Barriers to Rotation in ortho-Substituted Tertiary Aromatic Amides

Article pubs.acs.org/joc

Cite This: J. Org. Chem. 2018, 83, 3159−3163

Barriers to Rotation in ortho-Substituted Tertiary Aromatic Amides: Effect of Chloro-Substitution on Resonance and Distortion Elwira Bisz,‡ Aleksandara Piontek,‡ Błazė j Dziuk,‡ Roman Szostak,§ and Michal Szostak*,†,‡ ‡

Department of Chemistry, Opole University, 48 Oleska Street, Opole 45-052, Poland Department of Chemistry, Wroclaw University, F. Joliot-Curie 14, Wroclaw 50-383, Poland † Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States §

S Supporting Information *

ABSTRACT: Planarity of the amide bond represents one of the most widely recognized properties of amides. Herein, we report a combined structural and computational study on the effect of ortho-substitution on resonance and barriers to rotation in tertiary aromatic amides. We demonstrate that ortho-chloro substitution in a class of benzamides that are important from the reactivity and medicinal chemistry perspective results in increased barriers to rotation around both the N−C(O) and C−C(O) axes. The effect of steric hindrance on structures, resonance energies, barriers to rotation, and proton affinities is discussed. The present study strongly supports the use of ortho-substitution in common benzamides to strengthen amidic resonance. predicable manner (Figure 1B).10 In contrast, the effect of orthosubstitution of the aromatic ring on amidic resonance and barriers to rotation in benzamide derivatives has been rarely studied.11,12 The ortho-chlorinated tertiary aromatic amides represent an important structural motif that appears in a large number of biologically active compounds (Figure 1C).13 Moreover, orthochlorinated amides participate in selective cross-coupling reactions controlled by the amide bond geometry.14 The effect of di-ortho-substitution in benzamides has been utilized to restrict the bond conformation around the Ar−C(O) axis, leading to important advances in conformational relays and enantioselective synthesis.15 Currently, the effect of orthochloro-substitution on amidic resonance in common benzamides is unknown. As part of our ongoing studies in the area of amide bonds,16 here, we describe a combined structural and computational study on the effect of ortho-substitution on resonance and barriers to rotation in tertiary aromatic amides. We quantify the impact of ortho-chloro-substitution of the aromatic ring on structures, amidic resonance, barriers to rotation, and proton affinities. The data strongly support the use of ortho-substitution in common benzamides to strengthen amidic resonance. Currently, there are no examples of determining energetic properties of orthochlorinated benzamides that are relevant to medicinal chemistry and organic synthesis. Likewise, the effect of steric orthosubstitution of the aromatic ring in benzamide derivatives on structures and energetics of the amide bond is unknown.

1. INTRODUCTION Distortion of the amide bond from planarity has been the focus of intense research interest for almost eight decades.1−3 Bridged lactams have featured prominently as practical models for nonplanar amide linkages, leading to the discovery of a range of novel reactions of amides (Figure 1A).4,5 More recently, substantial efforts have been directed toward amide bond distortion in more common acyclic amides.6−9 A unifying element is that substitution at the nitrogen atom can now be exploited to increase the amide bond twist in a highly rational and

Figure 1. (A and B) Concepts in amide bond distortion. (C) Selected examples of medicinally relevant ortho-chloro-substituted benzamides. © 2018 American Chemical Society

Received: January 3, 2018 Published: February 15, 2018 3159

DOI: 10.1021/acs.joc.8b00019 J. Org. Chem. 2018, 83, 3159−3163

Article

The Journal of Organic Chemistry

2. RESULTS AND DISCUSSION Amides selected for the present study are shown in Figure 2. We commenced our investigation by obtaining X-ray structures of

Table 1. Selected Crystallographic Structural Parameters of Acyclic Amides 1a−1c and Representative Amidesa entry

amide

1a 2a 3a 4b

1a 1b 1c Nglutarimide N-TMP formamide

5c 6d

NC(O) [Å]

