aziridine component (98,99). 

The importance of steric effects in determining the oxidation state of the product can be illustrated by a thioether linkage, eg (57). If a methyl group is forced to be adjacent to the sulfur bond, the planarity required for efficient electron donation by unshared electrons is prevented and oxidation is not observed (48). Similar chemistry is observed in the addition of organic nitrogen and oxygen nucleophiles as well as inorganic anions. 

Conversion to a more facile, sulfur-derived, leaving group can be achieved by treatment with sodium thiosulfate or salts of thio and dithio acids (75,87). Under anhydrous conditions, boron tribromide converts the 3 -acetoxy group to a bromide whereas trimethyl silyl iodide gives good yields of the 3 -iodide (87,171,172). These 3 -halides are much more reactive, even when the carboxyl group is esterified, and can be displaced readily by cyano and by oxygen nucleophiles (127). 

Nucleophilic substitution of the chlorine atom in 2-chloropyrazine and 2-chloroquinoxa-lines has been effected with a variety of nucleophiles, including ammonia and amines, oxygen nucleophiles such as alkoxides, sodium azide, hydrazine, sulfur containing nucleophiles, cyanide, etc., and reactions of this type are typical of the group (see Chapter 2.02). 

Oxygen nucleophiles may also add to cyano groups, in many instances providing entry into the isoxazole system (Chapter 4.16). These reactions are illustrated by the conversion of the 2-arylhydrazono-3-oxonitrile (325) into a 5-aminoisoxazole (327). Treatment of... 

S-Substituted thiiranium ions react with water and alcohols to give trans ring opening (Scheme 72). A report that oxygen nucleophiles attack sulfur as well as carbon has been shown to be incorrect (79ACR282). The intermediate thiiranium ion (57) in the presence of lithium perchlorate readily yields the carbenium ion which undergoes a transannular hydride... 

Oxygen nucleophiles (hydroxyl or nitrite) readily replace fluonne mperfluor-inated systems [10, II] (equations 6 and 7). 

Ruonne atoms in aromatic nitrogen heterocycles are readily replaced by oxygen nucleophiles [77] Bistnfluoromethyl hydroxylarmne anion is an mterest-ing nucleophile for the mtroduction of oxygen mto perfluoropyndine Rearrangement of the product occurs at 125 °C [18] (equation 12)... 

These Br nsted-type plots often seem to be scatter diagrams until the points are collated into groups related by specific structural features. Thus, p-nitrophenyl acetate gives four separate, but parallel, lines for reactions with pyridines, anilines, imidazoles, and oxygen nucleophiles.Figure 7-4 shows such a plot for the reaction of trans-cmmm c anhydride with primary and secondary aliphatic amines to give substituted cinnamamides.All of the primary amines without substituents on the a carbon (R-CHi-NHi) fall on a line of slope 0.62 cyclopentylamine also lies on this line. If this line is characteristic of normal behavior, most of the deviations become qualitatively explicable. The line drawn through the secondary amines (slope 1.98) connects amines with the structure R-CHi-NH-CHi-R. The different steric requirements in the acylation reaction and in the model process... 

Discuss possible reasons for the curvature in the Br nsted-type plot of Fig. 7.5 for the nucleophilic reactions of oxygen nucleophiles. 

Enolates can act either as carbon or as oxygen nucleophiles. The product depends on the electrophile e.g. 

Other oxygen nucleophiles demonstrating high reactivity toward 2,4,6-trichloro-s-triazine are A, A -dimethylformamide (10° > 0.5 hr) giving rapid disubstitution (325) A -alkylformamide (20°, 4 hr) in... 

The 8-nitro group in intermediate quinolone 225 can be easily displaced even with aliphatic oxygen nucleophiles. Starting compound 224 under various conditions provided directly tricyclic compound 226 and all attempts to isolate the expected intermediate 225 failed (Scheme 34) (91CCC1937). 

The Michael aclcliQon of oxygen-nucleophiles followed by subsequent cyclizadon or cycloaddidon provides an important method for the preparadon of oxygen-heterocycles such as tetrahydrofurans For example, 3-nitro-2//-chromenes bearing various snbsdtnents are prepared by the reaction of snbsdtnted sahcylaldehydes with nitro ilkenes fEq 4 14 ... 

---