Eusebio Juaristil University of North Carolina Chapel Hill, NC 27514
University of California and Berkeley. CA 94720
I(
The Attractive and Gauche Effects
Conformational analysis has been an extremely important tool in the understanding of the relationship between structure and energy of organic molecules, and an enormous amount of experimental work has been recorded in the last 25 years of its existence (I). Among the most studied systems are 1,2-disubstituted ethanes and cyclohexanes, and 5-substituted-1,3-heterocycles. As shown in eqns. 1-3, the conformational equilibria in these systems involve gauche-anti interconversion of the 1.4-heterobutane segments present in the molecules.
&LA
electronegarive subsrituents, wt!n though highly elecrronegative substiruents engender high dipole momrnLs in the (:-X and (.' T t)onds which should lead to enhanced dipole repulsion in the gauche form.
Y H&eH& H Y
H
R
H
Y
A
H
tram
gauche
I : -X Y=F - = -
11: X = F, Y-=OCOCH, 111: X = OCH,, Y = OCOCH, IV:X=Y=CN V:X=Y=OCH.
(1)
Y Y
Y
Y
For example, in the series XCHzCHzX (X = halogen), there is a gradual increase in the proportion of the gauche conformation in the direction I F, so that in the gas phase gauche-1,2-difluoroethane(I) clearly predominates, although it is not yet certain by how much. Whereas from infrared and Raman spectra Klaboe and Nielsen (7) concluded that both forms have eoual stabilitv. van Schaick. et al.. 18) in an electron diffractidn study found that in the vapor phase more than 98%of the molecules were in the eauche form. This leads to a minimum AGO value of 1.7 kcalfkol. On the other hand, the nuclear magnetic resonance work of Abraham and Kemp (9), and argon matrix Raman spectra of Huber-Walchli and Giinthard (10) suggest .. the trans conformer to he only 0.6 k~~l,mcgl higher in energy. However, studying Ramnn spwtrn a s a function of cemDerature 11arri.s ( 1 1 ) has found very litrle evidence for the trans conformer. While the preference for the trans structures observed when X = Y = CI, Br, I might be ascribed to acomhination of steric and dipolar effects alone (but vide infra), i t is clear that such a combination cannot account for the conformational equilibrium of the difluoride. Attractive wuche interactions are not restricted to svstems that contain carbon-halogen bonds. Neat samples of 2-fluoroethvl. and 2-methoxvethvl acetate. 111. (13) exist . . IS.. (12). . predominantly' i n the gauche conformation: 1 n the vapor phase, 1,2-dicyanoethane, IV, (14), and 1,2-dimethoxyethaue, V, (15) prefer the gauche form, eqn. (5). And in polyoxyethylene (15a, 16) the 0-CH2CHz-0 gauche arrangement is preferred.
-
Y
29
- y l ? L Y
gauche
(31
anti
In principle, the position of equilibria 1-3 (or a t least the energy difference between conformational isomers) can he determined hy use of Westheimer's eqn. (2)
AE,,. = AEF + AET + AEB+ aEV+ AED + AES (4) where Er is the sum of the com~ressionand stretchina- energies required to deform the bond lengths of the system from t hr "normal" u, the observed values. ET.is the sum of tursional energies (Pitzer strain), Es is the sumof energies due to deformations of bond angles (Baeyer strain), Ev is the sum of the non-bonded interactions, E D is the sum of energies due to intramolecular dipolar interactions, and Es is the energy nf - - ~nlvntion.~ -~~ Repulsive steric and polar interactions usually make the eauche conformation sienificantlv less stable relative to the anti one (4,5). There a;e, however, equilibria which cannot be ex~lainedin terms of eon. . (41: , . cases in which the eauche confoimation is favored more (or the anti less) than calculated in terms of steric and ~ o l ainteractions. r or cases in which the anti conformation is iavored more than the calculations lead one to believe. These cases have been treated in terms of special "conformational effects" (6). ~~~~~
~
The Attractive Gauche Effect
1.2-Heterosubstitutedethanes These compounds may exist in gauche and trans (or anti) conformations eqn. (5). Of these two forms, one may consider the gauche to be the less stable since i t is subject to nonbonded repulsions which are minimized in the trans arrangement. In addition, if X and Y are polar groups, the trans form is relatively stabilized since i t minimizes the dipolar repulsion present in the gauche conformation. On this basis, gauche structures should be disfavored in XCHzCHgY, especially when X and Yare polar groups or atoms. However, a preference for the gauche arrangement is observed for small 438 / Journal of Chemical Education