CO [Å]

NC(O) τ [°]

NC(O) χN [°]

CC(O) τ [°]

1.343 1.347 1.389 1.475

1.235 1.238 1.224 1.200

0.1 0.1 1.3 87.5

1.2 4.8 0.9 5.6

91.5 76.4 62.5 1.3

1.375 1.349

1.229 1.193

34.1 0.0

17.0 0.0

46.5 0.0

a

This study. X-ray structures. bRef 6b (Ph−C(O)-N-glutarimide). cRef 7a (4-MeO-C6H4−C(O)-N-TMP). dCalculated values, ref 18. TMP = 2,2,6,6-tetramethylpiperidine.

Figure 2. Structures of amides employed in the present study.

representative amides in the series (1a−c, Figure 3). Morpholinyl amides were selected for the crystallographic study due to high crystallinity; other attempted amides were not crystalline. These amides are further useful because of the Weinreb amide-type reactivity of morpholinyl amides.17 Selected structural parameters relevant to the amide bond geometry in 1a−c along with representative nonplanar and planar amides are presented in Table 1. We found that 1a−c (ortho-Cl2, ortho-Cl, para-Cl) contain close to perfectly planar amide bonds in the solid state (τ = 0.1− 1.3°; χN = 0.9−4.8°). Interestingly, the NC(O) amide bond length (1a, 1.343 Å; 1b, 1.347 Å; 1c, 1.389 Å) increases with decreased ortho-chloro-substitution in the series, while the C O bond length (1a, 1.235 Å; 1b, 1.238 Å; 1c, 1.224 Å) undergoes shortening, indicative of a stronger nN → π*CO conjugation in 1a than in 1c. Most importantly, the CC(O) bond twist (1a, τ = 91.5°; 1b, τ = 76.4°; 1c, τ = 62.5°) gradually changes from relatively nonplanar (1c) to fully perpendicular (1a) as a result of steric ClO interactions. Thus, the X-ray data clearly show an increase of amidic resonance upon substitution in the series of 1a−1c. Currently, there are a few crystallographic studies that gradually probe the effect of substitution on structural properties of the amide bond.18−20 This can be contrasted with the conformational preference of N-acylglutarimide (2, Figure 4),6b

Figure 4. Crystal structure of 2. Insets show Newman projections along the N−C(O) and C−C(O) bonds. See ref 6b for details.

which contains a perpendicular amide bond (τ = 87.5°; χN = 5.6°); however, the CC(O) bond is planar (2, τ = 1.3°). To our knowledge, this study demonstrates for the first time the capacity to fully control the molecular twisting of both NC(O) and CC(O) axes of the amide bond by complementary substitution of either the aromatic ring (1a) or the N-substituent (2). The COSNAR method (eq 1) was used to calculate resonance energies of amides selected for the study (Table 2).18,19 −RE = E T(amide) − [E T(amine) + E T(ketone) − E T(hydrocarbon)] (1)

We focused on dimethylbenzamides (1e−h), while selected morpholinyl amides (1a−d) and N,N-dimethylacetamide (DMAc, 1i) were computed for comparison. B3LYP/6-311+ +G(d,p) was selected to conduct geometry optimization as a result of good reproducibility of literature data and method practicality. Extensive studies have showed that this level is

Figure 3. Crystal structures of (a) 1a, (b) 1b, and (c) 1c. Insets show Newman projections along the N−C(O) and C−C(O) bonds. See the Supporting Information for expanded ORTEP structures, bond lengths (Å), and angles (°). 3160


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Table 2. Resonance Energies Calculated Using the Carbonyl Substitution Nitrogen Atom Replacement Method (COSNAR) (B3LYP/6-311++G(d,p))a

a

COSNAR, ref 18. nd = not determined.

