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Effect of the heteroatomic substituent on the pi-facial diastereoselectivity in Lewis acid catalyzed carbonyl ene reaction: A theoretical study
Journal of Molecular Structure: THEOCHEM 858 (2008) 107–112
Contents lists available at ScienceDirect
Journal of Molecular Structure: THEOCHEM journal homepage: www.elsevier.com/locate/theochem
Effect of the heteroatomic substituent on the pi-facial diastereoselectivity in Lewis acid catalyzed carbonyl ene reaction: A theoretical study Kuheli Chakrabarty, Sukhendu Roy, Gourab Kanti Das * Department of Chemistry, Visva-Bharati, Santiniketan-731235, West Bengal, India
a r t i c l e
i n f o
Article history: Received 21 November 2007 Received in revised form 15 January 2008 Accepted 24 February 2008 Available online 6 March 2008 Keywords: Diastereoselectivity Ene reaction Transition structures
a b s t r a c t Quantum chemical investigation on the optimized transition structures of intermolecular ene reaction containing various heteroatomic substituents at the a-carbon atom reveal that, the electrostatic effect produced by the ene moiety plays a crucial role in controlling the conformation of the transition structure. The stereoselectivity calculated from the proposed model agreed nicely with the reported experimental results. Ó 2008 Elsevier B.V. All rights reserved.
1. Introduction Carbonyl ene reaction is one of the most efficient methods for carbon–carbon bond formation with stereo control, featuring acyclic stereo control [1–3]. The synthetic utility of this reaction depends almost entirely on the functional groups present in the enophile employed. Most of the reported ene reactions are Lewis acid catalyzed carbonyl ene reaction. Presence of a stereogenic center adjacent to the carbonyl enophile or the ene component may lead to the asymmetric induction on the ene product. Asymmetric synthesis of diols and amino alcohols may be achieved using chiral hydroxy or chiral amino aldehyde enophiles. Mikami and co-workers reported [4,5] the reactions of chiral a-benzyloxy aldehyde and a-dibenzyl amino aldehyde with isobutylene, resulted syn diastereo facial selectivity in presence of various Lewis acids. The observed diastereoselectivity have been explained by the application of the Cram’s chelate model [6,7]. The Lewis acids are assumed to form a bidentate chelate complex with the enophile while generating the transition structure and the preferred site for incoming ene is from the less sterically hindered side. The postulation of the chelate model may appear to be reasonable for those Lewis acids in which the central metal is capable of providing more than one coordination site i.e. SnCl4, TiCl4, etc. However, Lewis acids like AlCl3, RAlCl2, R2AlCl (R = Me, Et) have been employed
* Corresponding author. Tel.: +91 3463 261144; fax: +91 3463 262672. E-mail addresses: [email protected], [email protected] (G.K. Das). 0166-1280/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.theochem.2008.02.029
in several ene reactions to catalyze the reaction by forming a monodentate complex. Felkin model [8], which is based on the torsional preference of the approaching nucleophile in generating the transition states, will give satisfactory result when the steric crowding at the stereogenic center adjacent to the carbonyl group predominates. Modification of the Felkin model by Anh and Eisenstein [9–12] was ascribed for determining the conformational preferences of the electronegative atoms present at the a-carbon. They pointed out that the transition state in Felkin model gets it’s stability by delocalization of the electron density from the nucleophile to the antibonding orbital of the anti vicinal bond. As a result the approaching nucleophile prefers to attack from an anti-periplanar direction of the electron withdrawing group present at the stereogenic center. However, this model is conceptually different from the Cieplak [13] hypothesis, which states that, the approaching nucleophile should attack from the direction anti-periplanar to the best electron donor vicinal bond. Other calculations [14–16] reveal that electrostatic effect operating between various atoms and groups dominates over the steric and electronic factors and thus controls the conformation of the TS. Our recent report [17] on the pi-facial selectivity in carbonyl ene reaction also shows that the consideration of the electrostatic interaction is sufficient to workout the preferable geometry of the transition structure. In this paper we report a model of electrostatic interaction, operating between the substituent and the interacting ene in the TS of the Lewis acid catalyzed carbonyl ene reaction. The rationalization of the stereo chemical outcomes in Lewis acid catalyzed ene reaction can be performed using this model.
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K. Chakrabarty et al. / Journal of Molecular Structure: THEOCHEM 858 (2008) 107–112
Intramolecular carbonyl ene reactions have been classified into six different types, depending on the connectivity between the ene and the enophile moiety [18]. Among them, (3,4) and (2,4) ene cyclizations are commonly known as Type-I and Type-II ene reaction and of immense synthetic applicability. Our previous studies on the Type-I [19] and Type-II [20] carbonyl ene reaction show that the ab-initio technique and single point DFT calculation on ab-initio optimized structures are suitable for calculating the relative energies. These relative energies can be used successfully to rationalize the observed diastereoselectivity of these reactions. Another report also shows that the activation energy for the ene reaction can be calculated by single point DFT calculation on ab-initio optimized structure [21]. We have employed both ab-initio and DFT calculation here for comparing the energies of a large number of conformers of the transition structures to determine the most favorable one.
Table 2 Relative energies of the possible transition structures (Fig. 2) with heteroatomic substituents, OH, OMe, NH2 or NMe2 present at the a-carbon atom Sl. No.
