Nucleophilic-electrophilic-general acid

Calixcrown 5, featuring two diethylaminomethyl side-arms at the polyether bridge, testifies an attempt at a higher order multifunctional catalysis of ester cleavage, namely, from nucleophilic-electrophilic to nucleophilic-electrophilic-general acid catalysis [20]. 

Looking at the mode of activation, one should consider two commonly accepted mechanisms (a) specific acid catalysis and (b) general acid catalysis. While specific acid catalysis refers to the reversible protonation of the electrophile with a strong acid in a pre-equilibrium step prior to nucleophilic attack, general acid catalysis involves the proton transfer or hydrogen bonding activation to the transition state in the rate-determining step e.g. nucleophilic attack), usually under weakly acidic or neutral conditions (Scheme 95) 366). 

Before beginning a detailed discussion of alkene reactions, let s review briefly some conclusions from the previous chapter. We said in Section 5.5 that alkenes behave as nucleophiles (Lewis bases) in polar reactions. The carbon-carbon double bond is electron-rich and can donate a pair of electrons to an electrophile (Lewis acid), for example, reaction of 2-methylpropene with HBr yields 2-bromo-2-methylpropane. A careful study of this and similar reactions by Christopher Ingold and others in the 1930s led to the generally accepted mechanism shown in Figure 6.7 for electrophilic addition reactions. 

The answer is to use an enamine. Work by Hunig has established that the best combination is the morpholine enamine (73) as the nucleophile and an acid chloride as the electrophile. The yields are generally excellent. 

Of the many reagents, both heterogeneous and homogeneous, that can facilitate chemical reactions, the cycloamyloses stand out. Reactions can be catalyzed with many species such as hydronium ions, hydroxide ions, general acids, general bases, nucleophiles, and electrophiles. More effective catalysis can sometimes be achieved by combinations of catalytic species as in multiple catalysis, intramolecular catalysis, and catalysis by com-plexation. Only the latter catalysis can show the real attributes of an efficient catalytic system, namely speed and selectivity. In analogy to molecular sieves, selectivity can be attained by stereospecific complexation and speed can be likewise attained if the stereochemistry within the complex is correct. The cycloamyloses, of any simple chemical compound, come the closest to these goals. 

A study of the reactions of butadiene, isoprene, or allene coordinated to nickel in a metallacycle, with carbonylic compounds, has been reported by Baker (example 11, Table IV). In the presence of phosphines, these metallacycles adopt a cr-allyl structure on one end and a ir-allyl structure on the other, as mentioned in Section II,A,1. The former is mainly attacked by aldehydes or electrophilic reagents in general, the latter by nucleophiles (C—H acids, see Table I, or amines, see Table IX). 

As we have seen (Section 4, p. 191) the range of effective molarities associated with ring-closure reactions is very much greater than that characteristic of intramolecular general acid-base catalysis the main classification is therefore in terms of mechanism. By far the largest section (I, Tables A-D) gives EM s for intramolecular nucleophilic reactions. These can be concerted displacements (mostly at tetrahedral carbon), stepwise displacements (mostly addition-elimination reactions at trigonal carbon), or additions, and they have been classified in terms of the nucleophilic and electrophilic centres. 

Fig. 10.14. Reactivity ofdiol epoxides (Nu = H20, HCT, or another nucleophile), a) Hydrolytic reaction of diol epoxides to tetrols. b) Internal H-bonding in diol epoxides with syw-config-uration and rendering the distal C-atom more electrophilic (modified from [104]). c) General representation of proton-catalyzed (A-H = H+), general acid catalyzed (A-H = acid), or intra-molecularly catalyzed (A-H = syn-OW group) activation of the distal C-atom toward... 

One of the central mechanistic questions regarding ubiquitination has been whether the reaction utilizes general acid/base catalysis, possibly in a manner analogous to the catalysis of peptide-bond cleavage. For example, an acidic catalytic residue could deprotonate the substrate lysine and make it a better nucleophile for attacking the ubiquitin thioester bond. In addition, a basic catalytic residue could polarize the thioester bond making the carbonyl carbon a better electrophile, and... 