accurate in predicting properties and resonance energies of amides.16c,d,19c The method was further verified by obtaining good correlations between the calculated structures and X-ray structures in the series. Examination of the data reveals that increasing the orthochloro-substitution (1e−g) leads to a significant increase of resonance (ΔER of 6.5 kcal/mol, 37% change in amidicity vs DMAc). Moreover, di-ortho-Cl2-substitution has a somewhat greater effect on amidic resonance than di-ortho-Me2-substituents (1e vs 1h, 22.5 vs 20.7 kcal/mol), which is consistent with longer C−Cl bonds and electrostatic Cllp−Olp interactions. The same effects are found in the morpholinyl series (1a−d); the values are attenuated by hyperconjugation of the morpholine ring. To gain a more in-depth comparison of the effect of orthosubstitution on rotational barriers around the N−C(O) and C− C(O) axes, we conducted a comprehensive survey of rotational profiles in amides 1e−g (Table 3 and Figures 5 and 6). Rotational profiles of morpholinyl amides 1a and 1d as well as separate profiles for each amide examined and expanded

Table 3. Summary of Rotational Barriers around N−C(O) and C−C(O) Bonds in Amides 1 (B3LYP/6-311++G(d,p))a entry

amides 1

N−C(O), ER [kcal/mol]

C−C(O), ER [kcal/mol]

1 2 3 4 5 6 7 8 9

1a 1b 1c 1d 1e 1f 1g 1h 1i

24.6 nd nd 18.9 23.2 22.9 16.5 21.3 19.5

24.9 nd nd 7.0 24.1 17.2 4.9 19.6

a

Representative data on acyclic twisted amides: refs 16c and d. Representative data on bridged lactams: refs 18, 16a, and b. nd = not determined.

comparisons are presented in the Supporting Information. In each case, the rotation was performed in both directions. We employed the X-ray structures of 1a−c as the starting geometry 3161


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Overall, the data indicate that ortho-substitution at the aromatic strongly affects the amide bond resonance and geometry around the C−C(O) axis by increasing the barriers to rotation. The effect on C−C rotation is approximately 3 times stronger than on N−C rotation. To provide further insight into the effect of ortho-substitution on the properties of the amide bond, proton affinities (PA) and differences in proton affinities (ΔPA) in ortho-substituted amides and representative amides were calculated (Table 4).18,16a,b Generally, planar amides undergo protonation at Table 4. Proton Affinities (PA) and Differences in Proton Affinities (ΔPA) in Amides 1 (B3LYP/6-311++G(d,p))a entry

amides 1

NPA [kcal/mol]

OPA [kcal/mol]

ΔPA [kcal/mol]

1 2 3 4 5 6 7 8 9

1a 1b 1c 1d 1e 1f 1g 1h 1i

211.9 nd nd 216.2 212.4 217.9 219.7 217.3 211.5

224.8 nd nd 228.6 225.5 227.2 229.8 230.3 224.1

12.9 nd nd 12.4 13.1 9.3 10.1 13.0 12.6

Figure 5. Plot of ΔE [kcal/mol] to O−C−N−C [°] in 1e, 1f, 1g, and 1h.

a

OPA of the morpholine ring oxygen: 1a, 199.3 kcal/mol; 1d, 200.6 kcal/mol. nd = not determined. Representative data on acyclic twisted amides: refs 16c and d. Representative data on bridged lactams: refs 18, 16a, and b.

oxygen (e.g., in formamide, O-protonation is favored by 11.5 kcal/mol).20 In the case of ortho-substituted amides, proton affinity to nitrogen decreases with increasing ortho-substitution (e.g., in the series of 1e−1g, ΔENPA of 7.3 kcal/mol), and this effect is consistent with an increased nN → π*CO conjugation. However, the steric hindrance at the ortho-position of the aromatic ring also disfavors proton affinity to oxygen (e.g., in the series of 1e−1g, ΔEOPA of 4.3 kcal/mol). The net effect is that while these ortho-substituted amides still favor protonation at the oxygen atom, ΔPA values are in the range of ortho-unsubstituted analogues.