All the TSs have been constructed using Molden [22] software and optimized using ab-initio quantum mechanical technique with RHF/6-31G* method. To confirm the reliability of the ab-initio method some basic transition structures have also been optimized using DFT method using B3LYP hybrid functional and 6-31G* basis set (Tables 1 and 2). For optimization and energy calculation GAMESS software [23] was used. Each species was characterized as corresponding to a saddle point on the energy hyper surface by means of vibrational analysis. All the relative energy values, given here, were calculated from the zero point energy (ZPE) corrected absolute energy of the transition structures. Single point energy calculation was done using B3LYP density functional and 6-31G* basis set for relatively larger systems for which DFT optimization were not performed. Calculation of the Molecular Electrostatic Potential (MESP) [24] for the transition structures are performed using the wave function of the optimized geometries. The calculated values are color mapped on the isodensity surface of the molecular system. 3. Results and discussion 3.1. Electrostatic potential around the TS of basic ethylenic and carbonyl ene reaction The schematic representation of the transition structure (TS) of the Lewis acid catalyzed basic ene reaction is given in the Scheme 1 (LA = Lewis acid, X = C, N, O, etc.). We have constructed the concerted TS of ethene–propene and methanal–propene (uncatalyzed and catalyzed by Lewis acid) ene reaction for comparing the electrostatic potential around the system. TS of the ene reactions of ethene–propene and methanal–propene were investigated and reported by Houk [25] and are shown in Fig. 1a and b. Fig. 1c represents the TS of a Lewis acid catalyzed carbonyl ene reaction where the oxygen atom of the enophile is coordinated to the Lewis acid AlH3. Our previous report [18,19] shows that the later structure serves as a good model for predicting
Relative energy (in kcal/mole) R2
R3
Endo
Exo
1 2 3 4 5 6 7 8 9 10 11 12
OH H H OMe H H NH2 H H NMe2 H H
H H OH H H OMe H NH2 H H NMe2 H
H OH H H OMe H H H NH2 H H NMe2
4.61a (3.75)b 0.00 (0.00) 3.54 (3.73) 6.06 (3.68) 0.00 (0.00) 1.72 (0.96) 4.84 (3.37) 3.87 (3.90) 0.00 (0.00) 5.31 (3.37) 2.05 (1.98) 0.00 (0.00)
4.03 1.72 3.30 6.92 3.28 1.45 4.47 3.65 2.60 5.80 1.83 2.54
a
RHF/6-31G*. B3LYP/6-31G*.
b
2. Computational methods
Substituent R1
3 4 CH 2 5 X
2
+
3
4
L.A.
5
1
L.A.
X
(2.40) (2.00) (5.37) (5.58) (2.78) (2.39) (2.95) (4.85) (2.41) (4.50) (2.18) (3.79)
2 1
H
X
H
TS Scheme 1. Lewis acid (LA) catalyzed intermolecular ene reaction.
the stereoselectivities in various ene cyclizations. Electrostatic potential (ESP) around these TSs have been calculated and are shown as the color map on isodensity surfaces (Fig. 1a0 –c0 ). From the color variation it is evident that a positive electrostatic potential is generated on the surface around the propene moiety when the formaldehyde (Fig. 1b) or the formaldehyde associated with the Lewis acid (Fig. 1c) is acting as the enophile in the (blue color represents the positive electrostatic potential). This effect is normally expected because, the principal orbital interaction in forming the TS is between the HOMO of ene and the LUMO of enophile [26] and the low lying LUMO of the carbonyl compound depletes electron more effectively from the ene (propene). The charge distribution on various atoms (Table 1) also supports this fact. The charge on atom 2 becomes positive from negative as we move from structure (a) to (c). In the following sections it will be explored how this developed positive charge on the ene component affects the conformational preferences of the heteroatomic substituent present on the a-carbon atom of the carbonyl group and determines the overall selectivity of the asymmetric ene synthesis. 3.2. Effect of nitrogen and oxygen containing functional group Substituents like hydroxy, methoxy, amino and N,N-dimethyl amino are selected and are placed individually at the a-carbon atom in the enophile part of the TS (Scheme 2, R1, R2 or R3 is the heteroatomic substituent). Depending on the orientation of the a-carbon atom with respect to the six-membered TS, two possible
Table 1 Charge distribution on the atoms of the six-membered transition structure of ene reaction (Scheme 1)
X = CH2 X=O X = O–AlH3 a b
1
2
3
4
5
H
0.50a (0.46)b 0.62 (0.53) 0.62 (0.55)
0.08 (0.02) 0.01 (0.00) 0.05 (0.03)
0.42 (0.34) 0.51 (0.38) 0.46 (0.37)
0.33 (0.27) 0.08 (0.01) 0.04 (0.02)
0.48 (0.41) 0.67 (0.51) 0.81 (0.55)
0.15 (0.16) 0.40 (0.33) 0.40 (0.33)
Calculated using RHF/6-31G*. Calculated using B3LYP/6-31G*.
