Subject steric course

The approach taken above estimates the effect of the metal by simply considering its electrostatic effect (subjected, of course, to the correct steric constraint as dictated by the metal van der Waals parameters). To examine the validity of this approach for other systems let s consider the reaction of the enzyme carbonic anhydrase, whose active site is shown in Fig. 8.6. The reaction of this enzyme involves the hydration of C02, which can be described as (Ref. 5)... 

The availability of isotopes has made it possible to complete the descriptions of the steric course of most of the individual reactions of carbohydrate metabolism and steroid metabolism and many of the reactions of fat and amino acid metabolism. The subject has been covered from various angles in several chapters of the third edition of the Enzymes, particularly in the one by Popjack b, in a comprehensive treatise 2>3>, and in numerous recent reviews 4 12>. The wealth of available detail defies any attempt to be complete. I will try, rather, to describe trends in current experimentation, and to fit these trends into historical perspective. In so doing, I will select examples rather arbitrarily, entirely out of my own interests, and I beg the reader s indulgence for this bias. 

Angular alkylations of fused-ring ketones are an important step in syntheses of terpenoids, steroids and related natural products. The steric course of these alkylations has therefore been the subject of several systematic investigations and has been reviewedl 3 71. Alkylation of the lithium enolate 38 (R = H) derived from octahydro-1 (2//)-naphthalenone (1 -decalone) primarily yields the civ-fused octahydro-8a-methyl-l(2F/)-naphthalenone (39, R = H)35,62,79. Due to steric reasons, the lithium enolate 38 (R = CH3), with an angular methyl group, provides the irans-fused product 39 (R = CH3). 

In a study of the addition of nitrosyl chloride or nitrosyl bromide to norbor-nene and norbomadiene, it was observed that (a) there was no structural rearrangement during the reaction, (b) a cis addition had taken place, (c) nucleophilic solvents such as ethanol or acetic acid were not incorporated in the products. These facts seem to speak against an ionic addition mechanism, while a free radical initiated by NO radicals was considered unlikely since nitric oxide is inactive toward norbomadiene. Therefore a four-center mechanism has been suggested [70], However, when a relatively simple, unstrained olefin such as A9-octalin was subjected to the reaction, only blue, crystalline, monomeric 9-nitroso-10-chlorodecalin was produced. This product had a trans configuration. Thus it is evident that the structure of the olefin has a significant bearing on the steric course of the addition [71]. 

The term stereoelectronic refers to the effect of orbital overlap requirements on the steric course of a reaction. Thus, because of stereoelectronic effects, the Sw2 substitution gives inversion (see Section 4.2) and E2 elimination proceeds most readily when the angle between the leaving groups is 0° or 180° (see Chapter 7, p. 369). Stereoelectronic effects also play an important role in pericyclic reactions, which are the subject of Chapters 11 and 12. 

Reductions of carbonyl groups with lithium aluminium hydride or sodium borohydride occur by hydride transfer to carbon from aluminium or boron, respectively. The course of reaction is subject to steric approach control and product development control [43-45]. Enzymic reactions may or may not form the epimer favoured in the chemical reduction. This has been discussed elsewhere [46]. It is quite clear that the steric course of a dehydrogenase reaction is determined by the structure of the enzyme. 

Myriad polydentate aza-macrocycles have been reported 41. The extent of the subject forces limitation of this discussion to only macrocycles containing a pyridine or dipyridine subunit. Most of these coronands have been synthesized by a SchifF base condensation of an aldehyde or ketone with a hfc-primary amine in the presence of a metal ion. The metal ion acts as a template, resulting in dramatic increases in yield of the desired cyclic product over linear polymerization products42 46. Lindoy and Busch45 have described this effect in two ways, kinetic and thermodynamic. If the metal ion controls the steric course of a series of stepwise reactions, the template effect is considered to be kinetic. If the metal ion influences an equilibrium in an organic reaction sequence by coordination with one of the reactants, the template effect is termed thermodynamic. It is the kinetic effect that is believed to be operative in most metal ion-assisted (in situ) syntheses of... 

As already mentioned, the steric course of acid- or base-catalyzed conjugate additions is usually subject to thermodynamic control. An interesting example of how hydrogen bonding in the product(s) may affect the stereochemical outcome of the addition reaction is provided by ajmalicine (25). When the enoate 25 was treated with 5% aqueous sulfuric acid, the 17-hydroxy-derivative 26 was obtained as a single diastereomer in 40% yield20. The configuration of the... 