Figure 6. Plot of ΔE [kcal/mol] to O−C−C−C [°] in 1e, 1f, 1g, and 1h.

and performed full optimization. For a discussion of hysteresis in conformational plots, see the Supporting Information. The plots determine the relationship between energy and N−C(O) and C−C(O) geometry by systematic rotation along the O−C−N− C and O−C−C−C dihedral angles. The rotational profiles around the N−C(O) bonds agree well with the resonance energies determined by the COSNAR method (ΔE = 1.2 kcal/mol). This (1) further validates the utility of the COSNAR approach in predicting resonance energies of amides18,19 and (2) confirms that ortho-chlorosubstitution results in an increase of amidic resonance in tertiary aromatic amides (1e vs 1g, ΔER of 6.7 kcal/mol). Most notably, the rotational profiles around the C−C(O) bond demonstrate a dramatic increase of rotational barriers in going from 1g (ortho-H2) to 1e (ortho-Cl2), ΔER of 19.2 kcal/ mol.11,12 This corresponds to a remarkable 1.2 × 1014-fold decrease in the rate of C−C(O) rotation at 298 K. As already expected, this effect is mirrored in the morpholinyl series (ΔER of 17.9, 1a vs 1d), while the effect of ortho-dimethyl-substitution (ΔER of 14.7 kcal/mol, 1g vs 1h) is slightly lower than in the ortho-dichloro series. This still corresponds to a 6.0 × 1010-fold decrease in the rate of C−C(O) rotation at 298 K.

3. CONCLUSIONS In summary, we have presented a computational study on the effect of ortho-substitution on resonance and barriers to rotation in tertiary aromatic amides. Ortho-substituted amides that feature prominently in biologically relevant compounds and are important for the reactivity reasons are characterized by increased barriers to rotation around both the N−C(O) and C− C(O) axes. The effect is consistent with steric repulsion between the ortho-substituent and the amide oxygen atom. Rotational profiles demonstrate a dramatic increase of rotational barriers around the C−C(O) bond (up to 19.2 kcal/mol) and a substantial increase of barriers to rotation around the N−C(O) bond (up to 6.7 kcal/mol). We have also determined proton affinities and differences in proton affinities in ortho-chlorosubstituted amides. Our study shows that amidic resonance can be varied between virtually nonexistent to >20 kcal/mol by a judicious choice of amide bond substitution. Further work on structural and energetic properties of amides is ongoing. We expect that these studies will ultimately enable the development of a well-defined resonance scale of the amide bond. 3162


