Predicting the regioselectivity of nucleophilic addition to arynes using frontier molecular orbital contribution analysis

Tetrahedron Letters 58 (2017) 3362–3365

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Predicting the regioselectivity of nucleophilic addition to arynes using frontier molecular orbital contribution analysis Saber Mirzaei a,⇑, Hormoz Khosravi b a b

Faculty of Chemistry, Razi University, P.O. Box: 67149-67346, Kermanshah, Iran Faculty of Chemistry, K. N. Toosi University of Technology, P.O. Box: 15418-49611, Tehran, Iran

a r t i c l e

i n f o

Article history: Received 20 May 2017 Revised 28 June 2017 Accepted 12 July 2017 Available online 14 July 2017

a b s t r a c t The regioselectivity of nucleophilic addition to substituted arynes was predicted using frontier molecular orbital contribution analysis. This model indicates that the percentage of the LUMO on the reacting terminus of the aryne is responsible for the observed regioselectivity; the nucleophile attacks the carbon possessing higher contribution of the LUMO. Ó 2017 Elsevier Ltd. All rights reserved.

Keywords: Aryne Contribution analysis Frontier molecular orbital Regioselectivity

Understanding the chemistry of arynes (benzynes, indolynes, pyridynes) is an intriguing subject in organic chemistry.1 In recent years the regioselectivity of nucleophilic addition to arynes has been one of the most challenging facets of understanding these highly reactive triple bonds for both synthetic and computational chemists. Several groups have tried to justify the regioselectivity of nucleophilic addition to arynes based on the charge distribution, steric effects and electron density.2,3 Finally, Houk and co-workers proposed a model based on distortion effects.4 In this model the distortion of arynes is responsible for their regioselectivity; the flatter the internal angle, the more favorable the terminus for nucleophilic attack. According to this model, the flatter terminus is more electrophilic and also requires less distortion energy in its transition state structure for reaction with a nucleophile. Angle differences of 4° or greater represent synthetically useful levels of regioselectivity, while lower values correspond to low and variable levels of selectivity. Additionally, Houk and co-workers employed frontier molecular orbital (FMO) coefficients to qualitatively justify the regioselectivity of cycloaddition reactions.5 However, using the FMO coefficients was not useful in justifying the selectivity and reactivity of some cycloaddition reactions (e.g. cycloaddition of Münchnone derivatives).6 To the best of our knowledge, the applicability of FMO theory for predicting the regioselectivity of nucleophilic addition to arynes has not been previously examined. ⇑ Corresponding author. E-mail address: [email protected] (S. Mirzaei). http://dx.doi.org/10.1016/j.tetlet.2017.07.047 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

Therefore, despite the success of the distortion model, herein, we report a model based on FMO theory. In this study, contribution analysis (CA) was used instead of the orbital coefficients. This model can predict the regioselectivity of nucleophilic attack on arynes based on the contribution that the reacting terminus has on the frontier orbital, the lowest unoccupied molecular orbital (LUMO), for arynes as an electophile.7 It should be noted that neither the distortion nor frontier molecular orbital contribution analysis (FMO-CA) approaches take into account the steric factors. Garg and Houk reported a systematic study of the regioselectivity for the nucleophilic addition to 3-substituted benzynes (Fig. 1). They justified their selectivity based on the distortion model.8 In order to evaluate the applicability of the FMO-CA model, these 3substituted benzynes were selected as the first group of arynes to be examined. In general, there are two different approaches toward performing contribution analysis; i) methods based on the wave function (e.g. Mulliken, Stout-Politzer, SCPA) and ii) methods based on the electron density (e.g. Hirshfeld, Becke). In order to find the best method and evaluate their basis set dependency, the LUMO-CA of the five 3-substituted benzynes were calculated using three different basis sets (ESI, Tables S1–S5). Table 1 lists the standard deviation (SD) of these calculations. The Hirshfeld method showed the lowest SD (0.1), therefore, this method was used for all calculations. Also, the standard deviation of the Becke method was very low (0.2) which indicates the superiority of density based methods over the wave function based methods for these examples.9

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Fig. 1. Nucleophilic addition of N-methylaniline to the model 3-substituted benzynes.

