Addition modes, steric factors

The availability of different metal ion binding sites in 9-substituted purine and pyrimidine nucleobases and their model compounds has been recently reviewed by Lippert [7]. The distribution of metal ions between various donor atoms depends on the basicity of the donor atom, steric factors, interligand interactions, and on the nature of the metal. Under appropriate reaction conditions most of the heteroatoms in purine and pyrimidine moieties are capable of binding Pt(II) or Pt(IV) [7]. In addition, platinum binding also to the carbon atoms (e.g. to C5 in 1,3-dimethyluracil) has been established [22]. However, the strong preference of platinum coordination to the N7 and N1 sites in purine bases and to the N3 site in pyrimidine bases cannot completely be explained by the negative molecular electrostatic potential associated with these sites [23], Other factors, such as kinetics of various binding modes and steric factors, appear to play an important role in the complexation reactions of platinum compounds. 

Carbonyl-addition reactions continue to be the speciality of the French group interested in germylphosphines. Thus the germaphospholan (68) adds to aldehydes to give diastereomeric products (69).62 Steric factors are believed to control the mode... 

Fig. 21. Detailed mechanism for HO-1 catalysis. In 1, oxygenation and electron transfer forms the ferric (Fe +)-peroxy complex. Steric factors and H-bonding help to bend the peroxide toward the a-meso-heme position for regio-selective hydroxylation. One proposed mode of forming verdoheme is shown in part 2. A key part of step 2 is the resonance structures between Fe + and Fe +/radical, which enable the porph3rrin ring to be oxygenated. Although the mechanism shown does not require any reducing equivalents (176), there remain experimental inconsistencies on the requirement of an additional electron in step 2. However, reduction of the verdoheme iron is necessary to prepare the substrate for step 3, verdoheme to bihverdin.

The equilibrium between isothiocyanates and carbodiimides has been determined. The cycloaddition is favored by 59 to 79 kJ mol-1 with decomposition of the adduct being facilitated by electron donating groups on the aryl isothiocyanates (75JCS(P2)1475). Steric factors have also been shown to control the mode of addition and decomposition of isothiocyanates and carbodiimides (72JA3484). 

As expected, additions to alkynes are also subject to control by polar functions nearby. Thus, nucleophilic attack on trifluoromethylacetylene [116], cyanoacetylene [137], and ethylthioacetylene [138] occurs at the terminal jp-hybridized carbon atom, the substituent at the other end of the triple being an acceptor in all cases. This behavior is to be contrasted with the mode of addition on ethoxyacetylene [3 39], aminoacetylenes [120], The vinylogue, 4-dimethyl-aminobut-3-en-l-yne [121], reacts with aniline at the internal position of the akyne linkage. However, a 2 1 regiose-lectivity, favoring the methanol adduct predicted by the polarity alternation rule, has been observed for the addition of jV,jV-bis(trifluoromethyl)ethynylamine [122], It is not known whether steric factors play a role in the decreased regioselectivity. 

While the regiochemistry of simple electrophilic additions to double bonds is controlled by a combination of electronic (Maikovnikov rule), stereoelectronic (trans diaxial addition to cyclohexenes) and steric factors,9 the intramolecular nature of electrophilic heteroatom cyclizations introduces additional conformational, stereoelectronic and entropic factors. The combination of these factors in cyclofunctionalization reactions results in a general preference for exo cyclization over endo cyclization (Scheme 4).310 However, endo closure may predominate in cases where electronic or ring strain factors strongly favor that mode of cyclization. The observed regiochemistry may differ under conditions of kinetic control from that observed under conditions of thermodynamic control. 

Houk s model (Fig. 3 [206,207]) assiunes that the factors that are responsible for the non-planarity of the norbornene double bond intervene in the transition states of the cycloadditions of 5-cis-butadiene moieties grafted at C(2), C(3) of norbornane and 7-oxanorbornane systems. The tighter the transition states, the higher the endo face selectivity. The less synchronous the cycloaddition (e.g., with non-symmetrical dienophiles coordinated to Lewis acids), the lower the endo face preference, steric factors competing in favor of the exo mode of addition. This theory is verified for a large number of cycloadditions including those we reported for deuterated 2,3-dimethylidenebicyclo [2.2.1] heptane [208]. 

