Effect of Substituted Groups on the Electronic Circular Dichroism of

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Effect of Substituted Groups on the Electronic Circular Dichroism of Aldols: A Combined Experimental and Time-Dependent DFT Study† Guanna Li,‡,§ Guoqing Jia,‡,§ Qiang Gao,‡,§ Zhaochi Feng,*,‡ and Can Li*,‡ State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China, and Graduate UniVersity of Chinese Academy of Sciences, Beijing, 100049, China ReceiVed: May 21, 2010; ReVised Manuscript ReceiVed: October 19, 2010

A series of aldol products synthesized from the reactions of acetone and cyclohexanone with 2,3,4-substituted benzaldehydes have been studied by electronic circular dichroism (ECD) and time-dependent density functional theory (TDDFT). The influence of various functionals and basis sets on the simulated ECD properties has been tested, and the dependence of the spectra on the flexibility of the molecules has also been demonstrated. The relationship between substituents and chromophores has been discussed in detail. For aldol products of 3,4-substituted nitrobenzaldehydes, Cotton effects observed in the region of 230-400 nm lead to critical ECD pattern, with electron transfer between the nitrobenzene group and the β-hydroxy ketone moiety. The cyclohexanone group exhibits interaction with the nitrobenzene group, which results in a transition mechanism essentially different from that of acetone. The ECD pattern is also modified by the additional chirality localized at the cyclohexanone group. The most prominent effects observed in the nitro-group-substituted aldols are the electrophilic effect and conjugative effect between the nitro group and the benzene ring. These are not observed strikingly for the other substituents studied in this work. Introduction Electronic circular dichroism (ECD) spectroscopy has been regarded as one of the most widely used chiroptical techniques for stereochemical analysis. It measures the difference of the absorption coefficients between left and right circularly polarized light and can provide rich information which is often completely obscured in ordinary absorption spectra. The optical information obtained from ECD can elucidate the structure-chiroptical relationships of chiral molecules, which are essentially important for chemical and biochemical applications.1-9 In principle, structure-chiroptical semiempirical rules have been established to correlate the sign and intensity of observed Cotton effects with the absolute configurations (ACs) of chiral analytes in the past.10-17 However, it fails to correctly predict the ACs for various molecules and turns out to be constrained for general use.18-21 With the advances in modern theoretical chemistry,22-26 the capabilities of successfully assigning ACs and unraveling the chiroptical properties of chiral molecules have been reported frequently during the past decade.27-40 An in-depth understanding of ECD, which combines experiment and a reliable description of the excited electronic states by quantum chemical methods, gets quite satisfactory results.41-49 Aromatic rings constitute the most common and important chromophores among organic molecules.14,50-55 The direct asymmetric aldol reaction is one of the most important C-C bond-forming reactions and has been widely used in constructing natural and nonnatural products. Accompanying the carboncarbon bond forming process is the formation of a new stereocenter taking control of both the absolute and the relative configuration of the aldol products.56,57 In this work, our study †

Part of the “Alfons Baiker Festschrift”. * Corresponding authors. Phone: +86-411-8437-9070 (C. Li); +86-4118437-9303 (Z. C. Feng). Fax: +86-411-8469-4447. E-mail: [email protected]; [email protected]. ‡ Dalian Institute of Chemical Physics. § Graduate University of Chinese Academy of Sciences.

mainly focuses on the ECD properties of a set of chiral aldol products originating from a 2,3,4-substituted benzaldehyde reaction with ketones, which represent the simplest chiral aromatic β-hydroxy ketone systems containing the phenyl chromophore and exhibit Cotton effects exclusively allied with the benzene transitions. The motivation of this work is to apply ECD spectroscopy and quantum chemistry to the catalytic chiral molecular system. The dependence of the experimental ECD spectra on substituted positions and various types of substituents is discussed by simulating the spectra at the TDDFT level using mainly the B3LYP/aug-cc-PVDZ combination of functional and basis sets. A detailed analysis of the electron transitions in terms of orbital contributions is provided. Experimental and Computational Methods Experimental Details. The products of aldol reactions were prepared following the method described in the literature (Scheme 1).56 The dr and ee values of all compounds determined by analysis of the mixture of anti/syn products and by HPLC (Chiralpak AD-H) are >90%. ECD experiments were performed at room temperature (22 °C) using a dual-beam DSM 1000 ECD spectropolarimeter (OLIS, USA). The optical system of the instrument was configured with a 150 W xenon lamp, circular light polarizer, and two end-mounted photomultipliers. The samples are diluted with an appropriate amount of ethanol to obtain the ECD spectra with high S/N. Each ECD measurement was recorded over the wavelength range from 190 to 400 nm with a 1 cm path length quartz cell. The samples used to measure ECD spectra were diluted to a very low concentration according to their UV-vis adsorption band intensities at ca. 210 nm which were close to 0.8 ε/mol-1 L cm-1. Computational Details. The calculations were performed using Gaussian 03 D.01.58 The geometry parameters of all compounds (Chart 1) were fully optimized using the B3LYP59-61 functional and 6-31+G(d) basis set. Frequency calculations were also carried out to make sure the geometries obtained were local