Table 1 Standard deviation (SD) of five contribution analysis methods using three different basis sets (6-31G*, 6-311++G(2d,2p), aug-cc-pVTZ) for the model 3-substituted benzynes (Fig. 1). All values obtained using the B3LYP functional. X

Mulliken

Stout-Politzer

SCPA

Hirshfeld

Becke

OMe F Cl Br I

3.2 0.6 1.9 1.3 2.3

2.6 4.8 6.0 12.8 42.4

4.0 5.1 5.3 4.4 4.7

0.2 0.0 0.0 0.1 0.2

0.1 0.2 0.2 0.3 0.1

Average SD

1.9

13.7

4.7

0.1

0.2

Table 2 LUMO-CA (B3LYP/6-31G*) of the model 3-substituted benzynes and their experimental ratios. Entry

X

C1%

C2%

D(C1-C2)%

Experimental ratio (C1:C2)8

1 2 3 4 5

OMe F Cl Br I

41.3 42.1 40.8 40.6 40.3

32.3 34.0 35.5 35.8 35.9

9.0 8.1 5.3 4.8 4.4

>99 >99 20:1 13:1 9:1

Table 2 lists the LUMO-CA for the model 3-substituted benzynes using the Hirshfeld method. The values were obtained from the fully optimized structures (B3LYP/6-31G⁄ and LanL2DZ for iodine).9 As illustrated in Table 2, 3-methoxy benzyne (X = OMe) showed the highest difference between the C1 and C2 termini (C1-C2 = 9.0%) with the nucleophile preferentially attacking at the carbon with higher LUMO contribution (C1). The regioselectivity of 3-methoxy benzyne has been reported by several groups,10 each reporting C1 as the favored site of nucleophilic attack. This regioselectivity prediction was also valid for all remaining 3-substituted benzynes (Table 2).8 The experimental ratios (Table 2) indicated almost identical selectivity for the methoxy and fluorine groups (Entries 1 and 2).8 However, FMO-CA and distortion models show different selectivity for OMe and F. Based on the distortion model, the F substituted benzyne has a larger internal angle difference (17°) in comparison to OMe (15°). In contrast, the LUMO-CA indicates OMe (C1-C2 = 9.0%) as more selective in comparison to F (C1C2 = 8.1%). Also, the DDGà (DGà(C1) DGà(C2)) values show higher selectivity for OMe (5.2 kcal/mol) in comparison to F (4.1 kcal/mol).8 In this example the FMO-CA model is in better agreement with the obtained transition states energy differences (DDGà). The experimental ratios (Table 2) shows decreasing selectivity from F to I; the LUMO-CA predicts the same trend. The F and I substituents showed the highest (C1-C2 = 8.1%) and the lowest (C1C2 = 4.4%) difference in favor of C1, respectively. Regarding the halogen containing benzynes (Entries 2–5), it appears that their selectivity depends on the electronegativity of the substituted atom; the greater electronegativity of the halogen leads to a higher degree of regioselectivity. The calculated LUMO-CA values, compared to the experimental observations, reveal the quantitative

Fig. 2. Nucleophilic addition of amines (R-NH2) to model 3-(trimethylsilyl) benzynes.

Table 3 LUMO-CA (B3LYP/6-31G*) of the model 3-(trimethylsilyl) benzynes and their experimental ratios. Entry