The diastereofacial selectivity observed in the cycloaddition of chiral a,P-unsaturated sulfoxides with various dienes has received considerable attention from a synthetic viewpoint and is discussed extensively in the following sections. In the majority of cases, the diastereofacial selectivity of the cycloaddition is explained in terms of steric factors. The diastereofacial differentation is accounted for by the preferred addition of the dienes to the energetically favoured s-trans or s-cis conformer of a,P-unsaturated sulfoxides from the less sterically crowded side of the double bond, i.e. syn to the lone-pair electrons on sulfur. The s-trans and s-cis conformations for two different a,P-unsaturated sulfoxides (lowest energy conformers) are shown in Figure 5.5, together with the preferred orientation of attack of the diene on steric grounds alone. In Figure 5.5, the mode of addition of cyclopentadiene shown leads to the endo cycloadduct with respect to the sulfoxide this is not always the case, and often endolexo mixtures are obtained with other a,p-unsaturated sulfoxide dienophiles and dienes. 

Hydrogen abstraction from tertiary carbon has an activation energy lower by approximately 15 kj mol than an abstraction reaction on secondary carbon (Ref. 2, p. 386), and is the predominant mode of formation of hydroperoxides in PP. In addition to energy considerations, the hydrogen abstraction rate constant is dependent on steric factors and polymer conformation. It is found, for instance, that fes (Scheme 15.1) in solution is lower in a theta solvent than in a good solvent, owing to increased steric repulsion in a contracted molecular coil [7]. 

With two y,8 double bonds, two a,/3 double bonds, and the possibilities of cis and trans ring fusions with syn and anti configurations, 20 isomeric dimers are possible. Surprisingly, only one product is formed in a head-to-tail fashion. The sole product of the irradiation of the 3,5-diene-7-ketosteroid (76), however, is the head-to-head dimer. The specificity and mode of addition arise presumably through the effect of the specific environment of the chromaphore. The dimerization of (75) is believed to involve the addition of the a,fi double bond of a photoexcited molecule to the less hindered y,8 double bond of a ground state molecule. The photocondensation of (76) with cyclopentene, in which steric hindrance should not be a controlling factor, was found to yield a cyclobutane product involving the a,/ bond of the steroid in contrast to dimerization across the y,8 bond. 

The modes of addition shown in Figure 6.3 are similar to those shown in Figure 6.2 and are consistent with extant mechanistic work [6,9] they accurately predict the identity of the slower reacting enantiomer. It should be noted, however, that variations in the observed levels of selectivity as a function of the steric and electronic nature of substituents and the ring size cannot be predicted based on these models alone more subtle factors are clearly at work. In spite of such mechanistic questions, the metal-catalyzed resolution protocol provides an attractive option in asymmetric synthesis. This is because, although the maximum possible yield is 40 %, catalytic resolution requires easily accessible racemic starting materials and conversion levels can be manipulated so that truly pure samples of substrate enantiomers are obtained. 

Reaction of p-nitrobenzenesulfonyl azide with alkylidenecycloalkanes 22-25187 does not yield isolable triazolines as expected, but the reaction products derived from alkenes 22 and 23 suggest a single triazoline intermediate, whereas in the case of tetrasubstituted derivative 24 both possible reaction modes are present,187 owing to weak double bond dissymmetry. Product analysis from 25 indicates some conflict between electronic and steric control in the addition, but provides evidence that electronic factors are much more important than steric effects in controlling regioselectivity.187 Reaction of the exocyclic olefins 22 and 23 appears to be controlled more by the interaction of the LUMO of the azide and the HOMO of the alkene.187 p-Nitrobenzenesulfonyl azide is reported to react with members of the novel... 

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