J. PhyS. Chem. 1982, 86, 4787-4771
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Proposed Procedure for Using Electrostatic Potentlals To Predict and Interpret Nucleophilic Processes Peter Polltzer,' Samuel J. Landry, and Torbjorn Warnheim Deperhnent of Chemistry, Unlverslty of New Orleans. New CMemw, Louisiana 70 148 (Received: May 20, 1982)
The electrostatic potential of a molecule is well established as an effective tool for predicting and interpreting its reactive behavior toward electrophiles;the latter will tend, at least initially, to go to the most negative regions. The electrostaticpotential has been used very little for analyzing nucleophilic processes, however, because positive potentials are not necessarily indicative of a corresponding affinity for nucleophiles; they may simply reflect the highly concentrated nature of the nuclear charges. Our aim in this work has been to develop a procedure whereby electrostatic potentials could be applied successfully to nucleophilic reactions. We show that this is indeed possible if the potential is computed for the molecule in a state of distorted geometry, which is already somewhat amenable to the approach of the nucleophile. The specific mode of distortion depends upon the type of molecule (i.e., aromatic, unsaturated aliphatic, etc.). Several examples are given, and it is shown that our proposed procedure correctly predicts the experimentally observed reactive behavior in each case.
Introduction It is now well established that the electrostatic potential produced by the electrons and nuclei of a molecule in the surrounding space is an effective tool for predicting and interpreting ita reactive behavior toward electrophiles.' An approaching electrophile's initial tendency is to go to those regions of the molecule in which the electrostatic potential is most negative. The electrostatic potential at a point i is given by
in which Z A is the charge on nucleus A, located at f i A , and p ( 3 is the electronic density function of the molecule. V ( 3 is a real physical property, rigorously defined and experimentally measurable.2 Of course the electrostatic term is only one of several contributions to the energy associated with an interaction, and accordingly the electrostatic potential of a molecule cannot, in general, be taken as a measure of its energy of interaction with some species. The potential does not take into account the properties of an attacking entity, nor does it reflect the polarizations and distortions that may occur in the course of an interaction. Nevertheless, the electrostatic potential provides certain well-defined information that can permit important insight into the reactive behavior of molecules. It has been widely and successfully used for estimating and comparing the reactivities of various molecular sites and regions toward electrophiles. It might be anticipated that V ( 3 should be equally useful for analyzing reactions with nucleophiles; their attack would be expected to occur preferentially at regions of positive potential. Unfortunately, however, the situation is more complicated than it was for electrophilic processes. The problem is that positive potentials do not necessarily (1)For recent reviews, see: (a) E. Scrocco and J. Tomasi, Adu. Quantum Chem., 11,116(1978);(b) P. Politzer and K. C. Daiker in 'The Force Concept in Chemistry", B. M. Deb, Ed., Van Nostrand-Reinhold, New York, 1981,Chapter 7. (2) P. Politzer and D. G. Truhlar, Eds., 'Chemical Applications of Atomic and Molecular Electrostatic Potentials", Plenum Press, New York, 1981. See chapters by the following: (a) D. G. Truhlar (Chapter 6),(b) M. Fink and R. A. Bonham (Chapter 7), (c) M. A. Spackman and R. F. Stewart (Chapter 17),and (d) G. Moss and P. Coppens (Chapter 18).
indicate a corresponding affinity for nucleophiles. For example, hydrogen atoms usually have positive regions around them but are not sites for nucleophilic attack. In general, the positive charges of atomic nuclei, being highly concentrated, produce positive electrostatic potentials that may outweigh the negative contributions of the dispersed electrons, yet not indicate a corresponding tendency to react with nucleophiles. It has been found that the electrostatic potentials of free neutral atoms are positive everywhere, reflecting the very concentrated nature of the nuclear ~ h a r g e . ~Thus, whereas a negative potential in a certain molecular region indicates that the charge rearrangement in forming the molecule created a region in which the electronic contribution is predominant, and which is therefore attractive toward electrophiles, a positive potential does not necessarily convey an analogous (but opposite) meaning; it would have been positive even if there had been no molecule formation and only free unperturbed atoms were present. For these reasons, the use of electrostatic potentials in studying molecular reactivity has been limited almost ~ exclusively to investigations of electrophilic p r ~ e s s e s . In view of the considerable success that has been achieved, it would be most useful and desirable to also be able to analyze nucleophilic processes in terms of electrostatic potentials. It is the purpose of this paper to demonstrate a procedure by which this can be done.
