Nucleophilic abstraction

To conclude this section on the effect of solvent on a-nucleophilicity, we refer to the current, rather controversial, situation pertaining to gas-phase smdies and the a-effect. As reported in our review on the a-effect and its modulation by solvent the gas-phase reaction of methyl formate with HOO and HO , which proceeds via three competitive pathways proton abstraction, nucleophilic addition to the carbonyl group and Sat2 displacement on the methyl group, showed no enhanced nucleophilic reactivity for HOO relative to This was consistent with gas-phase calculational work... 

In a study towards the synthesis of the tricarbonyliron complex of 8-methylenespiro[2.5]octa-4,6-diene 52 starting from spiro[2.5]octa-4,6-diene (49), conversion of its tricarbonyliron complex 50 via hydride abstraction, nucleophilic addition of hydroxide and oxidation gave the spiro[2.5]octa-5,7-dien-4-one-tricarbonyliron complex 51, which, however, could not be converted to the target complex 52 via Wittig olefination. An alternative approach to generate a Wittig reagent from spiro[2.5]octa-4,6-diene (49) via conversion to a phosphonium system 53 was likewise unsuccessful. ... 

Abstract. Nucleophilic addition of amines to olefins which are activated by electron withdrawing substituents occurs readily in aqueous dimethylsulfoxide. The reaction comprises two steps (1) nucleophilic addition to form a zwitterionic complex (2) removal of the ammonio proton of the zwitterion by a base. In most cases the first step is rate limiting but in some cases proton transfer is rate limiting. The latter situation prevails either when the reverse of the nucleophilic attack step is very rapid, as in the reaction of morpholine with benzylidenemalononitrile, or when the rate of proton transfer is depressed by a steric effect, as in the reaction of morpho-line with 1,l-dinitro-2,2-diphenylethylene. The steric effects in this latter system are among the most dramatic ones reported to date. Our data also show that the kinetic barrier to nucleophilic attack is substantially higher for nitro than for cyano activated olefins. This effect seems to be related to the well known fact that proton transfers involving nitro activated carbon acids are much slower than those of cyano activated carbon acids. 

As detailed in the sections above, cyclohexadienyl iron complexes of general formula 46 are readily obtained by Birch reduction, complexation and highly regioselective hydride abstraction. Nucleophilic addition to these complexes occurs only at the terminal positions of the q -cyclohexadienyl unit such that two products 47 and 48 may be produced. In the vast majority of cases 47 is... 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Alkenes in (alkene)dicarbonyl(T -cyclopentadienyl)iron(l+) cations react with carbon nucleophiles to form new C —C bonds (M. Rosenblum, 1974 A.J. Pearson, 1987). Tricarbon-yi(ri -cycIohexadienyI)iron(l-h) cations, prepared from the T] -l,3-cyclohexadiene complexes by hydride abstraction with tritylium cations, react similarly to give 5-substituted 1,3-cyclo-hexadienes, and neutral tricarbonyl(n -l,3-cyciohexadiene)iron complexes can be coupled with olefins by hydrogen transfer at > 140°C. These reactions proceed regio- and stereospecifically in the successive cyanide addition and spirocyclization at an optically pure N-allyl-N-phenyl-1,3-cyclohexadiene-l-carboxamide iron complex (A.J. Pearson, 1989). 

Thiazolium derivatives unsubstituted at the 2-position (35) are potentially interesting precursors of A-4-thiazoline-2-thiones and A-4-thiazoline-2-ones. Compound 35 in basic medium undergoes proton abstraction leading to the very active nucleophilic species 36a and 36b (Scheme 16) (43-46). Special interest has been focused upon the reactivity of 36a and 36b because they are considered as the reactive species of the thiamine action in some biochemical reaction, and as catalysts for several condensation reactions (47-50). 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

IS a two step process m which the first step is rate determining In step 1 the nucleophilic hydroxide ion attacks the carbonyl group forming a bond to carbon An alkoxide ion is the product of step 1 This alkoxide ion abstracts a proton from water m step 2 yielding the gemmal diol The second step like all other proton transfers between oxygen that we have seen is fast... 

All these facts—the observation of second order kinetics nucleophilic attack at the carbonyl group and the involvement of a tetrahedral intermediate—are accommodated by the reaction mechanism shown m Figure 20 5 Like the acid catalyzed mechanism it has two distinct stages namely formation of the tetrahedral intermediate and its subsequent dissociation All the steps are reversible except the last one The equilibrium constant for proton abstraction from the carboxylic acid by hydroxide is so large that step 4 is for all intents and purposes irreversible and this makes the overall reaction irreversible... 