K. Chakrabarty et al. / Journal of Molecular Structure: THEOCHEM 858 (2008) 107–112
109
Fig. 1. Ball and stick model of the transition structures (TS) of Scheme 1. (a) X = CH2; (b) X = O; (c) X = O–AlH3. (a0 )–(c0 ) are the isodensity surface (p = 0.04 a.u.) color mapped with electrostatic potential (blue > 0.30; light blue = 0.10; green = 0.00; yellow = 0.05; red < 0.10). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
R3
R1
R2
O H3Al
H
Scheme 2. Transition structure of the Lewis acid catalyzed ene reaction with heteroatomic substituent (R1, R2 or R3) at a-carbon atom.
transition structures, endo and exo, were constructed (Fig. 2). The Lewis acid AlH3 was placed in a position anti to the a-substituent to make a least sterically hindered system. The relative energies of different possible conformers (resulted from the variation of the positions of R1, R2, R3) are gathered in
R1 R2
R3
R3 H
3.3. Effect of the presence of a chiral center
R1 H
R2
2
O
H
H
1 O
H
H
H H
Al
H H
H
H
H
Al
H H
Table 2. The conformational preferences of all these substituents with respect to Ca–O, CaN bond have been determined on the basis of the absolute energy and the most favorable conformers are shown in Fig. 3. Relative energies as shown in Table 2 clearly indicate that the most stable conformational isomer is generated when the substituent occupies the R2 position in the endo structure. The most prominent feature is the direction of the lone pair (assumed from the orientation of other substituents) connected to the hetero atom. In all these cases it directs to the central carbon atom (C-2) of the ene moiety in the transition structure. Previously it was pointed out that a considerable positive charge is developed at the central carbon atom of the ene in Lewis acid catalyzed ene reaction and supported by the experimental result [27]. The charge distribution of each carbon or hetero atoms on the transition structures also confirms this fact and this developed positive charge interacts strongly with the lone pair of the substituent and consequently stabilize the geometry.
H
Fig. 2. Schematic representation of the model transition structure of Lewis acid catalyzed ene reaction between propene and a carbonyl molecule with a-carbon atom. Depending on the orientation of a carbon atom with respect to the transition structure the (a) endo and (b) exo isomers are possible.
The Lewis acid catalyzed ene reaction of chiral a-amino and a-benzyloxyaldehydes was reported by Mikami and co-workers and was shown to afford high level of diastereoselection in forming the isomeric products (Scheme 3) [4,5]. To rationalize the observed diastereoselectivity the authors employed the chelation model. However we have taken a different approach to verify the electrostatic model proposed in the previous sections. For this a set of hypothetical reactions (Scheme 4) is formulated to generate the transition structures. Reaction (a) and (b) of Scheme 4 represents the ene process with chiral carbonyl enophile containing oxygenated (hydroxy or methoxy) substituent whereas reaction (c) and (d) represent
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Fig. 3. Most favorable conformational isomers of the transition structures with heteroatomic substituent (a) OH, (b) OMe, (c) NH2 or (d) NMe2 present at the a-carbon and the corresponding electrostatic potential map on the isodensity surface.
reactions with the reactant containing nitrogenated substituent (amino or dimethyl amino) at the chiral center. The model of the possible transition structures for each reaction may be represented schematically by four diastereomeric structures (Figs. 2 and 4) each of which exists in three conformational isomers by interchanging the positions of R1, R2 and R3 groups among them. The relative energy values of all these structures are given in Table 3. The relative energies clearly indicate that, the conformation and
configuration of the TSs of entry number 8, 14, 20, 32 and 45 are the most favorable species. Substituents like hydroxy, amino and dimethyl amino show preferences for the diastereoisomeric structure a’ (Fig. 4) (entry number 8, 32 and 45) occupying the position R2. The preference for position R1 by methyl substituent in all these structures abides by the Felkin model since the incoming ene attacks the enophile carbonyl carbon in a direction opposite to the group R1. However the preferences for hydroxy, amino and di-
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Table 3 Relative energies of the possible transition structures (Figs. 2 and 4) with a chiral center bearing heteroatomic substituents, OH, OMe, NH2 or NMe2
OBn
OBn
OBn H
Sl. No.
OH
OH
syn (major)
anti
O
NR2 R
NR2
NR2
H
R
R O
OH
OH
anti
syn (major)
Scheme 3. Lewis acid catalyzed ene reaction of chiral a-amino and a-benzyloxyaldehydes [4,5].
H OR
OR
OR H AlH3
O
syn
a) R = H b) R = CH3 NR2
H
R
anti
NR2
NR2
H
R
R O c) R = H d) R = CH3
OH
H
OH
AlH3
H
OH
H
OH
H
anti
syn
Scheme 4. Hypothetical reactions to model the reactions shown in Scheme 3.