5-Heterosubstituted-l,3dioxanes Eliel and co-workers (17) in their systematic study of suhstituted heterocycles, have found evidence for gauche attraction in 5-fluoro- VI, 5-methoxy- VII, and 5-cyano-1,3dioxane VIII eqn. (6). XI
VI:X=F VII: X = OCH, VIII: X = CN
Present address: Syntex Diagnostic Division, 3221 Porter Drive, Palo Alto, CA 94304. 2
Other, more complex energy functions have been used (3)
-
As shown in ean. . (6) . . the rine dinole and the suhstituent dipole are involved in electrostatic repulsion in the 5-axially substituted (cis) . . comnounds. whereas the trans diastereoisomers have a nearly antiparallel arrangement of the two dinoles. As a consequence, in a solvent of low dielectric constant, one might expect the equilibria shown in eqn. (6) to be controlled mainly by dipole repulsion (4,5), implying a negative AGO. In CCld, however, it is the cis diastereoisomer of 5-fluoro-1,3-dioxane (VI) which is more stable: AGO = +0.36 kcallmol. Comparison of the AGO values for VI, VII, and VIII in acetonitrile with the corresnondine AGO values for wclohexyl-X shows that the equilibria are sh:lfted toward the axial side as the CH2 g r o u ~ are s exchanged for oxygen atoms in the dioxanes. since the non-hondeb intera&ns, according to the approximate distances measured in Dreiding models of the cyclohexyl derivatives, are not strongly repulsive, an attractive FIO, 010 and CNIO interaction was suggested (17). &
1.2-Diheterosubstitutedcyclohexanes
Additional evidence for an attractive gauche interaction may be found in Zefirov's work on 1,2-trans-disubstituted cvclohexanes (18) , . ean. . ,(7). I t is one of the basic nrincinles of conformational analysis that conformations with axial suhstituents in six-membered rines are less stable than those with corresponding equatorial groups (19.20). However, conformation E in eqn. (7) is destabilized by the gauche interaction of the substituents, X N , and by dipole-dipole repulsion. With these considerations in mind, Zefirov and co-workers (18) calculated the approximate values of steric, Ev, and polar, ED, interactions for compounds IX-XIV.3 Experimental AGO values (AGOexp)were-treated according to iqn. (8)
-
Figure 1. Caadinate diagram of 4G0x,r - E, versus 4Eo. (Mdified horn Figwe 2 in Reference 18. with the permission of Tetrahedron). As is clear from Figure 1, AGO, values for OICI, OBI, OD, and Clfl fragments fall on the line of unit slope. Therefore, the conformational behavior of compounds X, XI, XII, and XIV can be interpreted adequately in terms of steric and polar interactions. However, experimental values for 010 and FII fragments clearly fall in the region of additional attraction, wipesting that an effert not so far taken intu account i s w n tril~ut:ngapprecinl,ly to the sraldity of the gauche iorm. 'l'he oriutn of the caurhr mrracr;ve erfect has been d i s r t ~ w d by severay authorsu(24, 25). Wolfe (25) has proposed a rationalization based on Allen's dissection of the total energy in asystem into attractive and repulsive components (26). The attractive component of E is V,. the nuclear-electron attraction, and the repulsive component is (V,, V,. T), where V,, is the nuclear-nuclear repulsion, V. is the electron-electron repulsion, and T is the kinetic energy of the electrons (eqn.11). I t seems possible that for small and electronegative
+
+
(T+ V,, + V.) + ( V A (11) substituents (for example, F, 0 , CN) in a gauche arrangement, E
IX: X = OCH,, Y = OAc X: X = OCH,, Y = C1 XI: X = OCH,, Y = Br XII: X = OCH,, Y = I XIII: X = F. Y = I XIV: x = ci, Y = I AGO,. = 4G0x,q + A"x + 4G.u (8) since, for example, the increase in the ratio A/E eqn. (7) can be due either to strong repulsion of X and Y in the gauche orientation (AG0xN) or to small conformational free energies, -AGOx and -AGoY, of the suhstituents as measured in the corresponding monosubstituted cyclohexanes (23). Hence AGoxlv = AGO,, - AGOx - AGoy. In principle, if there are no "new" effects, AG0xN should be the sum of the steric (Ev) and polar ( U D )interactions of X and Y or 4G0x,v - EV = AED (10) In order to ascertain if there were in fact, any additional effects, a coordinate diagram of AGO* - E v versus AED was constructed with the line of unit slope indicated, and points for various X N combinations were spotted on this diagram (Fig. 1). The line of unit slope divides Figure 1 into two regions: a field of additional attraction below the line, and a field of additional repulsion above it. The ordinate distance from the experimental point to the line of unit slope corresponds to the energy of additional gauche attraction or repulsion.