10.1021/jp1046722  2011 American Chemical Society Published on Web 12/02/2010

Effect of Substituted Groups on the ECD of Aldols

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SCHEME 1: Aldol Reactions of Ketones with Different Aldehydes

CHART 1: Structures of All Chiral Aldol Products Evaluated in This Study

using both length and velocity representations. The differences between these two calculated values of rotational strengths were quite small. Therefore, only velocity representations are reported here. The ECD spectra were simulated by overlapping Gaussian functions for each transition according to the procedure described by Diedrich and Grimme.36 The width of the band at 1/e height is 0.2 eV. All the calculated excitation energies were blue-shifted by 0.18 eV to match the experimental results. Results and Discussion

minimums on the potential energy surface (PES). Relaxed PES scans were carried out at the same level with respect to the twisting angle between the benzene group and the β-hydroxy acetone moiety (Figure S1 in the Supporting Information). Boltzmann averaged ECD spectra were computed at 298 K by calculating the excited states of the low-energy conformations within 2 kcal/mol according to the lowest energies for the aldol products that experimental ECD results made available. It was found that the weighted average spectra had a profile similar to that of the most stable conformations. The ECD spectra of conformers of 1a within 2 kcal/mol are shown in Figure S2 (Supporting Information). The sum of the distribution of the most stable conformers (step 27, 28, 29) is up to 81%, and all of them display very similar ECD profiles. The same situations were also observed for other compounds. Therefore, the excitation analysis was discussed by comparing the experimental data with the ECD spectra of the most stable conformation of 1a-6. The number of excited states used to simulate the ECD spectra was 20, which was enough to include the excitations observed above 200 nm in experiment. Because of the known drawbacks of current implementations of TDDFT with respect to the charge transfer transitions,36 three different density functionals depending on the amount of Fock exchange, namely, B3PW91,62 BHLYP,63 and PBE0,64,65 were explored (Figure S3, Supporting Information). The BHLYP functional results in a blue shift of the adsorption bands; however, only slight differences were observed among the other functionals. Different basis sets with varying complexities were also tested in conjunction with the B3LYP hybrid functional to gauge their performance for the calculation of the ECD spectra (see Figure S3, Supporting Information). On the basis of these evaluations, TDDFT with B3LYP/aug-cc-PVDZ61,66-68 method was selected as it combines moderate accuracy with low computational cost and provides a simple intuitive interpretation.69,70 As can be seen, the weighted average spectra show similar band properties when compared to the ECD spectra of the most stable conformation. Additionally, the ECD spectra with the use of the PCM solvent model (ethanol solvent) were also calculated in the case of compounds where experimental results were available (see Figure S4, Supporting Information). The simulated ECD spectra without a solvent model agree better with the experiments rather than with the solvent. The error cancellation effect may be responsible for the results. Rotational strengths were calculated

ECD Spectra of Aldol Products of Acetone with NitroSubstituted Benzaldehydes. Figure 1 shows the experimental result and Boltzmann-averaged ECD spectrum for the most stable conformations below 2 kcal/mol for the aldol product of 2-nitrobenzaldehyde (compound 1a). There are six conformations observed in the PES profile that have relative energies below 2 kcal/mol. Four adsorption bands can be reproduced by the averaged spectrum, while the intensities of these bands are weaker than the experimental ones. Interestingly, although the compound could exist in many conformations speculated from PES results, the most stable conformation already displays significant adsorption signals which are very similar to that of the averaged spectrum, as can be seen in Figures 1 and 2. Furthermore, the contribution of the most stable conformer to the average spectrum is up to 81%, and all of them display very similar ECD profiles (see Figure S2, Supporting Information). Here, we choose the excitations calculated using the most stable conformation to analyze the transition mechanism of the system. The ECD spectra of experiment and the most stable conformation are shown in Figure 2. The rotational strength for each excitation is also labeled. The experimental ECD spectrum has two negative Cotton effects at 336 and 280 nm and two positive ones at 305 and 250 nm. The calculated negative Cotton effects at 328 and 278 nm and the positive ones at 295 and 254 nm can be, respectively, assigned to the bands observed at 336 and 280 nm and the bands at 305 and 250 nm. The molecular orbitals involved in the key

Figure 1. Experimental (dash dot) and calculated (solid) conformational averaged ECD spectra of aldol products of acetone reaction with 2-nitrobenzaldehydes (1a,(R)-4-hydroxy-4-(2-nitrophenyl)butan-2-one).

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Figure 2. Experimental (dash dot) ECD spectrum and calculated ECD spectrum of the most stable conformation of aldol products of acetone reaction with 2-nitrobenzaldehydes (1a,(R)-4-hydroxy-4-(2-nitrophenyl)butan-2-one). Vartical bars indicate the velocity representation rotational strengths.

