Nucleophilic substitution intermolecular additions

Additional experimental, theoretical, and computational work is needed to acquire a complete understanding of the microscopic dynamics of gas-phase SN2 nucleophilic substitution reactions. Experimental measurements of the SN2 reaction rate versus excitation of specific vibrational modes of RY (equation 1) are needed, as are experimental studies of the dissociation and isomerization rates of the X--RY complex versus specific excitations of the complex s intermolecular and intramolecular modes. Experimental studies that probe the molecular dynamics of the [X-. r - Y]- central barrier region would also be extremely useful. 

Lamaty and coworkers described a straightforward combination of three Pd-cata-lyzed transformations first, an intermolecular nucleophilic substitution of an al-lylic bromide to form an aryl ether second, an intramolecular Heck-type transformation in which as the third reaction the intermediate palladium species is intercepted by a phenylboronic acid [124]. Thus, the reaction of a mixture of 2-iodophenol (6/1-253), methyl 2-bromomethylacrylate 6/1-254 and phenylboronic acid in the presence of catalytic amounts of Pd(OAc)2 led to 3,3-disubstituted 2,3-di-hydrobenzofuran 6/1-255 (Scheme 6/1.66). In addition to phenylboronic acid, several substituted boronic acids have also been used in this process. 

Alcohols are not only source of ketyl radicals generated by hydrogen abstraction from the a-C-H position (Eq. (7), Table 1). Oxidation of alcohols with Pb(OAc)4, PhI(OAc)2, and S2082 with Ag(I) as catalyst produces alkoxy radicals (RO-) which may further undergo /3-scission (Eq. 13), intramolecular hydrogen abstraction, or intra- and intermolecular addition to alkenes, generating a nucleophilic carbon-centered radical useful for heteroaromatic substitution (Scheme 6) [2]. 

Intermolecular addition of carbon nucleophiles to the ri2-pyrrolium complexes has shown limited success because of the decreased reactivity of the iminium moiety coupled with the acidity (pKa 18-20) of the ammine ligands on the osmium, the latter of which prohibits the use of robust nucleophiles. Addition of cyanide ion to the l-methyl-2//-pyr-rolium complex 32 occurs to give the 2-cyano-substituted 3-pyrroline complex 75 as one diastereomer (Figure 15). In contrast, the 1-methyl-3//-pyrrolium species 28, which possesses an acidic C-3-proton in an anti orientation, results in a significant (-30%) amount of deprotonation in addition to the 2-pyrroline complex 78 under the same reaction conditions. Uncharacteristically, 78 is isolated as a 3 2 ratio of isomers, presumably via epimerization at C-2.17 Other potential nucleophiles such as the conjugate base of malononitrile, potassium acetoacetate, and the silyl ketene acetal 2-methoxy-l-methyl-2-(trimethylsiloxy)-l-propene either do not react or result in deprotonation under ambient conditions. 

Additional evidence for the occurrence of gas-phase intermolecular and intramolecular nucleophilic substitution was obtained in an investigation on the reactivity of mono- and dichlorophenols within the high-pressure mass spectrometer source under conditions of argon-enhanced negative ion mass spectrometry282. It was shown that the reactant anions involved in these processes are derived exclusively from the chlorophenols and not from possible impurities such as residual oxygen, water, etc. Thus, for example, the formation of an abundant [2M - H - Cl]" adduct was attributed to an intermolecular nucleophilic Cl displacement by an [M - H]" chlorophenoxide ion282. 

Cyclic sulfides (episulfides) are known and may be prepared by reaction of an epoxide (14) with potassium thiocyanate to give the episulfide (15), or by reaction of sodium sulfide with 1,4-or 1,5-dihalides for example, (16) yields the episulfide (17) (Scheme 11). The mechanism of the first reaction in Scheme 11 involves initial nucleophilic addition of the thiocyanate anion to the epoxide (14) followed by nucleophilic substitution to yield the episulfide (15) (Scheme 12). The second reaction is an intermolecular followed by an intramolecular nucleophilic substitution... 