Proposed Procedure The key feature of our proposed scheme for studying nucleophilic interactions is that the electrostatic potential is to be computed for the molecule in a distorted geometry, which is already to some degree amenable to the approach of the nucleophile. For instance, for nucleophilic substitution in an aromatic system, the atom or group to be replaced would be moved out of the molecular plane so as to create a quasi-tetrahedral carbon on which one position is unoccupied, leaving an open path of approach to the carbon. The electrostatic potential in the region of this (3) P. Politzer and R. G. Parr, J. Chem. Phys., 61,4258 (1974);P. Politzer in 'Homoatomic Rings, Chains and Macromolecules of Main Group Elementa", A. L. Rheingold, Ed., Elsevier, Amsterdam, 1977, Chapter 4. (4)For some exceptions, see: B. Pullman, A. Goldblum, and H. Berthod, Biochem. Biophys. Res. Commun., 77, 1166 (1977);A. Goldblum and B. Pullman, Theor. Chim.Acta, 47,345 (1978).
0022-3654f82/2Q86-4767$Q1.25/Q 0 1982 American Chemical Society
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The Journal of Physical Chemistty, Vol. 86, No. 24, 1982
path is to be taken as an indication of the attractiveness of the site for an attacking nucleophile. Although the electrostatic potentials used in analyzing electrophilic processes have generally been computed for the ground (undistorted) states of molecules, the creation of quasi-tetrahedral carbons has earlier been found to be extremely helpful in treating aromatic electrophilic substitution reactions." In either case, whether describing nucleophilic or electrophilic aromatic interactions, this approach is consistent with the generally accepted concept that they proceed via the formation of an intermediate tetrahedral complex.s For investigating nucleophilic processes involving nonaromatic systems, other types of distortion will be appropriate. Thus, for SN2 reactions involving saturated molecules, the electrostatic potential would be computed for the substrate in an intermediate stage of inversion of configuration, and attention would be focused upon the region that is open to the approach of the nucleophile. An example of this, as well as another type of distortion, will be given later. The procedure that has been proposed has been tested on several systems whose reactive behavior toward nucleophiles is experimentally well established. These systems are acrolein, the methanol-methyl chloride combination, and the fluorobenzene-pnitrofluorobenzene combination. The results, which shall be presented in this paper, were very satisfactory in each case.
Methods The electrostatic potentials used in this work were calculated by using eq 1and electronic density functions obtained from ab initio SCF molecular wave functions with either STO-6G or 6-31G (in the case of acrolein) basis sets? Experimentally determined geometries were used for the ground (undistorted) states of all of the molecules except p-nitrofluorobenzene; lo for the latter, the nitrobenzene structure was taken and the para hydrogen was replaced by fluorine, using the C-F distance from fluorobenzene.
Politzer et al.
"W.-I'-rjo
/
/ 2
so
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5 . -0
-7G-4
00
Flgure 1. Electrostaticpotentiil of acrolein in plane through carbonyl carbon (at right) and CY carbon, perpendicular to molecular plane (shown). Values are in kcallmol, and dashed contours correspond to negative potentials. The negative region in this figure is due to the oxygen, which is located above the plane of the figure. m m
0.0
'
'-3.1 j
,'-6.3
Results and Discussion Acrolein. Acrolein (I) is the simplest member of the
I
I1
I11
IV
family of a,@-unsaturatedcarbonyl compounds (11). Their ( 5 ) P. Politzer, R. A. DoTeUy, and K. C. Daiker, J.Chem.Soc., Chem.
Commun.,617 (1973);P. Pohtzer and H. Weinatein, Tetrahedron, 31,915 (1975). (6) J. Bertran, E. Silla, R. Carbo, and M. Martin, Chem. Phys. Lett., 31, 267 (1975). (7) 0.Chalvet, C. Decoret, and J. Royer, Tetrahedron, 32,2927 (1976). (8) See, for example: (a) R. T. Morrison and R. N. Boyd, 'Organic Chemistry",3rd ed., Mynand Bacon, Boston, MA,1973, Chapters 11 and 25; D. S.Kemp and F. Vellaccio, 'Organic Chemistry", Worth Publishers, New York, 1980, Chapter 20. (9) (a) SCF-MO program: W. J. Hehre, W. A. Lathan, R. Ditchfield, M. D. Newton, and J. A Pople, QCPE, 11, 236 (1973); (b) Electrostatic potential program: D. Peeters and M. Saua, QCPE, 11, 360 (1978). (10)M. D. Harmony, V. W. Laurie, R. L. Kuczkowski, R. H. Schwendemau,D. A. Ramaay, F. J. Lovas, W. J. M e r t y , and A. C. Maki, J . Phys. Chem. Ref. Data, 8, 619 (1979); the structure of nitrobenzene was obtained from L. E. Sutton, Ed.,Tables of Intaratomic Dmtance and Configuration in Molecules and Ions", Supplement, The Chemical Society, London, 1965, Special Publication No. 18.
