Hard and soft nucleophiles

A comparison of reactions of halide and acetate ions with quinone methide 57 has been provided by Richard, Toteva, and Crugeiras.219 The lack of correlation between rate and equilibrium constants is highlighted by the fact that iodide ion is 1400 times more reactive than acetate despite the reaction being thermodynamically less favorable by bkcalmol This is characteristic of a comparison of soft and hard nucleophiles, of which the former show lower intrinsic barriers306,307 The consistent behavior between different (TV+)... 

In contrast to soft nucleophiles which attack the allyl face opposite the palladium complex, hard nucleophiles (e.g., organozinc reagents) first coordinate to the metal center and then are transferred intramolecularly to the allyl ligand (see, e.g.. Table 1 in [13]). Therefore, the reaction of allyl-palladium complexes with hard nucleophiles usually involves retention of configuration. However, the classification as soft and hard nucleophiles is not always unambiguous. With acetate as the nucleophile, e.g., the stereoselectivity depends on the reaction conditions and both overall inversion as well as retention have been observed [18]. 

P. Dauban, L. Dubois, M. Dau, and R. H. Dodd, Reactivity of 2,3-aziridino-2,3-dideoxy-D-lyxono-y-lactone derivatives, rigid analogs of aziridine-2-carboxylic esters, toward soft and hard nucleophiles—control of lactone vs. aziridine ring-opening and C-2 vs. C-3 regioselec-tivity, J. Org. Chem., 60 (1995) 2035-2043. 

Palladium-catalyzed aUylations of soft and hard nucleophiles have been widely studied and reviewed. Even though some general rules have been established based on steric and electronic features of the substrate, the nucleophile, and the catalyst, there are some atypical examples for which the outcome of the allylation is not as usual. The presence of a directing group such as an alkenyl chain (eq 35) or the 2-pyridyldimethylsilyl group (eq 36) leads... 

Cp carbon atom of the ynamine at the electrophilic terminal pentatetraenylidene atom, followed by cycloreversion. These observations seem to indicate a marked preference of soft nucleophiles for the Ce carbon atom and hard nucleophiles for the central carbon of the unsaturated chain. 

Fig. 8.4 Schematic showing relative softness and hardness of nucleophiles and electrophiles as an indicator of sites of reaction of electrophilic metabolites.

For both nucleophiles, 2,5-dinitrofuran is the most active substrate, the thiophene derivative follows. On the other hand, the relative reactivity of 1-methyl-2,5-dinitropyrrole and 1,4-dinitrobenzene depends on the nature of the nucleophile. For the 4-MeC6H4S anion, the former is more active by about two powers of ten, but in the piperidinolysis reaction the 1,4-benzene is superior. These phenomena appear to be caused by differences in the polarizability of both substrate and nucleophiles. p-Tolylthiolate anion is a softer nucleophile in comparison with piperidine and the pyrrole system is certainly more polarizable than the benzene molecule. Therefore soft-soft interaction of 1-methyl-2,5-dinitropyrrole with 4-MeC6H4S and hard-hard interaction of 1,4-dinitrobenzene with piperidine should occur easier than interactions between reagents with opposite types of softness and hardness. 

Nucleophiles partition between the two mechanisms based on their hard-soft characteristics, with soft nucleophiles undergoing ligand attack and hard nucleophiles attacking at the metal. A limited class of nucleophiles appear capable of adding by either mechanism, with secondary factors controlling their choice of mode of addition. 

Swain and Scott found satisfactory correlations with Equation (27) which provided 5 values for a number of reactants. However, as indicated in Scheme 33, for the limited number of substrates conveniently studied,158,186 variations in 5 did not show a clearly discernible pattern (and no obvious correlation with reactivity). Moreover, Pearson and Songstad demonstrated that the correlations break down if extended to extremes of soft and hard electrophilic centers such as platinum, in the substitution of trara,s-[Pt(pyridine)2Cl2], or hydrogen in proton transfer reactions.255 Despite this, Swain and Scott s equation has stood the test of time and it is noteworthy that a serious breakdown in the correlations occurs only when the reacting atoms of both nucleophile and electrophile are varied. In this chapter we will restrict ourselves to carbon as an electrophilic center, and particularly, although not exclusively, to carbocations. 

The concept of soft and hard acids and bases (7), which is in effect an extension of the Chatt-Ahrland classification (2) of A and B metals, is applied in the 1963 paper by Pearson (7) particularly to equilibria involving mainly inorganic systems. This paper follows an earlier discussion by Edwards and Pearson (3) of the Swain-Edwards equation (4) (1) for nucleophilic reactivity. 

The reactions of carbanions show them to be very soft bases (relative to OH- for example) and consequently they react more rapidly than most nucleophiles with both soft and hard acids. Thus carbanions are more basic than OH- and react preferentially with carbonyl centres in the presence of hydroxide ions, e. g. in the Claisen condensation. 

As cyanide ions operate as ambident nucleophiles, alkylation reactions may generate isonitriles as well as nitriles (equation 2). A whole range of parameters is responsible for the outcome of reactions of this type and their particular role together with special counter influences is not easily evaluated. There is a large and growing number of papers on this topic, but one can concentrate here on a few selected review articles.Suffice it to say that Komblum s seminal article s from 1955 is still of special importance in this field. Pearson s principle of soft and hard acids and bases (HSAB) proved to be particularly helpful in the interpretation of experimental results. ... 