R1 H
R2
R2
R3 H
2
H
H
1 H
R1 R3
O
O
H
Al H
H
H H
a
b
a0
b0
a
b
a0
b0
a
b
a0
b0
a
b
a0
b0
Substituent at R1
R2
R3
OH H CH3 OH H CH3 OH CH3 H OH CH3 H OCH3 H CH3 OCH3 H CH3 OCH3 CH3 H OCH3 CH3 H NH2 CH3 H NH2 CH3 H H CH3 NH2 NH2 CH3 H NMe2 CH3 H NMe2 H CH3 NMe2 H CH3 NMe2 CH3 H
H CH3 OH H CH3 OH H OH CH3 H OH CH3 H CH3 OCH3 H CH3 OCH3 H OCH3 CH3 H OCH3 CH3 H NH2 CH3 H NH2 CH3 CH3 NH2 H H NH2 CH3 H NMe2 CH3 H CH3 NMe2 H CH3 NMe2 H NMe2 CH3
CH3 OH H CH3 OH H CH3 H OH CH3 H OH CH3 OCH3 H CH3 OCH3 H CH3 H OCH3 CH3 H OCH3 CH3 H NH2 CH3 H NH2 NH2 H CH3 CH3 H NH2 CH3 H NMe2 CH3 NMe2 H CH3 NMe2 H CH3 H NMe2
Relative energy (kcal mol1)
Conformation around CaX (X = N or O)
6.37a (5.94)b 0.92 (0.61) 3.20 (3.57) 5.23 (3.87) 2.14 (2.95) 3.61 5.21) 5.07 (4.23) 0.00 (0.00) 5.19 (5.26) 4.55 (5.36) 2.24 (2.71) 4.28 (2.71) 9.15 (5.47) 0.00 (0.00) 1.89 (1.37) 7.86 (7.43) 2.58 (3.26) 4.79 (4.98) 6.95 (4.36) 0.02 (0.18) 2.96 (2.37) 6.45 (6.15) 5.15 (4.26) 2.68 (3.52) 6.73 (5.85) 3.92 (3.88) 1.02 (0.71) 6.04 (5.00) 4.39 (5.75) 3.08 (4.12) 5.39 (5.42) 0.00 (0.00) 6.04 (4.89) 5.37 (5.27) 2.54 (3.93) 4.74 (6.30) 7.39 (5.96) 2.01 (2.95) 3.15 (2.41) 6.85 (6.53) 5.61 (6.16) 2.39 (4.83) 6.91 (5.86) 5.62 (5.15) 0.00 (0.00) 7.26 (7.17) 2.85 (3.58) 4.72 (3.09)
+sc sc ±ap +sc sc ±ap sc +sc ±ap sc +sc ±ap +sc ac ±ap ±ap sc +sc sc ±ap ±ap sc sc sc ±ap sc +sc ±ap sc +sc +sc sc ±ap ±ap sc +sc ±ap sc ±sp sc +sc sc ±ap +sc sc ±ap sc +sc
RHF/6-31G*. B3LYP/6-31G*//RHF/6-31G*.
2
Al H
a b
1 H
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
TS (Figs. 2 and 4)
H
H H
H
Fig. 4. Two diastereomeric transition structures (a0 ) and (b0 ) of (a) and (b) (Fig. 2) when R1, R2 and R3 are different.
formation in Scheme 4. However, experimental result (Scheme 3) supports the preference for syn configuration. It appears to us that for such substituent chelation model may take a predominant role in determining the overall selectivity. 4. Conclusion
methyl amino groups for R2 position can be rationalized on the basis of electrostatic interaction between the heteroatom and the ene moiety. Models of all the favorable transition structures are shown in Fig. 5. All these transition structures lead to the product with configuration syn of Scheme 4 which agrees the experimental results of stereoselectivities in Scheme 3. For methoxy substituent two TSs (entry 14 and 20) are preferable and these corresponds to the structure a and a0 of Fig. 4. As both these structures are almost equally favorable, there will be no selectivity for the product
The above discussion reveals that, a positive electrostatic field is generated around the ene moiety in the TS of a Lewis acid catalyzed ene reaction. This electrostatic field is responsible for the conformational preferences of the heteroatomic substituent present at the stereogenic center adjacent to the carbonyl group of the carbonyl enophile. This interaction is capable to direct the energetically most favorable conformation of the TS for many substituent and thus, alter the overall stereoselectivity of the asymmetric ene reaction.
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Acknowledgments One of us (K.C.) is thankful to DST for the financial assistance through DST-WOSA/SR/CS-24/2004. We are thankful to the University Grants Commission, New Delhi, India for the financial support of this research through a major research project (F-31-107/2005 (S.R.)) and through special assistance programme. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]
[24]
Fig. 5. Energetically favorable conformers of the carbonyl ene reaction bearing chiral centers at the a-carbon atom. Heteroatomic substituent like (i) OH, (ii) and (iii) OCH3, (iv) NH2 or (v) NMe2 is present at the chiral center.