Figure 3. Experimental (dash dot) and calculated (solid) conformational averaged ECD spectra of aldol products of acetone reaction with 3-nitrobenzaldehydes (1b, (R)-4-hydroxy-4-(3-nitrophenyl)butan-2-one).

transitions are shown in Figure S5a (Supporting Information) and Table 1. The major negative Cotton effect at 328 nm is generated by electron transition from HOMO-4 involving a π bonding of the 2-nitrobenzene group to its corresponding π* (LUMO). However, two positive rotational strengths at 310 and 295 nm are ascribed to the ECD band at 305 nm. Although they both show electron transfer between the β-hydroxy acetone moiety and the nitrobenzene group, their intensities are very weak. Three transitions (HOMO-3 f LUMO, HOMO-5 f LUMO, HOMO f LUMO+1) contribute to the negative Cotton effect at 280 nm. HOMO-5 and HOMO-3 to LUMO are n f π* and π f π* transitions localized at the nitrobenzene group, and orbital HOMO to LUMO+1 is composed of the n f π* transition at the carbonyl group and the π f π* transition at the benzene group. The intense excitation from HOMO-3 to LUMO contributes to the strong positive ECD band at 250 nm. The electron transitions related to those strong ECD signals mostly localize at the 2-nitrobenzene and hydroxy groups. There is no obvious intramolecular electron transfer between the β-hydroxy acetone moiety and the nitrobenzene group. In the case of compound 1b, the distance between -NO2 substitution and β-hydroxy acetone elongation and the repulsion

effect between these two groups is reduced. Therefore, the flexibility of this compound is more flexible than compound 1a. The PES result indicates that more than 20 conformations could coexist at room temperature. The Boltzmann-averaged adsorption spectrum is obtained by weighing all the conformations whose relative energies are in the range of 2 kcal/mol compared to the most stable one. Figure 3 shows the experimental and weighted average ECD results. The experimental negative band around 300 nm is in agreement with the experimental signal; however, the positive band at lower wavenumber is composed of two weak positive bands at 255 and 270 nm, and again, the intensities of the simulated bands are relatively weaker than the experiment. The ECD spectrum (see Figure 4) of the most stable conformation as labeled in the PES profile can reproduce the weighted average profile considerably. To further understand the signals in detail, the ECD results of both experiment and the most stable conformation are displayed in Figure 4. The rotational strengths are shown as well. There are two Cotton effects between 220 and 400 nm in the experimental result. In the TDDFT calculation, six rotational

TABLE 1: Experimental and Simulated Key Transitions and Related Rotational Strengths of Compounds 1a-c compd

exptla

calcdb

transition (%)c

λ/nmd

Rvele

1a

336(-25.2) 305(+17.6)

328(-15.3) 295(+3.2)

280(-38.1)

278(-2.3)

250(+75.3) 300(-2.8)

254(+28.0) 315(-1.6)

260(+9.8)

280,256 (+4.3, 1.9)

HOMO-4 f LUMO (0.40) HOMO f LUMO (0.79) HOMO-1 f LUMO (0.52) HOMO-3 f LUMO (0.41) HOMO-5 f LUMO (0.52) HOMO f LUMO (0.38) HOMO-3 f LUMO (0.42) HOMO-4 f LUMO (0.92) HOMO f LUMO (0.88) HOMO-5 f LUMO (0.89) HOMO-1 f LUMO+1 (0.38) HOMO f LUMO+1 (0.31) HOMO-1 f LUMO (0.66) HOMO-2 f LUMO (0.81) HOMO-3 f LUMO (0.84) HOMO f LUMO (0.49) HOMO-5 f LUMO (0.88) HOMO-2 f LUMO+1 (0.44) HOMO-2 f LUMO (0.94) HOMO-4 f LUMO (0.84)

328 310 295 277 272 270 256 321 302 280 273

-43.7 7.5 11.6 -7.3 -1.9 -18.0 62.0 -2.8 -3.5 5.9 8.4

266 261 322 282 280 272 257 245

-31.2 30.3 -2.3 -4.5 -15.8 27.2 -5.0 -1.7

1b

1c

293(-) 267(+) 245(-)

a

Experimental wavelength. b Simulated wavelength after curve fitting. wavelength. e Rotational strength in velocity form, 10-40 erg-esu-cm/Gauss.

c

Molecular orbitals involved for each transition.

d

Excitation



Figure 4. Experimental (dash dot) ECD spectrum and calculated ECD spectrum of the most stable conformation of aldol products of acetone reaction with 3-nitrobenzaldehydes (1b, (R)-4-hydroxy-4-(3-nitrophenyl)butan-2-one). Vertical bars indicate the velocity representation rotational strengths.

