Neutral nucleophile

Regarding the substituent effect on reactivity of groups in positions 4 and 5 there is little information in the literature. The reactivity of halogen in position 5 seems to be increased when an amino group is present in position 2. Substitution products are easily obtained using neutral nucleophiles such as thiourea, thiophenols, and mercaptans (52-59). 

The Lewis base that acts as the nucleophile often is but need not always be an anion Neutral Lewis bases can also serve as nucleophiles Common examples of substitutions involving neutral nucleophiles include solvolysis reactions Solvolysis reactions are substitutions m which the nucleophile is the solvent m which the reaction is carried out 8olvolysis m water (hydrolysis) converts an alkyl halide to an alcohol... 

The reactions of dinitrothiophenes with nucleophiles have been studied systematically. In the case of 2,3-dinitrothiophene, reaction with neutral nucleophiles yields more of the... 

Spontaneous perfluoroalkylatwn ofenamines occurs in the presence of fluor-inated perhalogenoalkanes [743, 744] This condensation is interpreted by a SET process (mechanism analogous to equation 57 with a neutral nucleophile in place of a charged nucleophilic reagent). Formation of chlorodifluoromethylcyclo... 

The nature of the nucleophile plays a major role in the SN2 reaction but does not affect an S l reaction. Because the SN1 reaction occurs through a rale-limiting step in which the added nucleophile has no part, the nucleophile can t affect the reaction rate. The reaction of 2-methyl-2-propanoI with HX, for instance, occurs at the same rate regardless of whether X is Cl, Br, or 1. Furthermore, neutral nucleophiles are just as effective as negatively charged ones, so S 1 reactions frequently occur under neutral or acidic conditions. 

Nucleophile The nucleophile must be nonbasic to prevent a competitive elimination of HX (Section 11.7), but otherwise does not affect the reaction rate. Neutral nucleophiles work well. 

The two main reasons for studying the reversible reaction (3) were (a) to complete the picture of the Koch reaction in terms of quantitative information and (b) to set up a scale of reactivity towards a neutral nucleophile for carbonium ions of different structure. The first item is important from a practical point of view because there are reactions competing with the carbonylation step (3), which can be divided into intramolecular and intermolecular processes. Rearrangement of the intermediate alkylcarbonium ion, e.g. 

Reaction of 165 with neutral nucleophiles such as aniline leads to disubstitution of the PC12 group but with no further substitution. Sterically undemanding charged nucleophiles replace all the three chlorines (Scheme 20) <2004CEJ4915>. 

As pyramidal amides5,32 their Sn2 reactivity with neutral nucleophiles like /V-methylaniline parallels that of a-haloketones with amines, which, as described in an earlier section, are also strongly affected by steric effects on the a -carbon.183 SN2 reactions are in general strongly and adversely influenced by steric effects and branching / to the reactive centre and the same appears to be true for /V-acyloxy-/V-alkoxyamides 30b and 29a-e. Broadly speaking, their mutagenic activity is affected similarly. 

For neutral nucleophiles the electrostatic interaction between N and X will stabilize the syn more than the anti geometry due to the proximity of the two oppositely charged groups while the opposite will obtain when N is charged. 

The usual kinetic law for S/v Ar reactions is the second-order kinetic law, as required for a bimolecular process. This is generally the case where anionic or neutral nucleophiles react in usual polar solvents (methanol, DMSO, formamide and so on). When nucleophilic aromatic substitutions between nitrohalogenobenzenes (mainly 2,4-dinitrohalogenobenzenes) and neutral nucleophiles (amines) are carried out in poorly polar solvents (benzene, hexane, carbon tetrachloride etc.) anomalous kinetic behaviour may be observed263. Under pseudo-monomolecular experimental conditions (in the presence of large excess of nucleophile with respect to the substrate) each run follows a first-order kinetic law, but the rate constants (kQbs in s 1 ruol 1 dm3) were not independent of the initial concentration value of the used amine. In apolar solvents the most usual kinetic feature is the increase of the kabs value on increasing the [amine]o values [amine]o indicates the initial concentration value of the amine. 