[25] [26] [27]
R.W. Hoffmann, Angew. Chem. Int. Ed. Engl. 23 (1984) 932. Y. Yamamoto, Acc. Chem. Res. 20 (1987) 243. R.W. Hoffmann, Int. Ed. Engl. 26 (1987) 489. K. Mikami, T.P. Loh, T. Nakai, Tetrahedron Asymmetry 1 (1990) 13. K. Mikami, M. Kaneko, T.P. Loh, M. Terada, T. Nakai, Tetrahedron Lett. 31 (1990) 3909. D.J. Cram, F.A.A. Elhafez, J. Am. Chem. Soc. 74 (1952) 5821. D.J. Cram, K.R. Kopeckycky, J. Am. Chem. Soc. 81 (1959) 2748. M. Cherest, H. Felkin, N. Prudent, Tetrahedron Lett. (1968) 2205. N.T. Anh, O. Eisenstein, Tetrahedron Lett. (1976) 155. J. Huet, Y.M. Bernard, N.T. Anh, J. Seyden-Penne, Tetrahedron Lett. (1976) 159. N.T. Anh, O. Eisenstein, Nouv. J. Chem. 1 (1977) 61. N.T. Anh, Top. Curr. Chem. 88 (1980) 145. A.S. Cieplak, J. Am. Chem. Soc. 103 (1981) 4540. M.N. Paddon-Row, Y.D. Wu, K.N. Houk, J. Am. Chem. Soc. 114 (1992) 10638. B. Ganguly, J. Chandrasekhar, F.A. Khan, G. Mehta, J. Org. Chem. 58 (1993) 1734. G. Mehta, J. Chandrasekhar, Chem. Rev. 99 (1999) 1437. K. Chakrabarty, S. Roy, G.K. Das, N. Mondal, J. Mol. Struct. (Theochem) 805 (2007) 1–7. K. Mikami, M. Shimizu, Chem. Rev. 92 (1992) 1021. N. Mondal, K. Chakrabarty, S. Roy, G.K. Das, J. Mol. Struct. (Theochem) 684 (2004) 187–195. N. Mondal, S.C. Mandal, G.K. Das, J. Mol. Struct. (Theochem) 680 (2004) 73– 81. J. Pranata, Int. J. Quant. Chem. 62 (1997) 502. G. Schaftennar, J.H. Noordik, J. Comput. Aid. Mol. Des. 14 (2000) 123. M.W. Schmidt, K.K. Baldridge, J.A. Boatz, S.T. Elbert, M.S. Gordon, J.J. Jensen, S. Koseki, N. Matsunaga, K.A. Nguyen, S. Su, T.L. Windus, M. Dupuis, J.A. Montgomery, J. Comput. Chem. 14 (1993) 13. S.R. Gadre, R.N. Shirsat, in: Electrostatics of Atoms and Molecules, Universities Press (India) Limited, 2000. Chapter 2. R.J. Loncharich, K.N. Houk, J. Am. Chem. Soc. 109 (1987) 6947–6952. S. Inagaki, H. Fujimoto, K. Fukui, J. Am. Chem. Soc. 98 (1976) 4693– 4701. M.F. Salomon, S.N. Pardo, R.G. Salomon, J. Am. Chem. Soc. 102 (1980) 2473.
Contents lists available at ScienceDirect
Journal of Molecular Structure: THEOCHEM journal homepage: www.elsevier.com/locate/theochem
Effect of the heteroatomic substituent on the pi-facial diastereoselectivity in Lewis acid catalyzed carbonyl ene reaction: A theoretical study Kuheli Chakrabarty, Sukhendu Roy, Gourab Kanti Das * Department of Chemistry, Visva-Bharati, Santiniketan-731235, West Bengal, India
a r t i c l e
i n f o
Article history: Received 21 November 2007 Received in revised form 15 January 2008 Accepted 24 February 2008 Available online 6 March 2008 Keywords: Diastereoselectivity Ene reaction Transition structures
a b s t r a c t Quantum chemical investigation on the optimized transition structures of intermolecular ene reaction containing various heteroatomic substituents at the a-carbon atom reveal that, the electrostatic effect produced by the ene moiety plays a crucial role in controlling the conformation of the transition structure. The stereoselectivity calculated from the proposed model agreed nicely with the reported experimental results. Ó 2008 Elsevier B.V. All rights reserved.
1. Introduction Carbonyl ene reaction is one of the most efficient methods for carbon–carbon bond formation with stereo control, featuring acyclic stereo control [1–3]. The synthetic utility of this reaction depends almost entirely on the functional groups present in the enophile employed. Most of the reported ene reactions are Lewis acid catalyzed carbonyl ene reaction. Presence of a stereogenic center adjacent to the carbonyl enophile or the ene component may lead to the asymmetric induction on the ene product. Asymmetric synthesis of diols and amino alcohols may be achieved using chiral hydroxy or chiral amino aldehyde enophiles. Mikami and co-workers reported [4,5] the reactions of chiral a-benzyloxy aldehyde and a-dibenzyl amino aldehyde with isobutylene, resulted syn diastereo facial selectivity in presence of various Lewis acids. The observed diastereoselectivity have been explained by the application of the Cram’s chelate model [6,7]. The Lewis acids are assumed to form a bidentate chelate complex with the enophile while generating the transition structure and the preferred site for incoming ene is from the less sterically hindered side. The postulation of the chelate model may appear to be reasonable for those Lewis acids in which the central metal is capable of providing more than one coordination site i.e. SnCl4, TiCl4, etc. However, Lewis acids like AlCl3, RAlCl2, R2AlCl (R = Me, Et) have been employed
* Corresponding author. Tel.: +91 3463 261144; fax: +91 3463 262672. E-mail addresses: [email protected], [email protected] (G.K. Das). 0166-1280/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.theochem.2008.02.029
in several ene reactions to catalyze the reaction by forming a monodentate complex. Felkin model [8], which is based on the torsional preference of the approaching nucleophile in generating the transition states, will give satisfactory result when the steric crowding at the stereogenic center adjacent to the carbonyl group predominates. Modification of the Felkin model by Anh and Eisenstein [9–12] was ascribed for determining the conformational preferences of the electronegative atoms present at the a-carbon. They pointed out that the transition state in Felkin model gets it’s stability by delocalization of the electron density from the nucleophile to the antibonding orbital of the anti vicinal bond. As a result the approaching nucleophile prefers to attack from an anti-periplanar direction of the electron withdrawing group present at the stereogenic center. However, this model is conceptually different from the Cieplak [13] hypothesis, which states that, the approaching nucleophile should attack from the direction anti-periplanar to the best electron donor vicinal bond. Other calculations [14–16] reveal that electrostatic effect operating between various atoms and groups dominates over the steric and electronic factors and thus controls the conformation of the TS. Our recent report [17] on the pi-facial selectivity in carbonyl ene reaction also shows that the consideration of the electrostatic interaction is sufficient to workout the preferable geometry of the transition structure. In this paper we report a model of electrostatic interaction, operating between the substituent and the interacting ene in the TS of the Lewis acid catalyzed carbonyl ene reaction. The rationalization of the stereo chemical outcomes in Lewis acid catalyzed ene reaction can be performed using this model.
