Barriers to Rotation in ortho-Substituted Tertiary Aromatic Amides

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Barriers to Rotation in ortho-Substituted Tertiary Aromatic Amides: Effect of Chloro-Substitution on Resonance and Distortion Elwira Bisz, Aleksandra Piontek, B#a#ej Dziuk, Roman Szostak, and Michal Szostak J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00019 • Publication Date (Web): 15 Feb 2018 Downloaded from http://pubs.acs.org on February 15, 2018

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The Journal of Organic Chemistry

Barriers to Rotation in ortho-Substituted Tertiary Aromatic Amides: Effect of Chloro-Substitution on Resonance and Distortion Elwira Bisz,‡ Aleksandara Piontek,‡ Błażej 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

RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to) Corresponding author [email protected]

ACS Paragon Plus Environment

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Abstract

Planarity of the amide bond represents one of the most widely recognized properties of amides. Herein, we report a computational study on the effect of ortho-substitution on resonance and barriers to rotation in tertiary aromatic amides. We demonstrate that ortho-chloro substitution of the aromatic ring 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.


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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 non-planar 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 towards 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 amide bond twist in a highly rational and 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, ortho-chlorinated 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 bond conformation around the Ar–C(O) axis, leading to important advances in conformational relays and enantioselective synthesis.15 At present, the effect of ortho-chloro-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 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. At present there are no examples of determining energetic properties of ortho-chlorinated benzamides that are relevant to medicinal chemistry and organic synthesis. Likewise, the effect of steric ortho-substitution of the aromatic ring in benzamide derivatives on structures and energetics of the amide bond is unknown.


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Figure 1. (a-b) Concepts in amide bond distortion. (c) Selected examples of medicinally-relevant orthochloro-substituted benzamides. 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 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 non-planar 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 = ACS Paragon Plus Environment

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76.4°; 1c, τ = 62.5°) gradually changes from relatively non-planar (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. At present, there are 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 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).

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


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Figure 3. Crystal structures of (a) 1a, (b) 1b, and (c) 1c. Insets show Newman projections along N– C(O) and C–C(O) bonds. See SI for expanded ORTEP structures, bond lengths (Å) and angles (deg).

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

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

entry

N–C(O)

C=O

NC(O) τ

NC(O) χN

CC(O) τ

[Å]

[Å]

[deg]

[deg]

[deg]

amide

1a

1a

1.343

1.235

0.1

1.2

91.5

2a

1b

1.347

1.238

0.1

4.8

76.4

3a

1c

1.389

1.224

1.3

0.9

62.5

4b

N-glutarimide

1.475

1.200

87.5

5.6

1.3

5c

N-TMP

1.375

1.229

34.1

17.0

46.5

6d

formamide

1.349

1.193

0.0

0.0

0.0

a

This study. X-ray structures. bRef. 6b (Ph-C(O)-N-glutarimide). cRef. 7a (4-MeO-C6H4-C(O)-N-TMP).

d

Calculated values. Ref. 18. TMP = 2,2,6,6-tetramethylpiperidine.


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The COSNAR method (eq 1) was used to calculate resonance energies of amides selected for the study (Table 2).18,19

–RE = ET(amide) – [ET(amine) + ET(ketone) – ET(hydrocarbon)] (eq. 1) We focused on dimethylbenzamides (1e-h), while selected morpholinyl amides (1a-d) and N,Ndimethylacetamide (DMAc, 1i) were selected 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 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 ortho-chloro-substitution (1e-g) leads to a significant increase of resonance (∆ER 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-Me2substituents (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.

Table 2. Resonance Energies Calculated using Carbonyl Substitution Nitrogen Atom Replacement Method (COSNAR) (B3LYP/6-311++G(d,p))a 1

ER [kcal/mol]

1

1a

21.7

2

1b

20.7

entry

amide


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a

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3

1c

nd

4

1d

19.6

5

1e

22.5

6

1f

20.9

7

1g

16.0

8

1h

20.7

9

1i

18.3

COSNAR, ref. 18. nd = not determined.

To gain a more in-depth comparison of the effect of ortho-substitution 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 5-6). Rotational profiles of morpholinyl amides 1a and 1d as well as separate profiles for each amide examined and expanded comparisons are presented in the SI. In each case, the rotation was performed in both directions. We employed the X-ray structures of 1a-c as the starting geometry 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.