The electrophiles or electrophilic intermediates that are or are postulated to be responsible for the carcinogenic action of chemicals include (i) positively charged carbonium, nitrenium, oxonium and episulfonium ions, (ii) free radicals, (iii) polarized double bonds, (iv) aldehydes, (v) strained rings such as epoxide, aziridine, lactones and sultones, and (vi) quinone/ quinoid/quinoneimine structures. Based on their reactivity (Table I), electrophiles may be graded from "soft" to "hard" similar to the concept of "soft" and "hard" acids and bases (18). In general, soft electrophiles react preferentially with soft nucleophiles whereas hard electrophiles react preferentially with hard nucleophiles. Thus, since the nucleophilic sites in the purine and pyrimidine bases in DNA are moderately hard nucleophiles, moderately hard electrophiles tend to have the greatest likelihood of covalent binding to DNA. Soft electrophiles often deplete the cellular pool of noncritical soft nucleophiles (such as GSH) before they can react with DNA. 

Electrophiles and nucleophiles can be classified as either hard or soft. Hard electrophiles and nucleophiles are more polarized than soft ones. Hard nucleophiles prefer to react with hard electrophiles, and soft nucleophiles prefer to react with soft electrophiles. Therefore, a Grignard reagent with a highly polarized C—Mg bond prefers to react with the harder C=0 bond, whereas a Gilman reagent with a much less polarized C—Cu bond prefers to react with the softer C=C bond. 

Geerlings De Proft, 2008 Cardenas et al., 2009 Senet, 1996). One may obtain a condensed-to-atom variant and also for the electrophilic, nucleophilic and radical attacks in the usual way. Moreover, the inverse of tu(r,r ) may generate a hierarchy of nucleophilicity kernel. Unlike the previous formulations, the overall treatment here is general and analytic with hardly any bearing on the explicit form of E(N). The traditional operational definition of local softness and hardness contain the same potential information and they should be interpreted as the local abundance or concentration of their corresponding global properties. 

The HS AB principle provides a good description of many nucleophile-electrophile interactions soft-soft and hard-hard interactions are both thermodynamically and kinetically favored. 

Two different pathways subsequently occur for soft or hard nucleophiles, soft nucleophiles, such as those derived from conjugate acids with a pX a < 25 and most heteroatoms, directly the attack the n-allyl unit (i.e. from outside the coordination sphere of the metal) from the opposite face of the palladium, resulting in a second inversion to give product 7. On the other hand, hard nucleophiles such as conjugate acids with a pA a > 25, attack the metal centre directly (transmetallation), followed by reductive elimination. This gives products with inversion of configuration, 6. ... 

Steric effects are also important in determining nudeophilicity. The reaction between a base and a proton is sterically completely undemanding. However, an Sn2 reaction is sterically much more challenging—at the transition state (9.1), five groups must be accommodated around the central carbon atom. Thus, as well as softness and hardness, we need to consider size. Bulky species, such as PhjC" and tert-BuO , are good bases but very poor nucleophiles. Triethylamine and quinuclidine, 9.2, have similar basicity, but quinuclidine is the better nucleophile, because the alkyl groups are tied back and out of the way. 

The stereochemistry of the Pd-catalyzed allylation of nucleophiles has been studied extensively[5,l8-20]. In the first step, 7r-allylpalladium complex formation by the attack of Pd(0) on an allylic part proceeds by inversion (anti attack). Then subsequent reaction of soft carbon nucleophiles, N- and 0-nucleophiles proceeds by inversion to give 1. Thus overall retention is observed. On the other hand, the reaction of hard carbon nucleophiles of organometallic compounds proceeds via transmetallation, which affords 2 by retention, and reductive elimination affords the final product 3. Thus the overall inversion is observed in this case[21,22]. 

Unsaturated sugars are useful synthetic intermediates (11). The most commonly used are the so-called glycals (1,5- or 1,4-anhydroalditol-l-enes). In the presence of a Lewis-acid catalyst, 3,4,6-tri-0-acetyl-l,5-anhydro-2-deoxy-D-arabinohex-l-enitol [2873-29-2] commonly called D-glucal triacetate, adds nucleophiles in both kineticaHy controlled and thermodynamically controlled (soft bases predominately at C-3 and hard bases primarily at C-1) reactions (11,13). 

It was mentioned earlier that 6-halopenlclllanlc acids are resistant to nucleophilic displacement. Displacement at the 6-positlon with soft nucleophiles (e.g. halide, RS ) but not hard nucleophiles e.g. MeO , amines) can be carried out, however, on 6-trifloxy- and 6-nonafloxy-penlclllanate esters (80TL2991). Some examples are shown in Scheme 38. 

The soft-nucleophile-soft-electrophile combination is also associated with a late transition state, in which the strength of the newly forming bond contributes significantly to the stability of the transition state. The hard-nucleophile-hffld-elechophile combination inqilies an early transition state with electrostatic attraction being more important than bond formation. The reaction pathway is chosen early on the reaction coordinate and primarily on the basis of charge distributiotL... 

In fee absence of fee solvation typical of protic solvents, fee relative nucleophilicity of anions changes. Hard nucleophiles increase in reactivity more than do soft nucleophiles. As a result, fee relative reactivity order changes. In methanol, for example, fee relative reactivity order is N3 > 1 > CN > Br > CP, whereas in DMSO fee order becomes CN > N3 > CP > Br > P. In mefeanol, fee reactivity order is dominated by solvent effects, and fee more weakly solvated N3 and P ions are fee most reactive nucleophiles. The iodide ion is large and very polarizable. The anionic charge on fee azide ion is dispersed by delocalization. When fee effect of solvation is diminished in DMSO, other factors become more important. These include fee strength of fee bond being formed, which would account for fee reversed order of fee halides in fee two series. There is also evidence fiiat S( 2 transition states are better solvated in protic dipolar solvents than in protic solvents. 

---