Figure 5. Calculated ECD spectra of the most stable conformation of aldol products of acetone reaction with 4-nitrobenzaldehydes (1c, (R)4-hydroxy-4-(4-nitrophenyl)butan-2-one). Vertical bars indicate the velocity representation rotational strengths.

strengths appear in this region. The medium negative Cotton effect at 300 nm is ascribed to the predicted band at 315 nm. The predominantly positive band at 260 nm belongs to the predicted positive band at 280 nm accompanied by a shoulder at 256 nm. As shown in Figure S5b (Supporting Information) and Table 1, the negative Cotton effect around 300 nm of the experiment is contributed by two negative rotational strengths at 321 and 302 nm. The first one is mainly due to the excitation from the nitro group to the benzene ring, and the second one is due to the excitation from HOMO to LUMO, involving the π f π* transition localized at the benzene group and the electron transfer from the β-hydroxy acetone moiety to the 3-nitrobenzene group. The same orbital transitions are also observed for compound 1a. Compared with 1a, although the excitation energies of these two transitions change slightly, the intensities of the rotational strengths change dramatically, as can be seen from Table S1 (Supporting Information). For the strong positive band observed at 260 nm, the simulated ECD spectrum exhibits four rotational strengths corresponding to it. They are generated from three positive transitions at 280, 273, and 261 nm and one negative transition at 266 nm. The excitations from orbital HOMO-5 and HOMO-2 to LUMO are n f π* and π f π* transitions localized at the nitrobenzene group, while the excitations from orbital HOMO-1 and HOMO to LUMO+1 include the carbonyl n f π* transition and electron transfer from the benzene group to the β-hydroxy acetone moiety. These orbital transitions obviously reflect the intramolecular electron transfer effect between the β-hydroxy acetone moiety and the 3-nitrobenzene group. The simulated ECD spectrum and rotational strengths for 1c are shown in Figure 5. As far as we are aware, there is no experimental information available because of the lack of substrate for this reaction. On the basis of good agreement between experiment and simulated results for compounds 1a and 1b, it is considered that the predicted ECD of compound 1c is reliable. Three Cotton effects with negative, positive, and negative signs appear between 220 and 400 nm. Excitations at 322, 282, and 280 nm are responsible for the first negative Cotton effect at 293 nm (Figure S5c, Supporting Information, Table 1). The corresponding transition at 322 nm is generated by excitation from orbital HOMO-3 to LUMO accompanied by an n f π* transition from the nitro group to the benzene ring. For the excitation at 282 nm, electron transfer occurs from the β-hydroxyl acetone moiety to the 3-nitrobenzene group

accompanied by benzene ring π f π* transition. The excitations at 272 nm can be assigned to the positive band at 267 nm. Electron transfer between the β-hydroxy acetone moiety and the 3-nitrobenzene group plays a critical role in generating this Cotton effect. Again, the carbonyl n f π* transition is observed. For Cotton effects at 257 and 245 nm, the former corresponds to a π f π* electron transfer transition, while the latter is associated with an electron transition from HOMO to orbital LUMO+1. For all the excitations mentioned above, electron transfer excitations occupy a dominant position. On the basis of the above results, it is clear that the nitro group substituted at the benzene ring shows a significant effect on the ECD spectra. For compound 1a, the nitro group twists an angle ca. 23° related to the benzene ring owing to the steric hindrance of the β-hydroxy acetone moiety. The electron transfer transition between the nitrobenzene group and the β-hydroxy acetone moiety is hindered because of spatial resistance. The conjugative and electron-withdrawing effects are also weakened. It can be seen from Figure S1 (Supporting Information) that the 2-substituted aldol products are less flexible than the other ones because of the high energy barrier. Consequently, most of the transitions are localized except for a very weak π f π* transition band at 305 nm (HOMO-1 f LUMO). The nitro group of compounds 1b and 1c topologically conjugates with the benzene ring, which facilitates the occurrence of electron transfer transition. The electron-withdrawing effect of the nitro group is inferred to be another important factor for the strong electron transfer effect. In conclusion, the spectral differences among compounds 1a-1c are determined by spatial effect and electron-withdrawing and conjugative effects between the nitro group and the benzene ring. These factors result in essential differences of electric dipole transition and magnetic dipole transition. This can also be confirmed by the ECD properties of compound 4, the aldol product of benzaldehyde (Figure S6a, S6b, Table S1, Supporting Information). The transitions of compound 4 are simpler and blue-shifted, mostly from the benzene ring to the β-hydroxy acetone moiety. In the case of compound 1a-c, a red shift of the bands and electron transfer between the β-hydroxy acetone moiety and the benzene ring are mostly contributed from the interaction between the nitro group and the benzene ring. It shows that ECD not only is a chiral-sensitive technology but also can be applied to identify the relative position of the substituent group.

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Figure 7. Experimental (dash dot) and calculated (solid) conformational averaged ECD spectra of aldol product of cyclohexanone reaction with 2-nitrobenzaldehydes. (3a,(S)-2-((R)-hydroxy-(2-nitrophenyl)methyl)cyclohexanone).

Figure 6. Calculated ECD spectra of the most stable conformation of aldol products of acetone reaction with 2 (solid), 3 (dash), and 4 (dash dot)-substituted chloro-benzaldehydes (2a, 2b, 2c, (R)-4-(2, or 3, or 4-chlorophenyl)-4-hydroxybutan-2-one (a)) and bromo-benzaldehydes (2d, 2e, 2f, (R)-4-(2, or 3, or 4-bromophenyl)-4-hydroxybutan-2-one (b)).