108
K. Chakrabarty et al. / Journal of Molecular Structure: THEOCHEM 858 (2008) 107–112
Intramolecular carbonyl ene reactions have been classified into six different types, depending on the connectivity between the ene and the enophile moiety [18]. Among them, (3,4) and (2,4) ene cyclizations are commonly known as Type-I and Type-II ene reaction and of immense synthetic applicability. Our previous studies on the Type-I [19] and Type-II [20] carbonyl ene reaction show that the ab-initio technique and single point DFT calculation on ab-initio optimized structures are suitable for calculating the relative energies. These relative energies can be used successfully to rationalize the observed diastereoselectivity of these reactions. Another report also shows that the activation energy for the ene reaction can be calculated by single point DFT calculation on ab-initio optimized structure [21]. We have employed both ab-initio and DFT calculation here for comparing the energies of a large number of conformers of the transition structures to determine the most favorable one.
Table 2 Relative energies of the possible transition structures (Fig. 2) with heteroatomic substituents, OH, OMe, NH2 or NMe2 present at the a-carbon atom Sl. No.
All the TSs have been constructed using Molden [22] software and optimized using ab-initio quantum mechanical technique with RHF/6-31G* method. To confirm the reliability of the ab-initio method some basic transition structures have also been optimized using DFT method using B3LYP hybrid functional and 6-31G* basis set (Tables 1 and 2). For optimization and energy calculation GAMESS software [23] was used. Each species was characterized as corresponding to a saddle point on the energy hyper surface by means of vibrational analysis. All the relative energy values, given here, were calculated from the zero point energy (ZPE) corrected absolute energy of the transition structures. Single point energy calculation was done using B3LYP density functional and 6-31G* basis set for relatively larger systems for which DFT optimization were not performed. Calculation of the Molecular Electrostatic Potential (MESP) [24] for the transition structures are performed using the wave function of the optimized geometries. The calculated values are color mapped on the isodensity surface of the molecular system. 3. Results and discussion 3.1. Electrostatic potential around the TS of basic ethylenic and carbonyl ene reaction The schematic representation of the transition structure (TS) of the Lewis acid catalyzed basic ene reaction is given in the Scheme 1 (LA = Lewis acid, X = C, N, O, etc.). We have constructed the concerted TS of ethene–propene and methanal–propene (uncatalyzed and catalyzed by Lewis acid) ene reaction for comparing the electrostatic potential around the system. TS of the ene reactions of ethene–propene and methanal–propene were investigated and reported by Houk [25] and are shown in Fig. 1a and b. Fig. 1c represents the TS of a Lewis acid catalyzed carbonyl ene reaction where the oxygen atom of the enophile is coordinated to the Lewis acid AlH3. Our previous report [18,19] shows that the later structure serves as a good model for predicting
Relative energy (in kcal/mole) R2
R3
Endo
Exo
1 2 3 4 5 6 7 8 9 10 11 12
OH H H OMe H H NH2 H H NMe2 H H
H H OH H H OMe H NH2 H H NMe2 H
H OH H H OMe H H H NH2 H H NMe2
4.61a (3.75)b 0.00 (0.00) 3.54 (3.73) 6.06 (3.68) 0.00 (0.00) 1.72 (0.96) 4.84 (3.37) 3.87 (3.90) 0.00 (0.00) 5.31 (3.37) 2.05 (1.98) 0.00 (0.00)
4.03 1.72 3.30 6.92 3.28 1.45 4.47 3.65 2.60 5.80 1.83 2.54
a
RHF/6-31G*. B3LYP/6-31G*.
b
2. Computational methods
Substituent R1
3 4 CH 2 5 X
2
+
3
4
L.A.
5
1
L.A.
X
(2.40) (2.00) (5.37) (5.58) (2.78) (2.39) (2.95) (4.85) (2.41) (4.50) (2.18) (3.79)
2 1
H
X
H
TS Scheme 1. Lewis acid (LA) catalyzed intermolecular ene reaction.
the stereoselectivities in various ene cyclizations. Electrostatic potential (ESP) around these TSs have been calculated and are shown as the color map on isodensity surfaces (Fig. 1a0 –c0 ). From the color variation it is evident that a positive electrostatic potential is generated on the surface around the propene moiety when the formaldehyde (Fig. 1b) or the formaldehyde associated with the Lewis acid (Fig. 1c) is acting as the enophile in the (blue color represents the positive electrostatic potential). This effect is normally expected because, the principal orbital interaction in forming the TS is between the HOMO of ene and the LUMO of enophile [26] and the low lying LUMO of the carbonyl compound depletes electron more effectively from the ene (propene). The charge distribution on various atoms (Table 1) also supports this fact. The charge on atom 2 becomes positive from negative as we move from structure (a) to (c). In the following sections it will be explored how this developed positive charge on the ene component affects the conformational preferences of the heteroatomic substituent present on the a-carbon atom of the carbonyl group and determines the overall selectivity of the asymmetric ene synthesis. 3.2. Effect of nitrogen and oxygen containing functional group Substituents like hydroxy, methoxy, amino and N,N-dimethyl amino are selected and are placed individually at the a-carbon atom in the enophile part of the TS (Scheme 2, R1, R2 or R3 is the heteroatomic substituent). Depending on the orientation of the a-carbon atom with respect to the six-membered TS, two possible
Table 1 Charge distribution on the atoms of the six-membered transition structure of ene reaction (Scheme 1)
X = CH2 X=O X = O–AlH3 a b
1
2
3
4
5
H
0.50a (0.46)b 0.62 (0.53) 0.62 (0.55)
0.08 (0.02) 0.01 (0.00) 0.05 (0.03)
0.42 (0.34) 0.51 (0.38) 0.46 (0.37)
0.33 (0.27) 0.08 (0.01) 0.04 (0.02)
0.48 (0.41) 0.67 (0.51) 0.81 (0.55)
0.15 (0.16) 0.40 (0.33) 0.40 (0.33)
Calculated using RHF/6-31G*. Calculated using B3LYP/6-31G*.