Unsubstituted monocyclic acetals (symmetrical molecules) are not suitable for studies of the stereochemistry of polymerization. Because there are no reliable data on the stereochemistry of polymerization of the substituted monocyclic acetals, the only available information relating to the steric course of polymerization comes from studies of bicyclic acetals. This subject has been reviewed. ... 

The steric environment of the atoms in the vicinity of the reaction centre will change in the course of a chemical reaction, and consequently the potential energy due to non-bonded interactions will in general also change and contribute to the free energy of activation. The effect is mainly on the vibrational energy levels, and since they are usually widely spaced, the contribution is to the enthalpy rather than the entropy. When low vibrational frequencies or internal rotations are involved, however, effects on entropy might of course also be expected. In any case, the rather universal non-bonded effects will affect the rates of essentially all chemical reactions, and not only the rates of reactions that are subject to obvious steric effects in the classical sense. 

The course of the reaction of furan and DMAD is temperature dependent (73CJC4125). The initially formed monoadduct (118) acts as a dienophile and further addition of furan can occur at the di- or tetra-substituted double bonds. In such additions to norbornene-type dienophiles the diene is subject to steric approach control and approach to the exo face is preferred. At 25 °C the tetrasubstituted double bond acts as a dienophile and the endo,exo... 

We cannot, then, expect this approach to understanding chemical reactivity to explain everything. We should bear in mind its limitations, particularly when dealing with subjects like ortho/para ratios in aromatic electrophilic substitution, where steric effects are well known to be important. Likewise solvent effects (which usually make themselves felt in the entropy of activation term) are also well known to be part of the explanation of the principal of hard and soft acids and bases. Some mention of all these factors will be made again in the course of this book. Arguments based on the interaction of frontier orbitals are powerful, as we shall see, but they must not be taken so far that we forget these very important limitations. 

The acid or base catalyzed hydrolysis of polyacrylamide (PAM) or Its partially hydrolyzed counterpart (HPAM) In aqueous solutions has been the subject of numerous studies. In part because this system provides an opportunity for evaluating the influence of polymer composition, and steric and electrostatic effects on the course of a simple organic reaction In a convenient solvent medium. 

The course of alkylation of 2- and 6-substituted-3-pyridinols is subject 10 a steric effect. Sodium salts of 3-pyridinol in ethanol are N-alkylated by methyl bromo- or iodoacetate. However, 2-bromo-3-pyridinol is N-alkylated by methyl and ethyl iodide in dimethylformamide but is 0-alkylated by haloacetates to XII-563 (Rj = Br, R = H). 2-Bromo-6-methyl-3-pyridinol (XH-562, Rj = Br, R = CH3) is A-alkylated by methyl and ethyl iodide and 6>-alkylated by diazomethane, but reacts with bromoacetic acid in chlorobenzene to give 3-hydroxy-6-methyl-2-pyridone (XII-565), possibly via 2-(a-bromoacetoxy)-6-methyl-3-pyridinol (XII-S64). With 6-methyl-2-methylthio-3-pyridinol (XII-562 Rj = CH3S, R = CH3), A-alkylation should be favored electronically, particularly by electron release by the 2-methylthio group. However, quaternization is difficult even with the simple alkyl halides and only 0-alkylation is observed when methyl iodoacetate is used. ... 

Potentially, there are many significant advantages associated with affinity labeling of myeloma proteins, as compared to conventional antibodies. (The myeloma proteins must, of course, have antihapten activity.) The homogeneity of the protein permits detailed sequence analysis and thus a precise localization of the affinity label. In addition, one might expect that in theory all of the sites of the myeloma protein population could be labeled. In the case of conventional antibodies this has generally not been possible because of heterogeneity of active sites evidently not all sites contain an appropriate side chain, or some side chains subject to attack by the affinity label are not sterically available. 

The present-day qualitative approach to the bonding in transition metal organometallic complexes is based on a combination of two models. The first, the 18-electron rule, has already been met in Chapter 2 (see Table 2.8)—iigands that bond to a transition metal in a low valence state normally do so in such a way that the metal atom is, formally, surrounded by 18-electrons . Of course with a few exceptions, the classical complexes of the Werner type and which are the subject of most of this book do not obey this rule, so that it is clear that much hinges on the low valence state requirement. Equally, the fact that most transition elements form neutral bis-fy -cyclopentadiene complexes, M(C5H5)2, shows that even for organometallic complexes of transition metals it is only an approximation. Many examples of molecules with more, and many examples with fewer, than 18 valence-shell electrons are known. Those with more tend to be readily oxidized, those with fewer tend either to be sterically hindered or readily add further ligands. 

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