First order nucleophilic substitution

In the case of the hexacarbonyls, the rate-expression contains not only the same type of first-order term but in addition one second-order overall. For good entering groups (but not CO, for example) the rate expression contains a term strictly first-order in both the complex and the entering nucleophile. The first-order rates of CO exchange are practically identical with the rates of substitution in hydrocarbon solvents, but there is nevertheless some acceleration in ether (THF, dioxan) solutions. This solvent-dependence is not so well-marked ° as in the case of nickel tetracarbonyl. The second-order rate of substitution very strongly depends upon the basicity of the entering nucleophile... 

FIGURE 2.10 Differentiation of SN1 (substitution nucleophilic unimolecular, first order) and SN2 (substitution nucleophilic bimolecular, second order) reactions. 

The first step, which is rate-determining, is an ionization to a carbocation intermediate that reacts with the nucleophile in the second step. Because the transition state for the rds includes R-X but not Y, the reaction is unimolecular and is labeled S l (substitution nucleophilic unimolecular). First-order kinetics are observed, with the rate being independent of the nucleophilic identity and concentration. 

Fluoro-6-benzyloxy-9-y -D-ribofuranosylpurine dissolved in methanolic methylamin, and allowed to stand 1 hr. at room temp. 2-methylamino-6-benzyloxy-9-y -D-ribofuranosylpurine. Y 72%. — In the above startg. m. the usual order of nucleophilic substitution, first at position 6 then at 2, is reversed. F. e. s. J. F. Gerster and R. K. Robins, Am. Soc. 87, 3752 (1965). 

The kinetics of nucleophilic aromatic substitution is almost always second order—first order in nucleophile and first-order in the aromatic electrophile. The intermediate structure is called the Meisenheimer complex (or Jackson-Meisenheimer complex). The Meisenheimer complex can sometimes be directly observed at low temperatures. In aprotic sol-... 

Photo-induced aromatic substitution reactions occur through an electron transfer process, which creates an aromatic radical anion or aromatic radical cation as intermediate. This intermediate couples with the electrophile or nucleophile radical to give the product. This mechanism is called Sr I (where the abbreviations stand for substitution, radical, nucleophilic, and first order). Photoirradiation of aromatic compounds in the presence of nucleophiles gives nucleophilic-substituted products different from those of thermal reaction. For example, 3,4-dimethoxynitrobenzene on UV irradiation in presence of hydroxide ion gives 3-hydroxy-substituted product, while on heating gives 4-hydroxy-substituted product [57]. 

These reactions follow first-order kinetics and proceed with racemisalion if the reaction site is an optically active centre. For alkyl halides nucleophilic substitution proceeds easily primary halides favour Sn2 mechanisms and tertiary halides favour S 1 mechanisms. Aryl halides undergo nucleophilic substitution with difficulty and sometimes involve aryne intermediates. 

The first mechanistic studies of silanol polycondensation on the monomer level were performed in the 1950s (73—75). The condensation of dimethyl sil oxanediol in dioxane exhibits second-order kinetics with respect to diol and first-order kinetics with respect to acid. The proposed mechanism involves the protonation of the silanol group and subsequent nucleophilic substitution at the siHcone (eqs. 10 and 11). 

Substituted 2-haloaziridines are also known to undergo a number of reactions without ring opening. For example, displacement of chlorine in (264) with various nucleophilic reagents has been found to occur with overall inversion of stereochemistry about the aziridine ring (65JA4538). The displacements followed first order kinetics and faster rates were noted for (264 R = Me) than for (264 R = H). The observed inversion was ascribed to either ion pairing and/or stereoselectivity. 

The points that we have emphasized in this brief overview of the S l and 8 2 mechanisms are kinetics and stereochemistry. These features of a reaction provide important evidence for ascertaining whether a particular nucleophilic substitution follows an ionization or a direct displacement pathway. There are limitations to the generalization that reactions exhibiting first-order kinetics react by the Sj l mechanism and those exhibiting second-order kinetics react by the 8 2 mechanism. Many nucleophilic substitutions are carried out under conditions in which the nucleophile is present in large excess. When this is the case, the concentration of the nucleophile is essentially constant during die reaction and the observed kinetics become pseudo-first-order. This is true, for example, when the solvent is the nucleophile (solvolysis). In this case, the kinetics of the reaction provide no evidence as to whether the 8 1 or 8 2 mechanism operates. 

In general, the reaction between a phenol and an aldehyde is classified as an electrophilic aromatic substitution, though some researchers have classed it as a nucleophilic substitution (Sn2) on aldehyde [84]. These mechanisms are probably indistinguishable on the basis of kinetics, though the charge-dispersed sp carbon structure of phenate does not fit our normal concept of a good nucleophile. In phenol-formaldehyde resins, the observed hydroxymethylation kinetics are second-order, first-order in phenol and first-order in formaldehyde. 