ECD Spectra of Aldol Products of Acetone with Chloro and Bromo-Benzaldehydes. To further evaluate the electronwithdrawing and conjugative effects of the nitro-group and their influences on the ECD spectra, calculation of the chloro- and bromo-substituted compounds 2a-f is also carried out. Compared with compounds 1a-c, the ECD spectra of 2a-f are much simpler (Figure 6). Both 2a and 2c display a negative Cotton effect at ca. 275 nm and a positive Cotton effect at ca. 240 nm. The similar excitation energies and intensities are also observed for 2d and 2f. Both 2b and 2e show a strong negative band at ca. 240 nm, which is different from the other four compounds. Figures S7a and S7b and Table S2 (Supporting Information) show the molecular orbitals involved in these excitations. Charge distributions are similar for compounds 2a-c. The same situation is also observed for compounds 2d-f. For compounds 2a, 2c, 2d, and 2f, the predicted negative Cotton effects at around 275 nm are contributed by the carbonyl n f π* transition and the electron transfer transition from the substituted benzene group to the β-hydroxy acetone moiety. However, the contributions from the chloro and bromo groups are not as notable as those from the nitro group. There are two kinds of transitions ascribed to the positive Cotton effect at ca. 240 nm. The major excitation of these compounds corresponds to the promotion of an electron from the HOMO to the LUMO. The molecular orbitals mainly localize at the substituted benzene ring and β-hydroxy acetone moiety, thereby implying that it is an electron transfer transition. Furthermore, the minor rotational strength besides the major one is due to a π f π* excitation at the substituted benzene ring. However, the substituted groups have negligible contributions. For compounds 2b and 2e, the negative

Figure 8. Experimental (dash dot) ECD spectrum and calculated ECD spectrum of the most stable conformation of aldol product of cyclohexanone reaction with 2-nitrobenzaldehydes. (3a,(S)-2-((R)-hydroxy(2-nitrophenyl)methyl)cyclohexanone). Vertical bars indicate velocity representation rotational strengths.

band at about 240 nm also results from transition from the benzene π orbital to the carbonyl π* orbital. For all the electron transfer transitions, electrons transfer from the benzene ring to the β-hydroxy acetone moiety. A reverse electron transfer transition is not observed. The above results indicate that the predicted ECD spectra and molecular orbitals involved in the key transitions have an analogous profile for chloro- and bromo-group-substituted aldols, regardless of the different substituents or different substituted positions. This can be understood by two aspects. First, the electron-withdrawing ability of these substituted groups is weaker than the nitro group. In the electron transfer transitions, they play a minor role in the electron-withdrawing effect. Second, the conjugative effect between these substituents and the benzene chromophore was not clearly evident. This shows that the sensitivity of ECD spectra to the location of substituents is closely related to the nature of the substituents and to the relationship between substituents and chromophores. Cyclohexanone Group and Double Chiral Center Effectiveness. The effects of different ketones and double chiral centers on the ECD properties are also studied. Figure 7 shows the experimental and simulated weighted average ECD spectra of compound 3a, the aldol product of the cyclohexanone reaction with 2-nitrobenzaldehyde, while Figure 8 shows the ECD



TABLE 2: Experimental and Simulated Key Transitions and Related Rotational Strengths of Compounds 3a-c compd

exptla

calcdb

transition (%)c

λ/nmd

Rvele

3a

349(-4.4)

331(-23.3)

331

-35.7

311(+34.8) 280(-42.2)

301(+6.5) 276(-24.8)

HOMO f LUMO (0.26) HOMO-1 f LUMO (0.25) HOMO-2 f LUMO (0.20) HOMO-4 f LUMO (0.20) HOMO f LUMO (0.67) HOMO-1 f LUMO (0.58) HOMO f LUMO+1 (0.64) HOMO-3 f LUMO (0.47) HOMO-5 f LUMO (0.40) HOMO-3 f LUMO (0.44) HOMO-5 f LUMO (0.42) HOMO-4 f LUMO (0.52) HOMO-1 f LUMO+1 (0.72) HOMO-4 f LUMO (0.89) HOMO f LUMO (0.83) HOMO f LUMO+1 (0.53) HOMO-1 f LUMO (0.55) HOMO-5 f LUMO (0.85) HOMO-2 f LUMO (0.72) HOMO-3 f LUMO (0.75) HOMO f LUMO (0.59) HOMO f LUMO+1 (0.37) HOMO-5 f LUMO (0.81) HOMO-2 f LUMO (0.71) HOMO-1 f LUMO+1 (0.80)

320 305 292 275

-13.6 27.3 -7.2 -30.6

267

-15.5

254 234 322 306 295 287 280 267 322 305 285 281 279 227

69.8 10.6 -2.7 7.4 -43.4 28.5 -25.5 21.7 -3.9 -39.7 24.4 9.7 19.5 8.2

250(+38.3)

252(+47.8)

3b

297(-20.8)

292(-25.2)

3c

244(+5.0) 294(-20.9)

264(+13.0) 309(-37.1)

261(+14.6)

281(+29.3)

a Experimental wavelength. b Simulated wavelength after curve fitting. wavelength. e Rotational strength in velocity form, 10-40 erg-esu-cm/Gauss.