K. Chakrabarty et al. / Journal of Molecular Structure: THEOCHEM 858 (2008) 107–112
109
Fig. 1. Ball and stick model of the transition structures (TS) of Scheme 1. (a) X = CH2; (b) X = O; (c) X = O–AlH3. (a0 )–(c0 ) are the isodensity surface (p = 0.04 a.u.) color mapped with electrostatic potential (blue > 0.30; light blue = 0.10; green = 0.00; yellow = 0.05; red < 0.10). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
R3
R1
R2
O H3Al
H
Scheme 2. Transition structure of the Lewis acid catalyzed ene reaction with heteroatomic substituent (R1, R2 or R3) at a-carbon atom.
transition structures, endo and exo, were constructed (Fig. 2). The Lewis acid AlH3 was placed in a position anti to the a-substituent to make a least sterically hindered system. The relative energies of different possible conformers (resulted from the variation of the positions of R1, R2, R3) are gathered in
R1 R2
R3
R3 H
3.3. Effect of the presence of a chiral center
R1 H
R2
2
O
H
H
1 O
H
H
H H
Al
H H
H
H
H
Al
H H
Table 2. The conformational preferences of all these substituents with respect to Ca–O, CaN bond have been determined on the basis of the absolute energy and the most favorable conformers are shown in Fig. 3. Relative energies as shown in Table 2 clearly indicate that the most stable conformational isomer is generated when the substituent occupies the R2 position in the endo structure. The most prominent feature is the direction of the lone pair (assumed from the orientation of other substituents) connected to the hetero atom. In all these cases it directs to the central carbon atom (C-2) of the ene moiety in the transition structure. Previously it was pointed out that a considerable positive charge is developed at the central carbon atom of the ene in Lewis acid catalyzed ene reaction and supported by the experimental result [27]. The charge distribution of each carbon or hetero atoms on the transition structures also confirms this fact and this developed positive charge interacts strongly with the lone pair of the substituent and consequently stabilize the geometry.
H
Fig. 2. Schematic representation of the model transition structure of Lewis acid catalyzed ene reaction between propene and a carbonyl molecule with a-carbon atom. Depending on the orientation of a carbon atom with respect to the transition structure the (a) endo and (b) exo isomers are possible.
The Lewis acid catalyzed ene reaction of chiral a-amino and a-benzyloxyaldehydes was reported by Mikami and co-workers and was shown to afford high level of diastereoselection in forming the isomeric products (Scheme 3) [4,5]. To rationalize the observed diastereoselectivity the authors employed the chelation model. However we have taken a different approach to verify the electrostatic model proposed in the previous sections. For this a set of hypothetical reactions (Scheme 4) is formulated to generate the transition structures. Reaction (a) and (b) of Scheme 4 represents the ene process with chiral carbonyl enophile containing oxygenated (hydroxy or methoxy) substituent whereas reaction (c) and (d) represent
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Fig. 3. Most favorable conformational isomers of the transition structures with heteroatomic substituent (a) OH, (b) OMe, (c) NH2 or (d) NMe2 present at the a-carbon and the corresponding electrostatic potential map on the isodensity surface.
reactions with the reactant containing nitrogenated substituent (amino or dimethyl amino) at the chiral center. The model of the possible transition structures for each reaction may be represented schematically by four diastereomeric structures (Figs. 2 and 4) each of which exists in three conformational isomers by interchanging the positions of R1, R2 and R3 groups among them. The relative energy values of all these structures are given in Table 3. The relative energies clearly indicate that, the conformation and
configuration of the TSs of entry number 8, 14, 20, 32 and 45 are the most favorable species. Substituents like hydroxy, amino and dimethyl amino show preferences for the diastereoisomeric structure a’ (Fig. 4) (entry number 8, 32 and 45) occupying the position R2. The preference for position R1 by methyl substituent in all these structures abides by the Felkin model since the incoming ene attacks the enophile carbonyl carbon in a direction opposite to the group R1. However the preferences for hydroxy, amino and di-
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Table 3 Relative energies of the possible transition structures (Figs. 2 and 4) with a chiral center bearing heteroatomic substituents, OH, OMe, NH2 or NMe2
OBn
OBn
OBn H
Sl. No.
OH
OH
syn (major)
anti
O
NR2 R
NR2
NR2
H
R
R O
OH
OH
anti
syn (major)
Scheme 3. Lewis acid catalyzed ene reaction of chiral a-amino and a-benzyloxyaldehydes [4,5].
