Orbital overlap, stereoelectronic

Which electrophile is lost from the amino acid residue is, of course, controlled by the enzyme. One way this may occur is by the enzyme binding the PLP imine so that the electrophile is in close proximity to a suitable or base to aid abstraction and also so that the a orbital of the bond to be broken is periplanar with the p r acceptor system, i.e. orthogonal to the plane of the pyridine ring (XXXI). Maximal orbital overlap, stereoelectronic control, will lower the activation energy for the reaction. Aldol-type reactions can also occur with PLP as in the laboratory the key to making carbon-carbon bonds is the formation of a stabilised carbanion. Proton abstraction from the initially formed imine gives a masked carbanion which can nucleophili-... 

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. 

There are four possible transition states in the reduction of 27 wherein maximum orbital overlap can be maintained with respect to the attacking hydride reagent and the developing electron pair on nitrogen. Two of these (cf. dotted arrow in 29 and 30) require boat-like transition states in order to satisfy the stereoelectronic requirements and are unfavorable kinetic-ally. Of the two possible chair-like transition states (cf solid arrow in 29 and 30) the latter suffers from a strong steric interaction between the nucleophile and the C-8 pseudo-axial hydrogen. The process 30 + 32 is thus disfavored by comparison with the process 29 31. 

Cyclization of the tetraene 236 with trifluoroacetic acid in dichlorometh-ane at temperatures of -50° to -25° gave yields of 237 up to 81% when Ar=c,-naphthyl (91). The stereospecific formation of the cis-fused A/B ring junction is a direct consequence of stereoelectronic control. Indeed, in the formation of the cis junction, the newly formed bond (238 - 239) is pseudo-axial and is therefore maintained parallel to the v-orbital of the cyclo-hexenyl double-bond. Such orbital overlap is impossible in forming an A/B... 

The 1,6-addition to a,s, y, a-dienones is also subject to stereoelectronic effects. Addition on the bottom face of dienone 137 leads to a chair-like intermediate while that on the top face leads to a boat-like intermediate 140 in order to maintain maximum orbital overlap. Also, in 140 the R group encounters an eclipsed 1,2-R/H interaction and more importantly, a 1.4-CH3/R steric interaction which resembles the bowsprit flagpole arrangement of a twist-boat form of cyclohexane. This analysis of Marshall and Roebke (48) predicts that the trans product 139 should prevail over the cis product 141. 

This so-called stereoelectronic factor operates to maximize or minimize orbital overlap, as the case requires, to obtain the most favorable energy. This was evident from the three- and four-center systems we have discussed by the VB and HMO methods. It was also implicit in favored anti-1,2-additions, 1,3-cyclizations (Fig. 23), fragmentations (e.g. (174)), etc. Here we have selected several reaction types to illustrate the principle. In this and other sections, we show that the tendency for reaction centers to be collinear or coplanar stems largely from orbital symmetry (bonding), but may also derive from steric and electrostatic effects, as well as PLM. 

In such conformation the scissible bond is collinear with the n orbitals of the aromatic system bearing the unpaired electron, and the best orbital overlap for intramolecular ET, required for bond cleavage, can be achieved. Interestingly, when competition between C-H and C-C bond cleavage is possible, stereoelectronic effects generally play a significant role, because the former process is depressed owing to its steric requirements, which are much smaller than those of a C-C bond. In such circumstances, therefore, the conformation with the latter bond collinear with the n system is the most favored (see later). 

Existing evidence indicates that C-alkylations of metal enolates with common electrophiles proceeds by an SN2-type mechanism that is, the highest occupied molecular orbital (HOMO) of the enolate attacks the lowest unoccupied molecular orbital (LUMO) of the alkylating agent. Scheme 16 illustrates the principle of stereoelectronic control, which states that the electrophile should approach in a plane perpendicular to the enolate to allow maintenance of maximum orbital overlap in the transition state (24) between the developing C—C bond and the ir-orbital of the carbonyl group. 

Denmark argued that the synclinal transition state 19 may be favored due to stabilization by stereoelectronic effects such as secondary orbital overlap or minimization of charge separation. The allylstannane HOMO and the aldehyde LUMO could participate in. secondary orbital overlap in transition state 19, with specific-interactions between the allylstannane a-carbon and the aldehyde oxygen [50, 55]. Alternatively, the preference for the synclinal transition state 19 can also be attributed to minimization of charge separation in the transition state, compared to the situation in the antiperiplanar transition state 20 [50, 56],... 