=
nuclear-electron attraction can he more important than nuclear-nuclear and electron-electron repulsion. Also i t seems logical that as the electronegativity of the substituent diminishes; and as the size of the orbitals in that substituent increase, nuclear-electron attraction will dwindle, but electron-electron repulsion will become dominant. Whether this particular explanation is valid or not, it is clear (vide supra) that there is some "special effect" which makes F/F, 010, OICN, OIF interactions be attractive. In contrast, CIII, 011, OIBr and OIC1 interactions are repulsive, and this can be explained solely on steric and polar grounds. The Repulsive Gauche Effect Inherent in eqn. (11) is the possibility for a secondagauche effect," an unusual repulsion between the two gauche suhstituents, X and Y, in 1,4-heterohutane segments.
3
fPC\
,By
This situation can arise (in terms of the above explanation) if the attractive term, V,,, is offset by a repulsive interaction, for example, electron-electron repulsion. Chemists are quite familiar with such repulsive effect. For example, overlap between electron lone pairs leads to the formation of bonding and antibonding orbitals, which are filled by four electrons. In this case the upper level is destabilized more than the lower one is stabilized (27.28) that is, IErepu~sivel> IEattraetivel .
;+h,\,E
Zefirov et 81. (18)calculated the energy of steric interactions, Ev, of gauche substituents by the Hill equation (21). Electrostatic interactions, ED,were calculated using Abraham's charge-charge made1 (22). Volume 56, Number 7, July 1979 / 439
In i970 Zefirov reported the first examples suggesting the existence of such a re~ulsiveconformational effect. gave .. it a name ("hockey-sticks" rffect), and explained its source (291. Still. it has l~ecnonlv recenrlv that more quantitative infurmat& concerning chis repulsive gauche interaction has appeared (18,30). 2-Substitvted- 1.4-oxathianes Evidence sustaining Zefirov's proposal (29) was provided by his group on the basis of the conformational behavior of 2-substituted-1,4-oxathianesXV-XVIII eqn. (12). It was found (31) that for Y = S the amount of isomer E increased in going from X = OBu" (XVII) to X = SBu" (XVIII). Furthermore, for X = OBun or SBun a sharp decrease in conformer A was observed in going from the 1,ldioxane to the 1,4-oxathiane system (XV to XVII, or XVI to XVIII). I t is clear from these results that 010 interactions (e.e.. in XV) are less repulsive than 01s interactions (e.g., in XVI and XVII), which in turn are less re~ulsivethan S1S interactions (e.~.,in XVIII). Obviously, rep;lsion increases with increase i n the size of X andlor Y, in agreement with the suggestion that, greater diffuseness of the 3 p and 3s orbitals should result in greater overlap and therefore greater electron-electron repulsion (29). "m
XV: X Y=0 ~- - = OBun. XVI: x = S B U ~ , ' Y= o XVII: X = OBu", Y = S XVIII: X = SBu", Y = S ~
~~
However, the possible influence of dipolar andlor nonbonded repulsions in these equilibria was not discussed (311, and there is an evident complication in the comparison of XV with XVI or XVII with XVIII due to the variation in the X I 0 anomeric effect when X is changed from 0 to S (32). 1.2-trans-Disubstituted cvclohexanes More quantitative data concerning the existence of the repulsive gauche effect comes from the work of Zefirov and co-workers on certain trans-1,2-disubstituted cyclohexanes (18). The conformational equilibria of deuterated XIX-XXIII eqn. (13) was studied by proton nmr spectroscopy, and AGO values were determined hv means of Eliel's equation (33). The influence of steric, Ev, and dipole-dipole, ED, interactions were taken into account by making a ACoxpi - E v = A E o plot, which, as already discussed above, is divided hy a straight line AGoxN - E v = AED into a region of additionalattraction and a region of additional repulsion (Fig. 2).