4 00
2'. 50
5'.00
7'. 50
10.00
I
14.0
Flgure 2. Electrostatic potential of acrolein In plane through C=C double bond, perpendicular to molecular plane (shown). The 0 carbon Is at the left. Values are In kcallmoi, and dashed lines correspond to negative potentials.
two characteristic functional groups, C=C and C=O, make possible several different resonance structures, including I11 and IV,which suggest that the carbonyl carbon and the @ carbon should be likely sites for nucleophilic attack. This expectation has been confirmed experimenbd.l~.~lJ~ In the case of aldehydes, such as acrolein, it has been observed that nucleophiles react predominantly at the carbonyl carbon.'l (11) Reference 8a, Chapter 27. (12) J. C. Stowell, 'Carbanions in Organic Synthesis", Wiley-Interscience, New York, 1979, pp 31-5.
The Journal of phvsical Chemistry, Vol. 86, No. 24, 1982 4769
Nucleophllic Processes
P
m
V
0;
61
-1
r
P 5 a LT h
L u1
a LT N
-3.1,
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7'. 50
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Flgure 3. Electrostatic potentlal of distorted acrolein In same plane as in Flgure 1. The oxygen and the carbonyl hydrogen, which are above and below this plane, have been moved toward the top of this figure, giving tetrahedral bond angles to the carbon on the right. The positive channel at the bottom of the figure is approxlmately In the fourth tetrahedral dlrection, which is lndlcated by the dotted line.
81 ?00
/
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4 00
61.00
1
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1k.00
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Figure 5. Electrostatic potentlal of methanol, in plane through atoms Indicated. Values are in kcal/moi, and dashed contours correspond to negative potentlais. m a
6
-1
a
61
7
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ai %0
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21
50
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Flgure 4. Electrostatic potentlal of distorted acroleln In same plane as in Figure 2. The two /3 hydrogens, whlch are above and below this plane, have been moved toward the top of this figure, gMng the /3 carbon tetrahedral bond angles. The fourth tetrahedral direction is indlcated by the dotted line.
In order to test whether electrostatic potential considerations will permit a correct choice between the two possible sites in acrolein, we have computed the potentials around each of the carbons in question, first in their equilibrium undistorted states (Figures 1and 2) and then after some degree of distortion (Figures 3 and 4). This distortion involved, in each case, moving the attached hydrogen(s) and/or oxygen out of the molecular plane until all bond angles around the carbon were tetrahedral. (No bond lengths were altered.) The vicinity of the fourth
I
3l.00
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\
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1b.00
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1
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Flgure 6. Electrostatic potentlai of methyl chloride, In plane through atoms indicated. Values are in kcai/mol, and dashed contours correspond to negative potentials.
tetrahedral direction is then the region of interest, since it is the likely channel of approach for a nucleophile. The electrostatic potentials of the undistorted carbons show nothing that would suggest a preference for nucleophilic attack at the carbonyl site. In striking contrast, however, the potential of the distorted carbonyl carbon shows a very definite positive channel in the fourth tetrahedral direction (Figure 3, dotted line), defining an attractive path of approach for a nucleophile. Distortion of the /3 carbon, on the other hand, produces no competitive positive pathway to that carbon (Figure 4). Thus, our proposed procedure correctly predicts that the carbonyl carbon is the most probable site for nucleophilic attack in acrolein.
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The Journal of Physlcal Chemistry, Vol. 86, No. 24, 1982
Q
3'.00
6l.00
9' 00
1.2.00
1k.00
7 9 00
Figure 7. Electrostatic potentlal of distorted methanol, in same plane as In Figure 5. C-H bonds are now perpendicular to symmetry axis of methyl group (dotted line).