X

R

C2%

C1%

D(C2-C1)%

Experimental ratio (C2:C1)11

1 2 3 4 5

Me Ph OMe F Cl

Furfuryl Cyclohexyl Allyl CH2Ph NHBoc

39.2 38.9 39.8 40.1 39.9

35.0 34.6 34.6 34.4 33.4

4.2 4.3 5.2 5.7 6.5

5.6:1 5.9:1 6.0:1 8.5:1 16.0:1

application of the FMO-CA model. These results are independent of the selected DFT functional (ESI, Table S6 and S7). The regioselectivity of substituted 3-(trimethylsilyl) benzynes (Me, Ph, OMe, F, Cl) was also investigated (Fig. 2). In all cases C2 possessed higher LUMO-CA values. Therefore, this terminus is the preferred site of attack, which was in agreement with the experimental outcomes (Table 3). This selectivity was attributed to the strong inductive effects of the silyl substituent.11 According to the experimental ratio, the C2 selectivity was not significantly affected by the substituents. However, the selectivity of Entry 5 is higher which can be attributed to the greater nucleophilicity of the tert-butyl carbamate (NHBoc). In spite of the insignificant substituent effects, the calculated LUMO-CA values were in good agreement with the experimental ratios. The distortion model indicates identical angle differences for Me, Ph and OMe (12°) and also for F and Cl (14°). In order to examine the generality of the FMO-CA model, several arynes for which their experimental regioselectivities has been determined were investigated (Table 4). Also, the FMO-CA model was tested for several arynes which do not have reported experimental observations (ESI, Table S8). The first five entries examine different indolyne structures. The LUMO-CA indicates a higher value on C5 (38.6%) of 4,5-indolyne in comparison to C4 (37.4%, Entry 1). This regioselectivity is overturned in 6-bromo-4,5-indolyne (Entry 3). Additionally, Br substitution at C3 enhances the selectivity of 4,5-indolyne, increasing the C4 preference from 1.2% to 3% (Entry 2). This selectivity enhancement was also reported experimentally.12 The FMO-CA model correctly predicts the selectivity for both 5,6- and 6,7-indolynes (Entries 4 and 5).12 The obtained values for Entries 1–5 show FMO-CA as a useful model for the quantitative determination of regioselectivity. The C3 position of 3,4-pyridyne (Entry 6) shows a higher value (37.4%) in comparison to C4 (36.5%). However, the experimental data showed either no or very weak C4 selectivity in the nucleophilic addition reaction.13 Based on the distortion model, the internal angle of C4 is bigger than C3, which eventuates in greater electrophilicity at C4. It should be noted that C3 shows a lower transition state (0.4 kcal/mol) in the nucleophilic addition reaction.13b This lower barrier can be attributed to the better interaction of 3,4-pyridyne and the nucleophile frontier orbitals. Nevertheless, it seems that the distortion model has better agreement with the experimental observations for 3,4-pyridyne. The addition of different substituents to 3,4-pyridyne can alter its regioselectivity (Entries 7 and 8), and the FMO-CA model correctly predicts these substitution effects. In contrast to

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Table 4 LUMO-CA (B3LYP/6-31G*) of selected arynes for which their regioselectivity has been determined experimentally. Entry

Aryne

1

LUMO-CA%

Experimental selectivity

C4 (37.4) C5 (38.6)

C512

Table 4 (continued) Entry

Aryne

13

LUMO-CA%

Experimental selectivity

C1 (39.2) C2 (37.6)

C116

C7 (37.7) C8 (37.8)

C817b

4-fluorobenzyne 14 4,5-indolyne C4 (35.9) C5 (38.9)

2

C512 7,8-quinolyne

3-bromo-4,5-indolyne C4 (39.8) C5 (36.0)

3

C412

Table 5 LUMO-CA (B3LYP/6-31G*) of nonaromatic alkynes. Entry

Alkynes

1

LUMO-CA%

Experimental selectivity

C3 (32.3) C4 (38.6)

C418

C3 (32.9) C4 (36.0)

C418

C1 (37.5) C2 (31.6)

C118

6-bromo-4,5-indolyne C5 (39.5) C6 (37.2)

4

C512 3,4-oxacyclohexyne 2

5,6-indolyne C6 (41.7) C7 (34.0)

5

C612

3,4-piperidyne 3 6,7-indolyne C3 (37.4) C4 (36.5)

6

Mix13

3-methoxy cyclohexanyne

3,4-pyridyne 7

13a

C3 (39.8) C4 (33.7)