Ammonolysis of 2-chlorobenzothiazole in liquid ammonia was studied by Lemons et al. and found to be approximately first-order with respect to this substrate at the fairly high concentrations used. The actual nucleophilic reagent was, as expected, the neutral species NH3, and reaction via the amide ion NH2 arising from the autoprotolysis equilibrium [Eq. (5)] was excluded on the grounds that addition of ammonium chloride did not depress the reaction rate. In accordance with this interpretation and in connection with the existence of aromatic substitutions other than normal it is of interest that 2-chlorobenzothiazole was found to react difiFerently with sodamide, although the products were unidentified in this case. 

Like the kinetic evidence, the stereochemical evidence for the SnI mechanism is less clear-cut than it is for the Sn2 mechanism. If there is a free carbocation, it is planar (p. 224), and the nucleophile should attack with equal facility from either side of the plane, resulting in complete racemization. Although many first-order substitutions do give complete racemization, many others do not. Typically there is 5-20% inversion, though in a few cases, a small amount of retention of configuration has been found. These and other results have led to the conclusion that in many SnI reactions at least some of the products are not formed from free carbocations but rather from ion pairs. According to this concept," SnI reactions proceed in this manner ... 

It has been pointed out that the types of solvents which are used here, are not generally such as would enter into strong association with the substrate. The molecularity of the substitution reaction may then stand more chance of being an operational concept. Amongst the binary carbonyls, the only systems which have been extensively studied have been nickel tetracarbonyl and the hexacarbonyls of group VI. For the former, the observation of a first-order rate is at least consistent with a rate-determining dissociation of one carbonyl ligand followed by reaction of the intermediate with whichever nucleophile should be available. 

Cyanide is not the only nucleophile to effect reactions as in Scheme 35, C, but of those studied so far only benzenesulfinate and phenoxide are similar (and also show second order kinetics) while others give simple substitution with no rearrangement (and show first order kinetics). No doubt ionization to a furylium ion plays an important part in some of these transformations, but it is harder to account for the behavior of 70 which yields a lactone (71) and almost no cyano products.198... 

Fig. 5 Logarithmic plots of rate-equilibrium data for the formation and reaction of ring-substituted 1-phenylethyl carbocations X-[6+] in 50/50 (v/v) trifluoroethanol/water at 25°C (data from Table 2). Correlation of first-order rate constants hoh for the addition of water to X-[6+] (Y) and second-order rate constants ( h)so1v for the microscopic reverse specific-acid-catalyzed cleavage of X-[6]-OH to form X-[6+] ( ) with the equilibrium constants KR for nucleophilic addition of water to X-[6+]. Correlation of first-order rate constants kp for deprotonation of X-[6+] ( ) and second-order rate constants ( hW for the microscopic reverse protonation of X-[7] by hydronium ion ( ) with the equilibrium constants Xaik for deprotonation of X-[6+]. The points at which equal rate constants are observed for reaction in the forward and reverse directions (log ATeq = 0) are indicated by arrows.

According to this mechanism, there is a first-order dependence on both the concentration of [ A B] and B, and the reaction is called an SN2 process (substitution, nucleophilic, second-order). Although many nucleophilic substitution reactions follow one of these simple rate laws, many others do not. More complex rate laws such as... 

Although the first term in Eq. (20.85) appears to be first-order in complex, it usually represents a second-order process in which the solvent (which is usually a nucleophile) is involved. The relationships show that if a plot is made of fcobs versus [A], the result is a straight line having a slope of fe2 and an intercept of fej. Therefore, the substitution process can be viewed as if it occurs by two pathways. This situation can be described as illustrated in Figure 20.8. 

There would seem to be two positions one can take with respect to the interpretation of the behavior revealed by Figs 1 and 2. The first, which would undoubtedly be favored by proponents of HSAB, is that the large deviations of the points for soft-base nucleophiles in Fig. 2 show that HSAB considerations do play an important role in determining the relative order of reactivity of a series of nucleophiles in nucleophilic substitutions at different electrophilic centers when those centers differ significantly in their degree of hardness , and that the failure to observe sizeable deviations from the correlation line in Fig. 1... 

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. 

Unless a more specific reference is given, rate coefficients in Section VI.B have been taken from the volumes of Reference 107c Volume 3, Part 1 (first order nucleophilic substitution) Volume 4, Part 2 (aromatic nucleophilic substitution). 

This reaction proceeds via the transition state illustrated in Fig. 10.2. An Sn2 reaction (second order nucleophilic substitution) in the rate limiting step involves the attack of the nucleophilic reagent on the rear of the (usually carbon) atom to which the leaving group is attached. The rate is thus proportional to both the concentration of nucleophile and substrate and is therefore second order. On the other hand, in an SnI reaction the rate limiting step ordinarily involves the first order formation of an active intermediate (a carbonium ion or partial carbonium ion, for example,) followed by a much more rapid conversion to product. A sampling of a and 3 2° deuterium isotope effects on some SnI and Sn2 solvolysis reactions (i.e. a reaction between the substrate and the solvent medium) is shown in Table 10.2. The... 

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