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54, 13277. (b) Wolf, C. Dynamic Stereochemistry of Chiral Compounds; RSC Publishing: Cambridge, 2008. (12) For selected studies on ortho-substituted benzamides, see: (a) Kessler, H. Angew. Chem., Int. Ed. Engl. 1970, 9, 219. (b) Mannschreck, A.; Mattheus, A.; Rissmann. J. Mol. Spectrosc. 1967, 23, 15. (c) Jungk, A. E.; Schmidt, G. M. J. Chem. Ber. 1971, 104, 3289. (d) Leibfritz, D. Chem. Ber. 1975, 108, 3014. (e) Kleinpeter, E. J. Mol. Struct. 1996, 380, 139. For a study on solvolysis of ortho-chloro derivatives, see: (f) Park, K. H.; Kevill, D. N. J. Phys. Org. Chem. 2012, 25, 2. (13) (a) Kayama, S.; Tabata, H.; Takahashi, Y.; Tani, N.; Wakamatsu, S.; Oshitari, T.; Natsugari, H.; Takahashi, H. Tetrahedron 2015, 71, 7046. (b) Kanase, Y.; Kuniyoshi, M.; Tabata, H.; Takahashi, Y.; Kayama, S.; Wakamatsu, S.; Oshitari, T.; Natsugari, H.; Takahashi, H. Synthesis 2015, 47, 3907. (c) Kondo, K.; Kan, K.; Tanada, Y.; Bando, M.; Shinohara, T.; Kurimura, M.; Ogawa, H.; Nakamura, S.; Hirano, T.; Yamamura, Y.; Kido, M.; Mori, T.; Tominaga, M. J. Med. Chem. 2002, 45, 3805. (d) Okaniwa, M.; Imada, T.; Ohashi, T.; Miyazaki, T.; Arita, T.; Yabuki, M.; Sumita, A.; Tsutsumi, S.; Higashikawa, K.; Takagi, T.; Kawamoto, T.; Inui, Y.; Yoshida, S.; Ishikawa, T. Bioorg. Med. Chem. 2012, 20, 4680. (14) Science of Synthesis: Cross-Coupling and Heck-Type Reactions; Molander, G. A., Wolfe, J. P., Larhed, M., Eds.; Thieme: Stuttgart, 2013. (15) Selected examples: (a) Clayden, J.; Lund, A.; Vallverdu, L.; Helliwell, M. Nature 2004, 431, 966. (b) Clayden, J. Chem. Soc. Rev. 2009, 38, 817. (c) Sola, J.; Fletcher, S. P.; Castellanos, A.; Clayden, J. Angew. Chem., Int. Ed. 2010, 49, 6836. (d) Knipe, P. C.; Thompson, S.; Hamilton, A. D. Chem. Sci. 2015, 6, 1630. (e) Barrett, K. T.; Metrano, A. J.; Rablen, P. R.; Miller, S. J. Nature 2014, 509, 71. (16) For bridged lactams, see: (a) Szostak, R.; Aubé, J.; Szostak, M. Chem. Commun. 2015, 51, 6395. (b) Szostak, R.; Aubé, J.; Szostak, M. J. Org. Chem. 2015, 80, 7905. For acyclic amides, see: (c) Szostak, R.; Shi, S.; Meng, G.; Lalancette, R.; Szostak, M. J. Org. Chem. 2016, 81, 8091. (d) Szostak, R.; Meng, G.; Szostak, M. J. Org. Chem. 2017, 82, 6373. (17) Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J. Synlett 1997, 12, 1414. (18) For classic computational studies on bridged lactams, see: (a) Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc. 1993, 115, 6951. (b) Greenberg, A.; Moore, D. T.; DuBois, T. D. J. Am. Chem. Soc. 1996, 118, 8658. See, also: (c) Morgan, J.; Greenberg, A. J. Chem. Thermodyn. 2014, 73, 206. (19) For selected theoretical studies on amide bonds, see: (a) Kemnitz, C. R.; Loewen, M. J. J. Am. Chem. Soc. 2007, 129, 2521. (b) Mujika, J. I.; Mercero, J. M.; Lopez, X. J. Am. Chem. Soc. 2005, 127, 4445. (c) Glover, S. A.; Rosser, A. A. J. Org. Chem. 2012, 77, 5492. (d) Glover, S. A.; Rosser, A. A.; Taherpour, A.; Greatrex, B. W. Aust. J. Chem. 2014, 67, 507. (e) Morgan, J.; Greenberg, A.; Liebman, J. F. Struct. Chem. 2012, 23, 197. (f) Morgan, J. P.; Weaver-Guevara, H. M.; Fitzgerald, R. W.; Dunlap-Smith, A.; Greenberg, A. Struct. Chem. 2017, 28, 327. (20) (a) Wiberg, K. B. Acc. Chem. Res. 1999, 32, 922. (b) Cox, C.; Lectka, T. Acc. Chem. Res. 2000, 33, 849.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00019. Crystallographic studies, Cartesian coordinates and energies, rotational barriers, and detailed description of computational methods used (PDF) Crystal data for amide 1a (CIF) Crystal data for amide 1b (CIF) Crystal data for amide 1c (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Michal Szostak: 0000-0002-9650-9690 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge Narodowe Centrum Nauki (grant no. 2014/15/D/ST5/02731, E.B., M.S.), Rutgers University (M.S.) and NSF (CAREER CHE-1650766, M.S.) for the generous financial support. We thank the Wroclaw Center for Networking and Supercomputing (grant no. WCSS159, R.S.).