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The rotational profiles around the N–C(O) bonds agree well with the resonance energies determined by the COSNAR method (∆E = 1.2 kcal/mol). This (1) further validates the utility of the COSNAR approach in predicting resonance energies of amides;18,19 and (2) confirms that ortho-chloro-substitution results in an increase of amidic resonance in tertiary aromatic amides (1e vs. 1g, ∆ER of 6.7 kcal/mol).

Plot of Energy vs. O−C−N−C Dihedral Angle 26

1e 1f 1g 1h

24 22 20 18

∆E [kcal/mol]

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 49 50 51 52 53 54 55 56 57 58 59 60


16 14 12 10 8 6 4 2 0 -150

-100

-50

0

50

100

150

O−C−N−C [°]

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


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Plot of Energy vs. O−C−C−C Dihedral Angle 26

1e 1f 1g 1h

24 22 20 18

∆E [kcal/mol]

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 49 50 51 52 53 54 55 56 57 58 59 60

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16 14 12 10 8 6 4 2 0 -150

-100

-50

0

50

100

150

O−C−C−C [°]

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

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), ∆ER of 19.2 kcal/mol.11,12 This corresponds to a remarkable 1.2 x 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 (∆ER of 17.9, 1a vs. 1d), while the effect of ortho-dimethyl substitution (∆ER of 14.7 kcal/mol, 1g vs. 1h) is slightly lower than in the ortho-dichloro series. This still corresponds to a 6.0 x 1010-fold decrease in the rate of C–C(O) rotation at 298 K. 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.

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


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a


N–C(O), ER

C–C(O), ER

[kcal/mol]

[kcal/mol]

entry

1

1

1a

24.6

24.9

2

1b

nd

nd

3

1c

nd

nd

4

1d

18.9

7.0

5

1e

23.2

24.1

6

1f

22.9

17.2

7

1g

16.5

4.9

8

1h

21.3

19.6

9

1i

19.5

-

Representative data on acyclic twisted amides: ref. 16c,d. Representative data on bridged lactams: ref.

18,16a,b. nd = not determined. 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 (∆PA) in ortho-substituted amides and representative amides were calculated (Table 4).18,16a,b Generally, planar amides undergo protonation at oxygen (e.g. in formamide, O-protonation is favored by 11.5 kcal/mol).20 In the case of orthosubstituted amides, proton affinity to nitrogen decreases with increasing ortho-substitution (e.g. in the series of 1e-1g, ∆ENPA 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, ∆EOPA of 4.3 kcal/mol). The net effect is that while these ortho-substituted amides still favor protonation at the oxygen atom, ∆PA values are in the range of ortho-unsubstituted analogues.

Table 4. Proton Affinities (PA) and Differences in Proton Affinities (∆ ∆PA) in Amides 1 (B3LYP/6311++G(d,p)))a ACS Paragon Plus Environment

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a

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NPA

OPA

∆PA

[kcal/mol]

[kcal/mol]

[kcal/mol]

1a

211.9

224.8

12.9

2

1b

nd

nd

nd

3

1c

nd

nd

nd

4

1d

216.2

228.6

12.4

5

1e

212.4

225.5

13.1

6

1f

217.9

227.2

9.3

7

1g

219.7

229.8

10.1

8

1h

217.3

230.3

13.0

9

1i

211.5

224.1

12.6

entry

1

1

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: ref. 16c,d. Representative data on bridged lactams: ref. 18,16a,b.

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-chloro 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 non-existent to >20 kcal/mol by a judicious choice of amide bond substitution. Further work on structural and


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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.

Acknowledgements.

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 generous financial support. We thank the Wroclaw Center for Networking and Supercomputing (grant no. WCSS159, R.S.).

Supporting Information. Cartesian coordinates and energies. Detailed description of computational methods used. CIF files for amides 1a-1c. This material is available free of charge via the Internet at http://pubs.acs.org.

Author Information. Corresponding author: [email protected] References (1) Greenberg, A.; Breneman, C. M.; Liebman, J. F., Eds. The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science; 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, ACS Paragon Plus Environment

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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) Bridged lactams: (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. Acyclic amides: (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, 1414.


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(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. Thermodynamics 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) Morgan, J.; Greenberg, A.; Liebman, J. F. Struct. Chem. 2012, 23, 197. (e) 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.


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Barriers to Rotation in ortho-Substituted Tertiary Aromatic Amides

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