The intermediate formed m the nucleophilic addition step abstracts a proton from the solvent to give the observed product... 

Both the basicity and the nucleophilicity of amines originate m the unshared electron pair of nitrogen When an amine acts as a base this electron pair abstracts a... 

The reaction is earned out by mixing the peptide and 1 fluoro 2 4 dmitrobenzene in the presence of a weak base such as sodium carbonate In the first step the base abstracts a proton from the terminal H3N group to give a free ammo function The nucleophilic ammo group attacks 1 fluoro 2 4 dmitrobenzene displacing fluoride... 

Experiments ( P nmr) using 0.8 and 2 equivalents of octyhnagnesium chloride with ethyl ben2enephosphinate indicate that the nucleophilic displacement occurs first, foHowed by proton abstraction (80). Interestingly, the order of the two steps is reversed when methyhnagnesium chloride is used (81). This reaction demonstrates the difference ia reactivity between the octyl and the methyl Grignard reagents. 

CgH COO from BPO. The first type involves direct radical displacement on the oxygen—oxygen bond and is the preferred mode for nucleophilic radicals, eg, -CH(R)OR7 The second type involves radical addition to, or abstraction from, the hydrocarbyl group adjacent to the peroxide this is the preferred mode for electrophilic radicals, eg, Cl C (eq. 32). In the last type (eq. 33), there is hydrogen donation from certain hydrogen-donating radicals, eg, ketyls (52,187,188,199). 

Rate studies show that base-cataly2ed reactions are second order and depend on the phenolate and methylene glycol concentrations. The most likely path involves a nucleophilic displacement by the phenoxide on the methylene glycol (1), with the hydroxyl as the leaving group. In alkaline media, the methylolated quinone intermediate is readily converted to the phenoxide by hydrogen-ion abstraction (21). 

The pyrazole molecule resembles both pyridine (the N(2)—C(3) part) and pyrrole (the N(l)—C(5)—C(4) part) and its reactivity reflects also this duality of behaviour. The pyridinic N-2 atom is susceptible to electrophilic attack (Section 4.04.2.1.3) and the pyrrolic N-1 atom is unreactive, but the N-1 proton can be removed by nucleophiles. However, N-2 is less nucleophilic than the pyridine nitrogen atom and N(1)H more acidic than the corresponding pyrrolic NH group. Electrophilic attack on C-4 is generally preferred, contrary to pyrrole which reacts often on C-2 (a attack). When position 3 is unsubstituted, powerful nucleophiles can abstract the proton with a concomitant ring opening of the anion. 

Isoxazoles are susceptible to attack by nucleophiles, the reactions involving displacement of a substituent, addition to the ring, or proton abstraction with subsequent ring-opening. Isoxazolium salts are even more susceptible to attack by a variety of nucleophiles, providing useful applications of the isoxazole nucleus in organic synthesis. Especially useful is the reductive cleavage of isoxazoles, which may be considered as masked 1,3-dicarbonyl compounds or enaminoketones. 

Unsubstituted 2,1-benzisoxazoles undergo C(3)-proton abstraction with base to give an intermediate iminoketene which can undergo further reaction with nucleophiles. However, alternative Michael addition pathways are possible and these have been discussed (81AHC(29)l,p.56). 

Nucleophilic attack on ring hydrogen (proton abstraction) (Section 5.05.3.5)... 

Nucleophilic Attack on Ring Hydrogen (Proton Abstraction)... 

There are several reaction sequences which involve such intramolecular hydrogen abstraction steps. One example is the photolytically intitiated decomposition of N-haloamines in acidic solution, which is known as the Hofinann-Loffier reactionThe reaction leads initially to y-haloamines, but these are usually converted to pyrrolidines by intramolecular nucleophilic substitution ... 

In order to avoid competitive bimolecular photoreactions such as ketone reduction by hydrogen abstraction, poor hydrogen donating solvents are recommended (acetonitrile, acetic acid, tertiary alcohols). In those cases where ketene trapping is desired, solvents must also be miscible with water or other protic nucleophiles. 

FIGURE 8.11 When a Lewis base reacts with an alkyl halide, either substitution or elimination can occur. Substitution (Sn2) occurs when the Lewis base acts as a nucleophile and attacks carbon to displace bromide. Elimination (E2) occurs when the Lewis base abstracts a proton from the p carbon. The alkyl halide shown is isopropyl bromide, and elimination (E2) predominates over substitution with alkox-ide bases. 

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