Figure 9. Experimental (dash dot) and calculated (solid) conformational averaged ECD spectra of aldol product of cyclohexanone reaction with 3-nitrobenzaldehydes. (3b, (S)-2-((R)-hydroxy-(3-nitrophenyl)methyl)cyclohexanone).

spectrum and rotational strengths of the most stable conformation. Despite the flexibility of the skeletal, the most stable conformation shows comparable properties with the averaged spectrum (see Figure 8). There are four Cotton effects in the region of 230-400 nm. The experimental weak negative band at 349 nm is assigned to the predicted negative band at 331 nm. The positive band at 311 nm is assigned to the predicted band at 301 nm, and the negative band at 280 nm is ascribed to the predicted band at 276 nm. The second positive Cotton effect at 250 nm in the experiment is according to the simulated positive Cotton effect at 252 nm. As can be seen from Figure S8a (Supporting Information) and Table 2, there are two rotational strengths that belong to the negative band at 349 nm. They are contributed by five different kinds of transitions. The band at 311 nm is generated by a transition from orbital HOMO-1 to LUMO. It is a π f π* transition at the benzene

c


d

Excitation

Figure 10. Experimental (dash dot) ECD spectrum and calculated ECD spectrum of the most stable conformation of aldol product of cyclohexanone reaction with 3-nitrobenzaldehydes. (3b, (S)-2-((R)-hydroxy(3-nitrophenyl)methyl)cyclohexanone). Vertical bars indicate velocity representation rotational strengths.

ring accompanied by electron transfer from the β-hydroxy cyclohexanone moiety. Three kinds of excitations at 292, 275, and 267 nm are ascribed to the negative band at 280 nm. They are predominated by transitions from HOMO-5 and HOMO-3 to LUMO. Two excitations are responsible for the positive band at 250 nm. They include a π f π* transition at the benzene ring and an n f π* transition at the carbonyl group. Electron transfer between the β-hydroxy cyclohexanone moiety and the 2-nitrobenzene group has not been observed for this compound except the transition from HOMO to LUMO. The experimental and simulated weighted average ECD spectra of compound 3b are shown in Figure 9. Also, the ECD spectrum of the most stable conformation is used to analysis the excitations as displayed in Figure 10. The molecular orbitals and transitions analysis are displayed in Figure S8b (Supporting Information) and Table 2. The negative band at 297 nm is assigned to the simulated band at 292 nm, which is contributed

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Figure 11. Experimental (dash dot) and calculated (solid) conformational averaged ECD spectra of aldol product of cyclohexanone reaction with 4-nitrobenzaldehydes. (3c, (S)-2-((R)-hydroxy-(4-nitrophenyl)methyl)cyclohexanone).

Figure 13. Calculated ECD spectra of 3c and 5 and their diastereomers 3c′ and 5′ (structures are inserted).

Figure 12. Experimental (dash dot) ECD spectrum and calculated ECD spectrum of the most stable conformation of aldol product of cyclohexanone reaction with 4-nitrobenzaldehydes. (3c, (S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclohexanone). Vertical bars indicate velocity representation rotational strengths.

by five excitations. There are three negative rotational strengths at 322, 295, and 280 nm and two positive ones at 306 and 287 nm. Two excitations from HOMO-5 and HOMO-4 to LUMO indicate the interaction between the nitro group and the benzene ring. Excitations from HOMO-1 and HOMO to LUMO are electron transfer transitions between the β-hydroxyl cyclohexanone moiety and the 3-nitrobenzene group, and the excitation from HOMO to LUMO+1 is a carbonyl n f π* transition. The experimental positive band at 244 nm is caused by the excitation at 267 nm, which is a π f π* transition limited in the nitrobenzene group. Molecular orbital analysis shows that electron transfer between the β-hydroxyl cyclohexanone moiety and the 2-nitrobenzene group has an apparent contribution. The Boltzmann averaged spectrum of compound 3c is shown in Figure 11. The experimental result displays a positive-negative couplet during 250-300 nm, which is comparable with the simulated bands at 309 and 281 nm for the most stable conformation (Figure 12). The simulated ECD spectra of compounds 1c and 3c are quite similar with each other in the 220-400 nm region. On the basis of molecular orbitals and rotational strength analysis (Figure S8c, Supporting Information, Table 2), two excitations can be assigned to the negative band at 294 nm, and three excitations contribute mostly to the positive

Figure 14. Experimental (dash dot) and calculated (solid) conformational averaged ECD spectra of aldol product of cyclohexanone reaction with 3-methoxybenzaldehyde. (6, (S)-2-((R)-hydroxy(4-methoxyphenyl)methyl)cyclohexanone).

