Good and Poor Nucleophiles

Answers to these questions can experimentally obtained via pairs of SN reactions, which are carried out as competition experiments. In a competition experiment, two reagents react simultaneously with one substrate (or vice versa). Two reaction products can then be produced. The main product is the compound that results from the more reactive (or or more nucleophilic/electrophilic, as the case may be) reaction partner. 

For example, if two nucleophiles are reacted with some alkylating agent, the nucleophile that reacts to form the main product is then the better nucleophile. From the investigation of a large number of competition experiments of this type, gradations of the nucleophilicity exist that are essentially independent of the substrate. 

Why are the differences in nucleophilicity relatively the same over many different substitution reactions Nucleophilicity describes the ability of the nucleophile to make an electron pair available to the electrophile (i.e., the alkylating agent). With this as the basic idea, the experimentally observable nucleophilicity trends can be interpreted as follows. 

The reason for this is the unavoidable overlap of the orbitals that contain the free electron 

An important lesson from this is that the idea of nucleophilicity in the real world of organic reactions is not easy to pigeonhole. Polarizability is important, but basicity is also very important and can be influenced by solvation. Values of the pKa of a given compound vary as a function of solvent, and so does basicity. You can make a species, anions in particular, more reactive by putting them in solvents that don t solvate them very well. Dipolar aprotic solvents interact nicely with cations, but not so well with anions. Polar protic solvents (e. g., water, alcohols) can hydrogen bond to anions, diminishing their basicity and literally blocking them sterically. 

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For the reaction of hydride donors, organometallic compounds and heteroatom-stabilized carbanions with acylating agents or carbonyl compounds one encounters a universal reactivity order RC(=0)C1 > RC(=0)H > R2C=0 > RC(=0)0R > RC C NR It applies to both good and poor nucleophiles, but—in agreement with the reactivity/selectivity principle (Section 1.7.4)—the reactivity differences are far larger for poor nucleophiles. 

In mechanistic studies, it is common to fall back on qualitative information relating to the particular metal or nonmetal center. After working with particular types of compounds, a lore develops about what are good, not-so-good and poor nucleophiles. Sometimes, it is recognized that this correlates with one of the basicity scales. It can be of special interest when a particular system or class of ligands fails to follow a reasonably established correlation. This may point to some factor that was overlooked and may provide some mechanistic insight. 

The first factor that determines whether substitution or elimination occurs is the nucleophilicity and basicity of the lone-pair-bearing compound. The factors that influence nucleophilicity and basicity have already been discussed (Chapter 1). Nucleophiles-bases can be classified very simplistically into good nucleophiles-poor bases, good nucleophiles-good bases, and poor nucleophiles-good bases toward C(sp3) halides. 

Col. 2 Strong base Weak base and poor nucleophile Weak base and OK nucleophile Good nucleophile... 

This actually doesn t work well. Recall (Chapter 10) that nucleophilicity is dependent on polarizability (the size of the atom). Large atoms (like sulfur or iodine) are very polarizable, and therefore, they are excellent nucleophiles. Small atoms are not polarizable, and they make poor nucleophiles. H is as small as they come, and therefore H is not a great nucleophile. H is a good base (in fact, it is an excellent base), but it is not a good nucleophile. So, we use LAH or NaBH4 as a source of nucleophilic H . We can think of LAH and NaBH4 as delivery agents of nucleophilic H. ... 

First, the order of ky values in different solvents is quite reasonably interpreted as a nucleophilicity order - e.g. ( 113)280 > HjO CH3NO2 > C2H5OH) and second, the k rate is (as is the k2) greatly reduced by steric crowding . Of course, a nucleophilic attack by solvent is a very likely process, a priori. In any solvent, the solvent itself will be the poorest nucleophile that can be studied since poorer ones will not effectively compete. Thus the k term of equation (21) corresponds to the ki value. The aquo intermediate of scheme (22) has been trapped by using reactions in the presence of OH , a poor nucleophile but good base . ... 

Here, in contrast with the above examples, the retrosynthetic process is purely "mental", since the mesylate, as a good leaving group, is a poor nucleophile and the "reaction" will never take place whatever the reaction conditions. 

In 2005, Rovis and Reynolds reported the synthesis of a-chloroesters from a,a-dichloroaldehydes using chiral, enantioenriched not chirald pre-catalyst 75c [115], As shown in Table 14, the reaction scope includes a variety of dichloroaldehydes 201 that afford desired esters 202 in good yields and enantioselectivities. The reaction is compatible with various phenols, including electron-rich and electron-poor nucleophiles. Standard reaction conditions accommodate a variety of aldehydes, although substrates containing P-branching inhibit reactivity. 

A bulky base (a good base, but poor nucleophile) can further discourage undesired substitution reactions. The most common bulky bases are potas-sium-t-butoxide (r-BuOK), diisopropylamine and 2,6-dimethylpyridine. 

A second method to efficientiy produce mediyl esters of carboxylic acids is to heat die acid with potassium carbonate and mediyl iodide. The mediyl ester is produced under mild conditions and is easily separated from die reaction byproducts. This method is somewhat different in tiiat die ester is formed by a nucleophilic displacement of iodide by die carboxylate ion. Normally carboxy-lates are not thought of as good nucleophiles—and tiiey are not—but mediyl iodide is a quite reactive electrophile which matches die poor nucleophilicity of die carboxylate satisfactorily. 

Triflate, tosylate and mesylate are the anions of strong acids. The weak conjugate bases are poor nucleophiles. Nucleophilicity increases in parallel with the base strength. Thus, amines, alcohols and alkoxides are very good nucleophiles. Base strength is a rough measure of how reactive the nonbonding electron pair is thus, it is not necessary for a nucleophile to be anionic. 

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