Anomeric and Associated Stereoelectronic Effects - ACS Publications

Chapter 2

Anomeric and Associated Stereoelectronic Effects Scope and Controversy Gregory R. J. Thatcher

Downloaded by UNIV LAVAL on March 18, 2013 | http://pubs.acs.org Publication Date: November 23, 1993 | doi: 10.1021/bk-1993-0539.ch002

Department of Chemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada

The anomeric and associated stereoelectronic effects applied to structure and conformation comprise the Edward-Lemieux effect, generalized anomeric effect (GAE), exo-anomeric effect, gauche effect and reverse anomeric effect. Extrapolation of these conformational effects to reactivity has yielded related stereoelectronic effects that have been labeled Deslongchamp's theory of stereoelectronic control, the kinetic anomeric effect and anti-periplanar lone pair hypothesis (ALPH). In much of the literature these effects are accepted as having profound effects on structure and reactivity. In many important enzyme systems catalysis is proposed to require stereoelectronic assistance. However, strong objections have been published as to the veracity of experimental and theoretical data and its rationale in support of these stereoelectronic effects. The basis for this criticism and the various areas of controversy, past and present, are discussed. An attempt is made to clarify the definitions of the various related stereoelectronic effects and the various hypotheses proposed in this area. The application of A L P H to the mechanism of ribonuclease is discussed.5 It has been stated that a wealth of evidence indicates that stereoelectronic stabilizing interactions are important in transition state structures and influence the course of chemical reactions involving acetals, esters, amides, phosphate esters and triple bondsf/]. The enzymes ribonuclease[2], chymotrypsin[5], lysozyme[^/], carboxypeptidase A[5], alcohol dehydrogenase^ and ribozymes [2] have been proposed to rely on stereolectronic effects to catalyze reaction. Furthermore, owing to the importance of stereoelectronic effects in enzymology, it has been suggested that some well-accepted catalytic principles will require reconceptualization[7]. Proposed stereoelectronic effects have been equally well applied in synthetic organic chemistry to explain and predict product distribution in a large range of reactions[#]. These stereoelectronic effects are, as proposed, intimately related to the anomeric effect. The anomeric effect describes the empirical observation of a preference for exocyclic substituents (O or halogen) to occupy the axial over the equatorial position at the 0097-6156/93/0539-0006$06.00/0 © 1993 American Chemical Society

In The Anomeric Effect and Associated Stereoelectronic Effects; Thatcher, G.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.

2. THATCHER

7

Scope and Controversy


anomeric carbon of a pyranose ring system[P]. It is the rapid extrapolation of the simple, phenomenological anomeric effect to yield stereoelectronic effects of enormous scope and impact on the reactivity of organic and inorganic molecules that has provoked deserved questioning and controversy. An effect of such importance requires rigorous examination before being established as dogma. Purpose The purpose of this overview chapter is not to provide a comprehensive review of the literature, nor a comprehensive list of references, but to set the stage for the papers to follow. The need then is to introduce many of the controversies that continue to embroil the study of the anomeric and related effects. As a fortuitous coincidence, an excellent comprehensive review on the structural and conformational aspects of the anomeric effect appeared some months before the ACS Symposium[70]. 1. STRUCTURE AND CONFORMATION 1.1. Definition and Clarification Much confusion and some of the controversy in this area has resulted from the use of the phrases stereoelectronic effect and anomeric effect to imply many different meanings. Stereolectronic effects are variously defined: "...those factors concerned with the conformational requirements of the groups involved in the reaction with respect to the electron orientations in the transition state"[77]; "Pertaining to the dependence of the properties (especially the energy) of a molecular entity in a particular electronic state (or of a transition state) on relative nuclear geometry"[72]; "The term stereoelectronic refers to the effect of orbital overlap requirements on the steric course of reaction"[73]; "Stereoelectronic effects arise from the different alignment of electronic orbitals in different arrangements of nuclear geometry"[77]. These definitions are sufficiently broad as to include effects attributed to interactions involving bonding and non-bonding electrons without defining the cause nor rationale of the effect. We may usefully decompose a phenomenological stereolectronic effect into its causal components which may be electrostatic (in particular dipole-dipole interactions), steric or electronic (interactions between bonding, non-bonding or anti-bonding electronic orbitals). In solution, solvation must also be considered. The term anomeric effect, originally defined by Lemieux (see above), would be

OAc:

^OAc

Scheme 1. The Edward-Lemieux Effect

better substituted by the Edward-Lemieux effect[14], since more recent usage of the term anomeric effect goes far beyond pyranose conformation[75]. The effect describes the relative stabilization of α-glycosides (Scheme 1). The generalized anomeric effect (GAE) describes the preference for synclinal (sc, gauche) over antiperiplanar (ap, trans) conformations in the molecular fragment W-X-Y-Z, where X possesses one or more pairs of non-bonding electrons, Ζ is electron-withdrawing and W and Y are of