H OR
OR
OR H AlH3
O
syn
a) R = H b) R = CH3 NR2
H
R
anti
NR2
NR2
H
R
R O c) R = H d) R = CH3
OH
H
OH
AlH3
H
OH
H
OH
H
anti
syn
Scheme 4. Hypothetical reactions to model the reactions shown in Scheme 3.
R1 H
R2
R2
R3 H
2
H
H
1 H
R1 R3
O
O
H
Al H
H
H H
a
b
a0
b0
a
b
a0
b0
a
b
a0
b0
a
b
a0
b0
Substituent at R1
R2
R3
OH H CH3 OH H CH3 OH CH3 H OH CH3 H OCH3 H CH3 OCH3 H CH3 OCH3 CH3 H OCH3 CH3 H NH2 CH3 H NH2 CH3 H H CH3 NH2 NH2 CH3 H NMe2 CH3 H NMe2 H CH3 NMe2 H CH3 NMe2 CH3 H
H CH3 OH H CH3 OH H OH CH3 H OH CH3 H CH3 OCH3 H CH3 OCH3 H OCH3 CH3 H OCH3 CH3 H NH2 CH3 H NH2 CH3 CH3 NH2 H H NH2 CH3 H NMe2 CH3 H CH3 NMe2 H CH3 NMe2 H NMe2 CH3
CH3 OH H CH3 OH H CH3 H OH CH3 H OH CH3 OCH3 H CH3 OCH3 H CH3 H OCH3 CH3 H OCH3 CH3 H NH2 CH3 H NH2 NH2 H CH3 CH3 H NH2 CH3 H NMe2 CH3 NMe2 H CH3 NMe2 H CH3 H NMe2
Relative energy (kcal mol1)
Conformation around CaX (X = N or O)
6.37a (5.94)b 0.92 (0.61) 3.20 (3.57) 5.23 (3.87) 2.14 (2.95) 3.61 5.21) 5.07 (4.23) 0.00 (0.00) 5.19 (5.26) 4.55 (5.36) 2.24 (2.71) 4.28 (2.71) 9.15 (5.47) 0.00 (0.00) 1.89 (1.37) 7.86 (7.43) 2.58 (3.26) 4.79 (4.98) 6.95 (4.36) 0.02 (0.18) 2.96 (2.37) 6.45 (6.15) 5.15 (4.26) 2.68 (3.52) 6.73 (5.85) 3.92 (3.88) 1.02 (0.71) 6.04 (5.00) 4.39 (5.75) 3.08 (4.12) 5.39 (5.42) 0.00 (0.00) 6.04 (4.89) 5.37 (5.27) 2.54 (3.93) 4.74 (6.30) 7.39 (5.96) 2.01 (2.95) 3.15 (2.41) 6.85 (6.53) 5.61 (6.16) 2.39 (4.83) 6.91 (5.86) 5.62 (5.15) 0.00 (0.00) 7.26 (7.17) 2.85 (3.58) 4.72 (3.09)
+sc sc ±ap +sc sc ±ap sc +sc ±ap sc +sc ±ap +sc ac ±ap ±ap sc +sc sc ±ap ±ap sc sc sc ±ap sc +sc ±ap sc +sc +sc sc ±ap ±ap sc +sc ±ap sc ±sp sc +sc sc ±ap +sc sc ±ap sc +sc
RHF/6-31G*. B3LYP/6-31G*//RHF/6-31G*.
2
Al H
a b
1 H
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
TS (Figs. 2 and 4)
H
H H
H
Fig. 4. Two diastereomeric transition structures (a0 ) and (b0 ) of (a) and (b) (Fig. 2) when R1, R2 and R3 are different.
formation in Scheme 4. However, experimental result (Scheme 3) supports the preference for syn configuration. It appears to us that for such substituent chelation model may take a predominant role in determining the overall selectivity. 4. Conclusion
methyl amino groups for R2 position can be rationalized on the basis of electrostatic interaction between the heteroatom and the ene moiety. Models of all the favorable transition structures are shown in Fig. 5. All these transition structures lead to the product with configuration syn of Scheme 4 which agrees the experimental results of stereoselectivities in Scheme 3. For methoxy substituent two TSs (entry 14 and 20) are preferable and these corresponds to the structure a and a0 of Fig. 4. As both these structures are almost equally favorable, there will be no selectivity for the product
The above discussion reveals that, a positive electrostatic field is generated around the ene moiety in the TS of a Lewis acid catalyzed ene reaction. This electrostatic field is responsible for the conformational preferences of the heteroatomic substituent present at the stereogenic center adjacent to the carbonyl group of the carbonyl enophile. This interaction is capable to direct the energetically most favorable conformation of the TS for many substituent and thus, alter the overall stereoselectivity of the asymmetric ene reaction.
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Acknowledgments One of us (K.C.) is thankful to DST for the financial assistance through DST-WOSA/SR/CS-24/2004. We are thankful to the University Grants Commission, New Delhi, India for the financial support of this research through a major research project (F-31-107/2005 (S.R.)) and through special assistance programme. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]
[24]
Fig. 5. Energetically favorable conformers of the carbonyl ene reaction bearing chiral centers at the a-carbon atom. Heteroatomic substituent like (i) OH, (ii) and (iii) OCH3, (iv) NH2 or (v) NMe2 is present at the chiral center.
[25] [26] [27]
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