band at 261 nm. Among these excitations, transition from HOMO to LUMO and transitions from HOMO-1 and HOMO to LUMO+1 are all due to the electron transfer between the β-hydroxy cyclohexanone moiety and the 3-nitrobenzene group. Transitions from orbital HOMO-5, HOMO-3, and HOMO-2 to LUMO are related to the interaction between the nitro group and benzene ring. Similar to compound 1c, Electron transfer between the β-hydroxy ketone moiety and the nitrobenzene group is significantly observed for 3c. Compounds 3a-c have certain differences from the aldol products of acetone. They all have two different stereochiral centers and one six-membered ring ketone moiety. There is a twist angle of 33° between the nitro group and the benzene ring for 3a; however, the nitro groups for 3b and 3c are coplanar



TABLE 3: Experiment, Simulated Key Transitions, and Related Rotational Strengths of Compound 6 compd

exptla

calcdb

transition (%)c

λ/nmd

Rvele

6

292(-5.7) 263(+3.5)

298(-23.4) 270(+20.4)

HOMO-1 f LUMO (0.71) HOMO f LUMO (0.80) HOMO f LUMO+1 (0.73)

297 272 246

-30.9 25.3 3.1

a Experimental wavelength. b Simulated wavelength after curve fitting. wavelength. e Rotational strength in velocity form, 10-40 erg-esu-cm/Gauss.

c


d

Excitation

to the simulated band at 298 nm, and the positive band observed at 263 nm corresponds to the simulated positive band at 270 nm. Molecular orbital analysis indicates three kinds of transitions (Table 3). However, the methoxyl group has a moderate contribution to these transitions. The same situation is also observed for chloro-group- and bromo-groupsubstituted aldol products. Conclusion

Figure 15. Experimental (dash dot) ECD spectrum and calculated ECD spectrum of the most stable conformation of aldol product of cyclohexanone reaction with 3-methoxybenzaldehyde. (6, (S)-2-((R)-hydroxy(4-methoxyphenyl)methyl)cyclohexanone). Vertical bars indicate velocity representation rotational strengths.

with benzene rings. This is the same situation as 1a-c. The excitation wavelengths of the characteristic absorptions and the signs of the Cotton effects are similar to 1a-c in some extent, but for the relative intensities, significant changes have taken place. On the basis of the calculated data, it can be seen that the cyclohexanone group has a general charge contribution to the excitations involved, especially for these electron transfer transitions. For non-nitro-substituted compound 5, only two predicted bands appear at 395 and 242 nm (Figure S9a, S9b, Supporting Information). The transitions involved mainly relate to the n f π* and π f π* excitations located at the carbonyl group and benzene ring, respectively (Table S3, Supporting Information). The electron transfer between the β-hydroxy cyclohexanone moiety and the benzene ring is not significant as observed in compounds 3b and 3c, from which the electrophilic effect of the nitro group is verified. It is expected that this is the reason for the specific ECD spectra of compounds 3a-c and 5 when compared with 1a-c and 4. To further verify the effect of the chiral center localized at cyclohexanone, ECD spectra of the diastereomers of compounds 3c and 5 are also investigated. It can be seen from Figure 13 that the band intensities of the diastereomers 3c′ and 5′ are much weaker than 3c and 5. Moreover, the bands are blue-shifted below 250 nm. This implies that the chiral center localized at the cyclohexanone group also has non-negligible influences on the absorption intensities. The ECD spectrum of compound 6 also shows a positivenegative couplet in the region of 250-300 nm (Figure 14). Both the weighted average spectrum and the spectrum of the most stable conformation show much stronger couplets than that of the experiment, as can be seen in Figure 14 and Figure 15, respectively. Molecular orbital analysis is demonstrated in detail in Figure S10 (Supporting Information) and Table 3. Only two rotational strengths are involved in the excitations, and they are as simple as the situation of compound 5. The experimental negative band at 292 nm corresponds

In summary, the ECD spectra of aldol products of an acetone and cyclohexanone reaction with 2-, 3-, or 4-substituted benzaldehydes have been studied by combining experiment and theoretical TDDFT calculation. Both different functionals and basis sets have been explored to figure out the suitable method for systems studied in this work. The general features of the experimental spectra can be reproduced by the combination of B3LYP/aug-cc-PVDZ functional and basis set. All minima found in the PES results within 2 kcal/mol with regard to the most stable conformation have been considered to calculate the Boltzmann averaged spectra. Despite the flexibility of the aldol products, the ECD spectrum of the most stable conformation for each compound is very similar with the Boltzmann conformational averaged profile, and the most stable conformers which have significant contributions to the average spectrum display similar ECD profiles with one another. Therefore, the transitions are discussed based on the excitations calculated by the most stable geometries. In some cases, the theoretical intensities are significantly underestimated by the theory. The PCM solvent effect does not improve the simulated data which may be due to the error cancellation of calculation. It is found that aldol products of nitro-substituted benzaldehydes lead to critical ECD patterns because of excitations involved in the nitrobenzene group but not for the 2-substituted aldols. Both the ECD intensities and signs change dramatically for aldol products of acetone reaction with 2-, 3-, or 4-substituted nitrobenzaldehydes. For the aldol product of 3- or 4-substituted nitrobenzaldehyde, electron transfer between the nitrobenzene group and the β-hydroxy ketone moiety is observed. Electronic and conjugative effects of the nitro group have obvious contributions to the excitations. However, these phenomena are not clearly observed for 2-substituted nitrobenzaldehyde because the interaction between the nitro group and benzene ring is hindered by spatial resistance. The ECD spectra for aldol products of cyclohexanone reaction with 2-, 3-, and 4-nitro-substituted benzaldehydes have a comparable profile to the acetone, but the orbital transitions involved are essentially different. The effects of the cyclohexanone group and double chiral centers on the ECD properties are demonstrated. It is found that the β-hydroxy cyclohexanone moiety shows general interaction with the nitrobenzene group, which is the reason for the difference in their profiles from those of 1a-c, and the chiral effectiveness at the cyclohexanone group is expected to be another factor for the spectral changes. This can be inferred