In his analysis of transition states (Z)-ll and ( )-ll, Keck pointed out that in (Z)-ll, the a-carbon of the (Z)-crotyltri-n-butylstannane is farther from the aldehyde oxygen in transition state (Z)-ll than is the a-carbon of the ( )-crotyltri- -butylstannane in transition state ( -11, and thus is less able to participate in secondary orbital overlap interactions. The decrease in stereoelectronic stabilization of transition state (Z)-ll, compared to ( )-ll, allows access to other competing transition states which can lead to the diastereomeric anti homoallylic alcohol 3 (e.g. transition. states 13 or 14, Fig. 11-3, see above) in the reactions of the (Z)-crotylstannane reagent. Also, the (Z)-crotyltri-n-butylstannane in transition state (Z)-ll probably experiences increased steric interactions with the aldehyde R group relative to ( l)-crotyltri-n-buty]stannane in transition state ( )-ll. 

Figure 6.67 Stereoelectronics of eliminations and additions, (a) Orbital overlap favouring anti elimination/addition. (b) Cartoon of least-motion arguments favouring anti elimination. The dotted line represents the reference plane, which is perpendicular to the plane of the paper, (c) Biirgi-Dunitz-like approach in Michael additions and examples.

We have understood the stereoelectronic factor as a tool to cause reactions to proceed fast when certain spatial relationships exist between the electrons involved in the bonds formed and broken [1]. The certain spatial relationships are, in fact, the mutual orientations of the reactive sites such as the collinearity of the three atoms involved in SN2 reactions and the near coplanarity of the four ligands on the developing double bond in vicinal eliminations to allow orbital overlap throughout, etc. Combine this orbital overlap factor with the conservation of orbital symmetry factor and we have an extremely powerful tool in our hands to help us delineate the stereochemistry of certain reactions that would otherwise be difficult to explain if left to the stereoelectronic factor alone. 

In the backdrop of the orbital symmetry rules, a need was felt to evaluate the strength of the orbital overlap component of the stereoelectronic effect by designing experiments in which both the competing pathways are orbital symmetry allowed but one pathway is preferred to the other pathway for better orbital overlap. Berson has explored this avenue exhaustively by replacing one double bond of a simple model system by a cyclopropane ring because such a structural change was expected to cause one of the two orbital symmetry-allowed pathways to enjoy better orbital overlap than the other pathway (see below). 

To sum up the above discussion, we have witnessed that the orbital overlap component of the stereoelectronic effect is indeed a very powerful tool as it controls both the stereochemistry and the rates of a range of pericyclic reactions by allowing exclusively one of the two possible symmetry-allowed pathways for the very simple reason of better overlap of the breaking bonds. 

Two of the factors that determine the reactivity of tethered ir-nucleophiles in Mannich-type cycliza-tions have been emphasized stereoelectronic effects and reaction medium effects. The stereoelectronics of orbital overlaps between the ir-nucleophile and the iminium electrophile are best evaluated by considerations such as antiperiplanar addition trajectories and Baldwin s rules for ring formation. The critical importance of the reaction medium has received serious attention only recently. However, it already appears clear that Tr-nucleophiles that would lead, upon cyclization, to relatively unstable carbocations can have their reactivity markedly increased by carrying out the cyclization in the presence of a nucleophilic solvent or additive which, by nucleophilic participation, can obviate the formation of high energy cyclic carbenium ion intermediates. 

Aware of the lack of orbital overlap (and stereoelectronic control) in the TBP resulting from attack of the 2 -hydroxyl apical to the leaving group, Gorenstein provides two alternatives. Both alternatives result in reinstatement of partial app overlap of the 3 -oxygen orbitals with the P—0(5 ) bond. 

Although this is the only chapter in which stereoelectronics appears in the title, you will soon recognize the similarity between the ideas we cover here and concepts like the stereospecificity of E2 elimination reactions (Chapter 17) and the effect of orbital overlap on NMR coupling constants (Chapter 18). We will also use orbital alignment to explain the Karplus relationship (Chapter 32), the Felkin-Anh transition state (Chapter 33), and the conformational requirements for rearrangement and fragmentation reactions (Chapter 36). 

The exclusive formation of 48 can be rationalized to be a result of stereoelectronically controlled reaction of the transient iminium salt generated from 47 under acidic conditions. Due to inversion at nitrogen, there are thus four possible transition states A—D (Fig. 8) which maintain maximum orbital overlap... 

Stereoelectronic factors control interactions between different atoms or molecules and interactions between different parts of a single molecule. Although our focus will be on the latter, we will also briefly illustrate the fundamentals of intermolecular interactions, because they broaden the conceptual foundation for subsequent discussion and illustrate the key patterns for orbital overlap without intramolecular constraints being imposed on the geometries. 

Two years later, in 1956, E. J. Corey, a young professor at the University of Illinois used stereoelectronic in the title of a paper ( Stereoelectronic Control in Enolization-Ketonization Reactions ). In this paper, he associated the faster loss of axial hydrogen in enolization and the faster gain of axial hydrogens in ketoniza-tion with the more favorable orbital overlap of the carbonyl it-system with the axial C-H bonds relative to the equatorial C-H bonds (Figure 1.4). 

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