Methanol and Methyl Chloride. Bimolecular nucleophilic substitution (SN2)in aliphatic systems is accompanied by inversion of configuration, which is explained by invoking a transition state of the form (V)
'08
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08
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Figure 8. Electrostatic potentlal of distorted methyl chloride, in same plane as in Figure 6. C-H bonds are now perpendicular to symmetry axis of methyl group (dotted line).
8 (F.
-1I
R3
V
in which X is the nucleophile and Y is the leaving group.l3 Since Cl- is a better leaving group than OH-, the reaction
X:- + H3C:Cl- X:CH3 + C1occurs more readily than does
X:- + H3C:OH
-+
XCH3
+ OH-
Figures 5 and 6 show our calculated electrostatic potentials for methanol and methyl chloride. Both have large positive regions, but these do not permit a clear-cut unambiguous prediction as to which molecule is more susceptible to nucleophilic attack. Such a prediction can be made, however, from Figures 7 and 8. These show the electrostatic potentials for the two molecules in the form of VI.
"\
---- c/H__-y
I
Y = CI
or OH
H
VI
The hydrogens are now in the plane that contains the carbon and is perpendicular to the symmetry axis of the methyl group; this axis (dotted line) is also the pathway for the approaching nucleophile. Methyl chloride has by far the more positive potential in the region of this pathway, so that it would correctly be predicted to be the more susceptible, of these two molecules, to an SN2nucleophilic (13) Reference Ba, Chapter 14; ref ab, Chapter 4.
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Figure 9. Electrostatic potentlal of fluorobenzene, in symmetry plane perpendicular to molecular plane. Values are in kcal/mol, and dashed contours correspond to negative potentials.
substitution reaction. Fluorobenzene and p-Nitrofluorobenzene. Aryl halides are notoriously reluctant to undergo nucleophilic (SN2) replacement of the ha10gen.l~ However, the presence of an NO2group in an ortho or para position greatly increases the reactivity of the halogen. In the cases of fluorobenzene (VII) and p-nitrofluoro-
VI1
VI11
benzene (VIII), some of the effects of the electron-with(14) Reference Ba, Chapter 25; ref Bb, Chapter 20.
The Journal of Physical Chemistry, Vol. 86, No. 24, 1982 4771
Nucleophlllc Processes a a LF.
-1
I
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81,
Ii
,
I
I
10
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Flgurr 12. Electroetatlc potential of dlstorted p-nltrofluorobenzene, In same plane as In Flgure 10. C-F bond Is now 51' out of the
molecular plane. The fourth quasCtetrahedral dlrectlon le Indicated by the dotted line.
and demonstrated, in this paper, that positive electrostatic potentiale of ground-state molecules are unreliable guides to sites for nucleophilic attack. We have therefore computed the potentials for the structures in which the fluorine was moved out of the molecular plane by 61°, an angle that creates a quasitetrahedral carbon with one unoccupied positi~n.~~' The electrostatic potentials along this fourth direction, the open pathway of approach to the carbon, can be compared in Figures 11 and 12. There is clearly a much stronger positive channel leading to the fluorinated carbon in pnitrofluorobenzene than in fluorobenzene, again permitting an accurate prediction of the experimentally observed behavior.
Summary We have demonstrated in this paper that the electrostatic potential can indeed be used as a tool for predicting and interpreting nucleophilic processes, provided that the , I
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Flgun 11. E ~ o s t a t l potrntlal c of dlsttorted fiuorobenzene, In same plane as In Flgun 9. E-F bond Is now S i o out of the mokcular plane. The fourth quasi-tetrahedral dlrectlon Is lndlcated by the dotted Ilne.
drawing nitro group are apparent even from the electrostatic potentials of the ground-state (undistorted) molecules, as seen in Figures 9 and 10. The extensive negative regions above and below the ring in fluorobenzene are absent in p-nitrofluorobenzene. This suggests that the aromatic ring in the latter should be the more attractive to nucleophiles. However, it has already been pointed out
molecules are examined in states of distorted geometries, which already somewhat anticipate the approach of the nucleophile. The specific mode of distortion to be applied depends upon the type of molecule (Le.,aromatic, unsaturated aliphatic, etc.); several examples have been given. Using this procedure, it has been possible to correctly predict the actual reactive properties of the molecules in all of the cases investigated.
Acknowledgment, We thank Dr. Linda N, Domelsmith for several very helpful discussions. We also greatly appreciate the support of this work by the U.S.Army Research Office.