8

THE ANOMERIC EFFECT AND ASSOCIATED STEREOELECTRONIC EFFECTS

intermediate electronegativity (Y is usually C, P, Si or S). Confusion occurs since recent definitions have: (1) specifically defined the GAO in terms of p-type electron lone pairs on X (although many researchers invoke sp hybrid orbitals, vide infra); (2) inferred a specific cause for the observed preference; or (3) dropped the adjective "general" entirely[7, 70]. Unlike the anomeric effect, the exo-anomeric effect has remained closely associated with carbohydrate chemistry. As originally defined by Lemieux, the result of this stereoelctronic effect on glycoside conformation is specifically to restrict the orientation of the acetal aglycon[77]. The introduction of this stabilising effect requires a complementary endo-anomeric effect in glycosides. The Edward-Lemieux effect can thus be energetically quantified as the difference between the sum of the endo- and exoanomeric effects for one of the anomers and the sum for the other glycoside anomer[77]. A further useful quantitative expression is anomeric stabilization defined as non-steric stabilization of the gauche conformer. This stabilization term unmasks electronic and electrostatic effects which might otherwise be overwhelmed by steric effects. It is not restricted to glycosides, but is of major application in glycosides and related cyclic systems, and may be expressed:


3

anomeric stabilization = AG°(heterocycle) - AG°(steric)

{1}

AG°(steric) may use Α-values from non-anomeric systems (e.g. cyclohexanes) and should be corrected for structural modifications in the heterocyclic system[7a*and η ->σ* hyperconjugation (Scheme 7a,b). Thus the use of sp -hybrids correctly predicts optimum conformational stabilization. There are problems inherent in the use of sp -hybrids. For example, in a recent high level, 3

0

π

3

3


12

THE ANOMERIC EFFECT AND ASSOCIATED STEREOELECTRONIC EFFECTS

0

R

9·

^ o ^

R

P^jm P^m P^7®C 2=

2=

6

£=τΐ

^

^5SX* 4

1 5 ^ Scheme 6. Destabilising 4e~ interactions in α and β-glycosides (sp hybrid orbitals shown). Conformational preferences are qualitatively ranked according to number of interactions and overlap (1=most favorable).


3

(a)

(b)

z

(c)

z

& & Φ trans

gauche

clinal

GAE: W-X-Y-Z fragment Scheme 7. W-X-Y-Z fragment, sp3 hybrids shaded and superimposed on η and η σ

π

atomic orbitals

theoretical examination of anomeric stabilization in the conformational energy profile of H O C H O H and H O C H O H , torsion angles were fixed at 60° (gauche, optimal G A E as defined by sp -hybrids) and 180° (trans, no anomeric stabilization)^]. However, a more recent study on the full rotational profile demonstrates that full anomeric stabilization is only present at a torsion angle of approx. 90° (clinal)[4J]. In fact, recent definitions of the G A E implicitly state that the important lone pair electrons (on Ο or S) are in a π-type atomic orbital (or p-orbital, Scheme 7c)[46]. +

2

2

2

3

1.5. Computational Studies The original manifestations of the anomeric effect were discovered experimentally. The increasing availability of high-powered computers and software capable of sophisticated semi-empirical and ab initio calculations on molecular orbital interactions has led to a burgeoning of theoretical studies directed at the GAE. Indeed, it may be argued that these calculations have eclipsed the very experimental data they were set to examine. The computational approach is ideally suited to decomposition of a conformational energy profile into its causal components. Two approaches may be taken. Firstly, one may semi-quanititatively (using a Fourier equation) decompose the energy profile into contributions from apparent individual interactions, for example: lone-pair/lone pair repulsive; steric-eclipsing repulsive; internal hydrogen bond stabilizing; electronic stabilizing. In this way, using sp -hybrid orbitals, Deslongchamps and Grein are attempting to assign general parameters to permit summation of conformational energies and prediction of conformational preference for general 3


2. THATCHER

13

Scope and Controversy 3

application^ 7]. In this case, as the authors admit, the validity of using sp orbitals is irrelevant, since specific atomic and molecular orbital interactions are ignored. Secondly, one may attempt to rigorously and specifically define each effect that contributes to the overall energy profile. In this way, contributions from steric interactions, electrostatic effects and a host of electronic orbital interactions (both 4e destabilizing and 2e- stabilizing interactions^]) have been defined. The first method has required a very large "reverse anomeric effect" parameter (5 kcal/mol in H N - C H N H ) ascribed to an electrostatic attraction between the positive nitrogen and a lone pair on the second heteroatom[^/7]. The second method in treating the reverse anomeric effect in H O - C H - N H , H O - C H - O H and a cyclic species (Scheme 8) has shown that hyperconjugative effects are actually overwhelmed by steric and electrostatic (dipole-dipole) effects[

Anomeric and Associated Stereoelectronic Effects - ACS Publications

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