Lewis acid complexes of p-substituted a,p-unsaturated ketones and aldehydes are unreactive toward alkenes. Crotonaldehyde and 3-penten-2-one can not be induced to undergo ene reactions as acrolein and MVK do. 34 The presence of a substituent on the p-carbon stabilizes the enal- or enone-Lewis acid complex and sterically retards the approach of an alkene to the p-carbon. However, we have found that a complex of these ketones and aldehydes with 2 equivalents of EtAlQ2 reacts reversibly with alkenes to give a zwitterion. 34 This zwitterion, which is formed in the absence of a nucleophile, reacts reversibly to give a cyclobutane or undergoes two 1,2-hydride or alkyl shifts to irreversibly generate a p,p-disubstituted-o,p-unsaturated carbonyl compound (see Figure 19). The intermolecular addition of an enone, as an electrophile, to an alkene has been observed only rarely. The specific termination of the reaction by a series of alkyl and hydride shifts is also very unusual. 35 The absence of polymer is remarkable. 

The reaction is first carried out in acid solution. The photolysis of the N-chloroammonium ions produces an aminium radical ion which, by abstraction of an H-atom from the methyl group, is converted into an alkyl radical. The latter initiates a chain reaction hy abstracting a Cl-atom from a new N-chloroammonium ion. After addition of a base, the ring closure occurs by intermolecular nucleophilic substitution via the corresponding S-chloroalkylamine. 

Induced intramolecular nucleophilic catalysis involves the formation of a molecular addition complex (Ad) between the reactant/substrate (R-A) and catalyst (W-B) followed by intramolecular nucleophilic substitution reaction between two reaction sites A and B giving products P3 and P4, where one of the products, say P4, is unstable, i.e., more reactive, and, hence, P4 undergoes further reaction to reproduce catalyst (W-B) and give the final stable product P5. This whole chemical process may be shown by Equation 2.27. Intramolecular induced nucleophilic catalysis involves the intermolecular nucleophihc substitution reaction between R-A and catalyst, (C-W-B), where nucleophilicity of the nucleophile is enhanced owing to intramolecular interaction between molecular sites B and C of catalyst. 

Intermolecular hydroalkoxylation of 1,1- and 1,3-di-substituted, tri-substituted and tetra-substituted allenes with a range of primary and secondary alcohols, methanol, phenol and propionic acid was catalysed by the system [AuCl(IPr)]/ AgOTf (1 1, 5 mol% each component) at room temperature in toluene, giving excellent conversions to the allylic ethers. Hydroalkoxylation of monosubstituted or trisubstituted allenes led to the selective addition of the alcohol to the less hindered allene terminus and the formation of allylic ethers. A plausible mechanism involves the reaction of the in situ formed cationic (IPr)Au" with the substituted allene to form the tt-allenyl complex 105, which after nucleophilic attack of the alcohol gives the o-alkenyl complex 106, which, in turn, is converted to the product by protonolysis and concomitant regeneration of the cationic active species (IPr)-Au" (Scheme 2.18) [86]. 

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

One of the first examples of addition of a zinc enolate to an alkyne was a report dealing with the zinc or cadmium stearate-catalyzed addition of substituted malonates to acetylene under pressure250. Later, Schultze described the intermolecular nucleophilic addition of the zinc enolate derived from diethyl bromomalonate to phenylacetylene in refluxing xylene leading to the alkylidene malonate 392 (equation 171)251. 

In a recent report, Shi et al. developed a valuable tool for the synthesis of 2,6-trans substituted morpholines by addition of water and alcohol to epoxy alkynes [109]. The procedure involved a domino three-membered ring opening, 6-exo-cycloisomerization, and subsequent intra-or intermolecular nucleophilic addition or a double-bond sequence. 

The main methods for the synthesis of hexacoordinate silicon compounds are similar to those for pentacoordinate complexes and were outlined in a recent review6. These methods include (a) addition of nucleophiles (neutral or anionic) to tetracoordinate silanes (b) intermolecular or intramolecular coordination to an organosilane (c) substitution of a bidentate ligand in a tetrafunctional silane. The following discussion focuses mainly on new complexes, reported since the recent reviews6,7 were published. 

The aziridination of olefins, which forms a three-membered nitrogen heterocycle, is one important nitrene transfer reaction. Aziridination shows an advantage over the more classic olefin hydroamination reaction in some syntheses because the three-membered ring that is formed can be further modified. More recently, intramolecular amidation and intermolecular amination of C-H bonds into new C-N bonds has been developed with various metal catalysts. When compared with conventional substitution or nucleophilic addition routes, the direct formation of C-N bonds from C-H bonds reduces the number of synthetic steps and improves overall efficiency.2 After early work on iron, manganese, and copper,6 Muller, Dauban, Dodd, Du Bois, and others developed different dirhodium carboxylate catalyst systems that catalyze C-N bond formation starting from nitrene precursors,7 while Che studied a ruthenium porphyrin catalyst system extensively.8 The rhodium and ruthenium systems are... 

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