980


from comparison of the ECD spectra of 3c and 5 with the ECD spectra of their diastereomers. For aldol products of chloro-group-, bromo-group-, and methoxy-group-substituted benzaldehydes, the electronic effect of the substitutions on the benzene ring is indistinctive. The ECD spectra of compounds 2a-f show minor discrepancies. Compound 6 also has similar excitations with compound 5, the non-nitrosubstituted product. The different transition mechanisms are crucial to explain the intensity and excitation differences among these compounds, and they result in the differences in transition electric dipole moment or magnetic dipole moment. Among all of the excitations, the n f π* transition at the carbonyl group and the π f π* transition at the benzene ring are the main features. It shows that ECD is not only chiral-sensitive but also can be applied to identify isomers with different substituent positions. The sensitivity of ECD to the location of substituents is closely related to the nature of the substituents and to the relationship between substituents and chromophores. Acknowledgment. This work was supported by the National Natural Science Foundation of China (NSFC, Grant Nos. 20621063). Supporting Information Available: PES scan at B3LYP/ 6-31+G(d) for all compounds. Simulated ECD spectra based on different basis sets and functionals. Simulated ECD spectra including the PCM solvent model. ECD spectra of the most stable conformers of 1a. All simulated ECD spectra of compounds 4 and 5. Molecular orbitals of all compounds. Experimental and predicted transitions and related rotational strengths for 2a-f, 4, and 5. Cartesian coordinates and absolute energies for all optimized structures at the B3LYP/6-31+G(d) level. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Berova, N.; Nakanishi, K.; Woody, R. W. Circular Dichroism: Principles and Applications; Wiley-VCH: New York, 2000. (2) Berova, N.; Di Bari, L.; Pescitelli, G. Chem. Soc. ReV. 2007, 36, 914–931. (3) Hembury, G. A.; Borovkov, V. V.; Inoue, Y. Chem. ReV. 2008, 108, 1–73. (4) Berova, N.; Pescitelli, G.; Petrovic, A. G.; Proni, G. Chem. Commun. (Cambridge, U. K.) 2009, 5958–5980. (5) Matile, S.; Berova, N.; Nakanishi, K.; Fleischhauer, J.; Woody, R. W. J. Am. Chem. Soc. 1996, 118, 5198–5206. (6) Gottarelli, G.; Lena, S.; Masiero, S.; Pieraccini, S.; Spada, G. P. Chirality 2008, 20, 471–485. (7) Bringmann, G.; Gulder, T. A. M.; Reichert, M.; Gulder, T. Chirality 2008, 20, 628–642. (8) Zhu, F.; Davies, P.; Thompsett, A. R.; Kelly, S. M.; Tranter, G. E.; Hecht, L.; Isaacs, N. W.; Brown, D. R.; Barron, L. D. Biochemistry 2008, 47, 2510–2517. (9) Balaz, M.; De Napoli, M.; Holmes, A. E.; Mammana, A.; Nakanishi, K.; Berova, N.; Purrello, R. Angew. Chem., Int. Ed. 2005, 44, 4006–4009. (10) Moffitt, W.; Woodward, R. B.; Moscowitz, A.; Klyne, W.; Djerassi, C. J. Am. Chem. Soc. 1961, 83, 4013–4018. (11) Moscowitz, A. AdV. Chem. Phys. 1962, 4, 67–112. (12) Snatzke, G. Angew. Chem., Int. Ed. 1979, 18, 363–377. (13) Fanti, M.; Orlandi, G.; Poggi, G.; Zerbetto, F. Chem. Phys. 1997, 223, 159–168. (14) Smith, H. E. Chem. ReV. 1998, 98, 1709–1740. (15) Superchi, S.; Giorgio, E.; Rosini, C. Chirality 2004, 16, 422–451. (16) Ishii, H.; Chen, Y.; Miller, R. A.; Karady, S.; Nakanishi, K.; Berova, N. Chirality 2005, 17, 305–315. (17) Pescitelli, G.; Di Bari, L.; Caporusso, A. M.; Salvadori, P. Chirality 2008, 20, 393–399. (18) Furo, T.; Mori, T.; Wada, T.; Inoue, Y. J. Am. Chem. Soc. 2005, 127, 8242–8243. (19) Ding, Y. Q.; Li, X. C.; Ferreira, D. J. Org. Chem. 2007, 72, 9010– 9017.

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