C3

C3 (33.8) C4 (37.9)

C413a

C2 (46.5) C3 (25.3)

C214

C4 (37.1) C5 (39.6)

C515

C1 (40.7) C2 (33.1)

C112a

C1 (38.9) C2 (37.8)

Mix16

5-bromo-3,4-pyridyne 8

2-sulfamate-3,4-pyridyne 9

2,3-pyridyne 10

4,5-benzofuranyne 11

3,5-dimethoxybenzyne 12

4-methoxybenzyne

3,4-pyridyne, its constitutional isomer 2,3-pyridyne (Entry 9) has very high selectivity in favor of C2.14 The high LUMO-CA difference (C2-C3 = 21.2%) is in good agreement with the experimental observations. Similarly to 4,5-indolyne, C4 is the preferred site of nucleophilic attack in 4,5-benzofuranyne (Entry 10).15 Entry 11 represents benzyne with more than one substituent. The methoxy group on C3 governs the selectivity, however, the regioselectivity (C1C2 = 7.6%) is lower compared to 3-methoxybenzyne (C1C2 = 9.0%, see Table 2). The last three structures (Entries 12–14) represent more challenging systems for both the FMO-CA and distortion models. 4Methoxybenzyne (Entry 12) and 4-fluorobenzyne (Entry 13) showed greater regioselectivity on C1.16 However, these selectivities are not significant, especially for the OMe group.16a The FMO-CA model indicates low orbital contribution difference (1.1%) for the OMe group in favor of C1. In contrast, the distortion model indicates the flatter angle for C2 (128°) in comparison to C1 (126°). Also, the distortion model indicates identical angles (127°) for C1 and C2 in 3-fluorobenzyne. In contrast, the FMO-CA model differentiates between C1 (39.2%) and C2 (37.6%) in 4-fluorobenzyne which is in better agreement with the experimental observations.16 b In this case FMO-CA is a better model. Finally, for 7,8-quinolyne (Entry 14), the distortion model shows preference for C7 (128°).17a However, the experimental data points to C8 (126°).17 b The FMO-CA model indicates almost identical values (37.8% for C8, 37.7% for C7). Garg and co-workers have studied the regioselectivity of nonaromatic alkynes (Table 5).15,18 The LUMO-CA indicated the

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correct terminus for nucleophilic addition. The experimental results reveal greater selectivity for 3,4-oxacyclohexyne in comparison to 3,4-piperidyne which has been attributed to the higher electronegativity of oxygen which leads to increased distortion.15 The LUMO-CA values of C3 and C4 indicate a greater difference for 3,4-oxacyclohexyne (C4-C3 = 6.3%) compared to 3,4-piperidyne (C4-C3 = 4.9%). This model, like the distortion model, can justify the higher regioselectivity of Entry 1 compared to Entry 2. These values indicate the reliability of the FMO-CA model for predicting the regioselectivity of nonaromatic compounds. In summary, this work represents a novel approach for predicting the regioselectivity of nucleophilic attack on arynes with high reliability; the nucleophile attacks the carbon with higher percentage of the LUMO. Additionally, the calculations indicate that LUMO-CA differences of 1.5% or greater correspond to synthetically useful levels of regioselectivity. This phenomenon can be attributed to better interaction (overlap) between the nucleophile and aryne frontier orbitals. The results of this study revealed that both distortion and FMO interactions control the regioselectivity of highly reactive aromatic and nonaromatic triple bonds, however, the separation of these two models is inherently difficult. The FMO-CA can be a good counterpart for the distortion model in predicting the regioselectivity of arynes, especially for the arynes with low degree of distortion (e.g. 4° or smaller).

3.

4.

5.

6. 7. 8. 9. 10.

Acknowledgments The authors express sincere appreciation to Professor A. A. Taherpour and Professor S. Balalaei for invaluable information and encouragement.

11. 12. 13.

A. Supplementary data 14.

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.07. 047.

15. 16.

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