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REFERENCES

(1) The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science; Greenberg, A., Breneman, C. M., Liebman, J. F., Eds.; Wiley: New York, 2000. (2) Tani, K.; Stoltz, B. M. Nature 2006, 441, 731. (3) Aubé, J. Angew. Chem., Int. Ed. 2012, 51, 3063. (4) For selected reviews, see: (a) Hall, H. K., Jr.; El-Shekeil, A. Chem. Rev. 1983, 83, 549. (b) Yamada, S. Rev. Heteroat. Chem. 1999, 19, 203. (c) Clayden, J.; Moran, W. J. Angew. Chem., Int. Ed. 2006, 45, 7118. (d) Szostak, M.; Aubé, J. Chem. Rev. 2013, 113, 5701. (5) For representative examples, see: (a) Liniger, M.; VanderVelde, D. G.; Takase, M. K.; Shahgholi, M.; Stoltz, B. M. J. Am. Chem. Soc. 2016, 138, 969. (b) Liniger, M.; Liu, Y.; Stoltz, B. J. Am. Chem. Soc. 2017, 139, 13944. (c) Komarov, I. V.; Yanik, S.; Ishchenko, A. Y.; Davies, J. E.; Goodman, J. M.; Kirby, A. J. J. Am. Chem. Soc. 2015, 137, 926. (d) Golden, J.; Aubé, J. Angew. Chem., Int. Ed. 2002, 41, 4316. (e) Sliter, B.; Morgan, J.; Greenberg, A. J. Org. Chem. 2011, 76, 2770. For a recent synthesis of Tröger’s base twisted amides, see: (f) Artacho, J.; Ascic, E.; Rantanen, T.; Karlsson, J.; Wallentin, C. J.; Wang, R.; Wendt, O. F.; Harmata, M.; Snieckus, V.; Wärnmark, K. Chem. - Eur. J. 2012, 18, 1038. (6) (a) Meng, G.; Szostak, M. Org. Lett. 2015, 17, 4364. (b) Pace, V.; Holzer, W.; Meng, G.; Shi, S.; Lalancette, R.; Szostak, R.; Szostak, M. Chem. - Eur. J. 2016, 22, 14494. (7) (a) Clayden, J.; Foricher, Y. J. Y.; Lam, H. K. Eur. J. Org. Chem. 2002, 2002, 3558. (b) Hutchby, M.; Houlden, C. E.; Haddow, M. F.; Tyler, S. N.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem., Int. Ed. 2012, 51, 548. (c) Clayden, J. Nature 2012, 481, 274. (8) (a) Yamada, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1083. (b) Yamada, S. Angew. Chem., Int. Ed. Engl. 1995, 34, 1113. (9) For recent elegant examples of amide distortion by peripheral metal coordination, see: (a) Adachi, S.; Kumagai, N.; Shibasaki, M. Chem. Sci. 2017, 8, 85. (b) Adachi, S.; Kumagai, N.; Shibasaki, M. Synlett 2018, 29, 301. (10) For reviews, see: (a) Liu, C.; Szostak, M. Chem. - Eur. J. 2017, 23, 7157. (b) Meng, G.; Shi, S.; Szostak, M. Synlett 2016, 27, 2530. (11) For a study on isomerization around the C−C(O) axis in benzamides, see: (a) Ahmed, A.; Bragg, R. A.; Clayden, J.; Lai, L. W.; McCarthy, C.; Pink, J. H.; Westlund, N.; Yasin, S. A. Tetrahedron 1998, 3163


Barriers to Rotation in ortho-Substituted Tertiary Aromatic Amides

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