XXIV: X = 0 xxv: X=S
Line 4 in the table the experimental values for the preference for the equatorial 5-methoxy and 5-methylthio compounds: 1.22 and 1.57 kcallmol, respectively. This preference for the confieuration in which the gauche interaction is nut present could not be justified in terms of steric [line 1 in the table. which is the differenre between conformational energies of equatorial and axial gruups (:nl(:ulnted by Hill's equation (2111 nnd elertnrstatic [line 2 in the table, charpecharge interncti~mswere calculated by Abraham's formula 12211 repulsions. The differenre hetween tho calculnted and cxoerimenral X o ' s line 3 in the 1at1lt:l reflects the maenitude of'the repulsive gauche effect, which is, as expected (297, larger for SIS than for SIO interactions. This renulsion is ~ r o b a h l v due to repulsive overlap of the filled 3p oibital of silfur with the 3~ orbital on another sulfur or the 2 s ~ filled 3 orbital on oxygen. In summary, a considerable amount of published material shows that the conformational behavior in 1,2-disuhstituted frameworks is regulated not only by steric and polar factors but also, in many cases, it is dominated by additional attractive or repulsive forces. Additional attraction is found in svstems containing small and strondv electroneeative atoms 0 , CN), and isirobably the result of a dominant nuclearelectron attraction.. V,,. between atoms or eroum. . Additional repulsion is observed in systems containing atoms of the elements lower in the periodic table, which are less electronegative and have more diffuse orbitals, and is probably the result of a dominant electron-electron repulsion, V. . These "special" interactions have been called attractive and repulsive gauche effects, respectively (18).
--
6,
Acknowledgment
I am indebted to Prof. E. L. Eliel for his interest in this work and for a careful reading of the manuscript. Support under NSF grant CHE75-20052 is gratefully acknowledged. I am also grateful to Prof. A. Streitwieser, Jr. for his stimulating influence a t Berkeley.
aEDlkdlmdi
XIX: XX: XXI: XXII: XXIII:
X X X X X
= = = = =
OCH,, Y = SCH, OAc, Y = SCH, SCH,, Y = C1 SCH,, Y = Br SCH,, Y = SC,H,
Indeed, AGO values belonging to SICI, S B r , and S/S fragments are clearly in the region of additional repulsion, and the ordinate distance from the experimental AGO values to the line of unit slope should represent the energy of gauche repulsion due to lone pair orbital overlap. 5-Substituted- 1,bdithianes Eliel and Juaristi have recently (30) equilibrated the 5substituted-1,3-dithianesXXIV and XXV eqn. (14), with the results shown in the table. 440 1 Journal o f Chemical Education
Figure 2. Cwrdinate diagram at AGOxn - Ev versus A&. (Mcdified fmm Figure 2 in Reference 18. with the permission of Tetrahedron). Cut no. 91415
Experimental and Calculated Energy Dinerences for 5-Methoxyand 5-Methvlthio-1.3-diLlanes
1 2 3
4 5
calcd calcd AGOsl.calcd AGOtoul AGO ,. - AGOBlrn AGO..
+0.37 -0.64 -0.27 -1.22 -0.95
+1.05 -0.36 +0.69 -1.57 -2.26
Literature Cited (11 E1iel.E. L..J. CHEM.EDUC.52.762 (19751. (21 el. Kaloustian, M. K.. J. CHEM. EDUC..51.777 119741. (3) Recent review. on "molecular mechsnics" or "tom field" calevlatiansare: Alfona, C.. and Fahar, D. H., Top. Cur,. Cham. 45.1 (1978: Simonetta. M., Acets. Chrm. Re$., 7, 345 (1974); Allinger. N. L., Ad". Phys. Org. Chrm., 13, 1 (1976): Ermer, O., Structure and Bonding, 27, I61 (19761; and others. (41 Eliel. E. L.,Allinger,N. L..Angyd.S. J.,andMonison,G. A.:'ConfomtiondAndmis." Wiley-l~terscience,New York, 1965, p. 13. (5) Mizushima. S.. '"Struclme of Moleculenand lntemd Rotation," AcademicPress, New
Chsm Soe, 94.1913 11972). (18) Zofirov. N. S.. Gurvich, L. G., Sharhkov. A. S., Krimer, M. Z.,snd VoraWevs, E. A., ~&hadron, 32.1211 (19761. (191 Barton, D. H. R., Experimtio, 6,316 119501. I201 H a ~ e l 0 , ..Tidrakr Kjami Berguos. Meroll., 3, 32 11943): Tap. Strreorhm., 6. 1
,,*,>,