A series of diaquatetraaza cobalt(III) complexes accelerated the hydrolysis of adenylyl(3 -50adenosine (ApA) (304), an enhancement of 10 -fold being observed with the triethylenetetramine complex (303) at pH 7. The pentacoordinated intermediate (305), which is formed with the complex initially acting as an electrophilic catalyst, then suffers general acid catalysis by the coordination water on the Co(III) ion to yield the complexed 1,2-cyclic phosphate (306), the hydrolysis of which occurs via intracomplex nucleophilic attack by the metal-bound hydroxide ion on the phosphorus atom. Neomycin B (307) has also been shown to accelerate the phosphodiester hydrolysis of ApA (304) more effectively than a simple unstructured diamine. 

Fig. 3 Possible catalytic functions of metal ions in the cleavage of a phosphodiester bond. Metal ions can act as (a) a general acid catalyst, (b) a general base catalyst, (c) a Lewis acid that stabilizes the leaving group, (d) a Lewis acid that enhances the deprotonation of the attacking nucleophile, and (e) an electrophilic catalyst that increases the electrophilicity of the phosphorus atom...

Br0nsted acid catalysis, the substrate electrophile is reversibly protonated in a pre-equilibrium step, prior to the nucleophilic attack (Scheme 2). In general acid catalysis, however, the proton is (partially or fuUy) transferred in the transition state of the rate-determining step (Scheme 2). Clearly, the formation of a hydrogen bond precedes proton transfer. 

The mechanism is closely related to general acid catalysis in which a proton transfers to the transition state in the rate-determining step, and to specific acid catalysis in which an electrophile is protonated prior to nucleophilic attack. 

All 1,4-(oxa/thia)-2-azolium salts are, in general, electrophilic species. Some of them, especially those where the positive charge is expected to locate predominantly inside the heterocyclic ring, are extremely electrophilic. Both kinds of oxathiazolium salts (6) and (7) exhibit this high electrophilic character, being attacked by solvents more nucleophilic than trifluoroacetic acid and nitromethane... 

The magnitude of general-acid-base catalysis by oxygen and nitrogen bases depends only on their pATa s, and is independent of their chemical natures (apart from an enhanced activity of oximes in general-acid catalysis). Nucleophilic reactivity depends markedly on the nature of the reagents. These reactions may be divided into two broad classes nucleophilic attack on soft and on hard electrophilic centers.47... 

Effective concentration 65-72 entropy and 68-72 in general-acid-base catalysis 66 in nucleophilic catalysis 66 Elastase 26-30, 40 acylenzyme 27, 40 binding energies of subsites 356, 357 binding site 26-30 kinetic constants for peptide hydrolysis 357 specificity 27 Electrophiles 276 Electrophilic catalysis 61 metal ions 74-77 pyridoxal phosphate 79-82 Schiff bases 77-82 thiamine pyrophosphate 82-84 Electrostatic catalysis 61, 73, 74,498 Electrostatic effects on enzyme-substrate association rates 159-161... 

General-Base and General-Acid Catalysis Avoids the Need for Extremely High or Low pH Electrostatic Interactions Can Promote the Formation of the Transition State Enzymatic Functional Groups Provide Nucleophilic and Electrophilic Catalysis Structural Flexibility Can Increase the Specificity of Enzymes... 

In general, the environment of polymer domain influences activities of nucleophile, electrophile and general base catalysis. It is easily understood that unusual pK values of amino acid residues in enzymes are given, as is shown in Table 15 (92). 

First, determine what kinds of conditions and catalysts are involved. In general, reactions may be classified as involving (a) strong electrophiles (including acid-catalyzed reactions), (b) strong nucleophiles (including base-catalyzed reactions), or (c) free radicals. These three types of mechanisms are quite distinct, and you should first try to determine which type is involved. 

Cage, solvent, 134 Cancellation assumption. 447 Catalysis, 263 acid, 453 buffer, 269 definitions of, 263 electrophilic, 265 general acid, 265, 268 general base, 265, 268, 271 intermolecular, 266 intramolecular, 266 nucleophilic, 266, 268, 271... 

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