For neutral nucleophiles (e.g. amines, alcohols, water) there is much evidence that the addition-elimination mechanism depicted in equation 1 fits very well most of the intermolecular and intramolecular nucleophilic displacements involving nitro-activated aromatic substrates1. 

These treatments have been also applied to S/yAr. For example, for a neutral nucleophile, all the classical pathways identified at present are represented by the general reaction mechanism shown by Scheme 2. A concerted mechanism, indicated by the diagonal path in Scheme 2, had not been discussed until lately, but was observed, among other systems, in the hydrolysis of l-chloro-2,4,6-trinitrobenzene and 1-picrylimidazole. The study was then extended to other related substrates and structure-reactivity relationships could be obtained78. 

Other interesting data in these reactions concern the H/D isotopic effect of the nucleophile/catalyst, for example when [2-hydroxypyridine] = [2 — 02H] = 0.08, fcobsH/ obsD = 1-5. Since a very poor H/D effect is usual in SjvAr reactions with neutral nucleophiles (amines) in apolar solvents10, the authors conclude that the unusually high H/D effect should be due to a difference in the Xh/Xd = 1.75 of the molecular complex. Nevertheless, the same effect could be explained on the basis of an autoassociation of... 

Some obscure facets of this intricate picture have been unveiled by Filippi and Speranza who investigated the stereochemistry and the intimate mechanism of a model solvolytic reaction taking place in an ion-dipole pair in the gaseous phase. ° Adducts (7 )-56 and R)-51 are obtained in the gas phase by association of the relevant chiral alcohols, i.e., (/ )-(- -)-l-phenyl-ethanol ((I )-44) and (/f)-(- -)-l-(pentafiuorophenyl)ethanol K)-55), with the CHs OHJ ion, generated by y-radiolysis of CH3F/H2 0 mixtures (Scheme 24). As mentioned above, the absence of neutral nucleophile molecules, i.e., CH3 OH, in the reaction medium ensures that the 0-labeled ethers 45 and 58 of Scheme 24 arise exclusively from the intracomplex solvolysis of R)-56 and R)-51, respectively. 

Studies of gas-phase S"n2 reactions at sp carbon have been made by Fourier transform ion cyclotron resonance mass spectrometry (FTlCRMS) and complemented by both semiempirical and ab initio MO calculations. The particular processes of interest involved intramolecular reactions in which neutral nucleophiles displace neutral leaving groups within cationic substrates, e.g. A-(2-piperidinoethyl)-2,4,6-triphenylpyridinium cation (59), in which the piperidino moiety is the nucleophile and 2,4,6-triphenylpyridine (60) is the leaving group. No evidence has been obtained for any intermolecular gas-phase 5) 2 reaction involving a pyridine moiety as a leaving group. The quantum mechanical treatments account for the intramolecular preference. 

Part of the great efficiency of the intramolecular reactions of [26] and [27] is undoubtedly due to the correct alignment of the rigidly held nucleophile and carbonyl group. Molecular models show that in one of the conformations of [27] in which steric interactions are minimized, the phenoxide ion is immediately adjacent to the carbonyl group and in an excellent position for perpendicular attack (Bender, 1960) but other factors must also be important. Correct orientation would not explain why anionic nucleophiles are superior to neutral nucleophiles. Extensive studies have not been carried out with nitrogen nucleophiles in carbamate ester hydrolysis, but Hegarty and Frost (1972) found that carbamate [29] underwent elimination to an isocyanate. This can be contrasted with the... 

The use of neutral nucleophiles, such as ammonia and hydrazine, causes a reversal of polarity of one of the transitory dipoles, and these displacement reactions are therefore more favorable than with azide. On the other hand, the greater basicity of these reagents are more likely to cause elimination. 

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