Stereochemical Analysis of Tertiary Trifluoroacetamides Leveraging Both Through-Space ¹H···¹⁹F Spin–Spin Couplings and Anisotropic Solvent-Induced Shifts

Abstract

In this study, the assignment of E/Z-isomers of N,N-dialkyl trifluoroacetamides (1–8) is investigated by using ¹H-nuclear magnetic resonance spectroscopy, and data pertaining to both through-space spin–spin couplings (TSCs) and aromatic solvent-induced shifts (ASISs) are utilized to develop a reliable and convenient approach for determining the stereochemistry of these isomers. Although TSCsobserved when the F from the CF₃ group is spatially close to protonsalone may be useful for determining E/Z isomers, through-bond couplings (TBCs) are also observed when the proton is five bonds apart from the F in the CF₃ group. Thus, an additional one-dimensional ¹H–¹⁹F heteronuclear Overhauser enhancement spectroscopy (HOESY) experiment is required to distinguish between the TSCs and TBCs. By contrast, the ASIS results for all compounds are consistent with the general observation that C₆D₆ preferentially shifts trans-methyl/methylene protons to the carbonyl oxygen atom over cis-methyl/methylene protons. Additionally, the ASISs with C₆F₆ of compounds 4–8 are analyzed to demonstrate the reliability of the ASIS-based method. Considering that ¹H–¹⁹F HOESY experiments are somewhat specialized and uncommon, factoring both the TSCs and ASISs during the deduction process proves highly effective for determining the stereochemical assignment of E/Z-isomers of N,N-dialkyl trifluoroacetamides.

Introduction

Recent studies have uncovered the remarkable chemical, physical, and biological properties of F, with more than 20% of currently manufactured drugs containing the F atom. Elucidating the steric and electronic effects of fluorine substituents in the molecular structures of drugs is therefore necessary for a rational drug design. In this context, we investigated the stereochemical structures of trifluoroacetamide compounds, N-acyl 5H dibenzo­[b,d]­azepin-7­(6H)-ones, expecting that the amide-derived E/Z conformations would significantly affect immunosuppressive activity by inhibiting the potassium channels (Kv1.3, IK-1) in T cells. To elucidate the steric and electronic effects of F substituents on the molecular structures of drugs, factoring the concept of through-space spin–spin couplings (TSCs) proves useful. TSCs are observed between two atoms when either possesses lone-pair electrons, and both are constrained at a distance smaller than the sum of their van der Waals radii. Two nuclei, such as ¹⁹F/¹⁹F, ¹⁹F/¹H, or ¹⁹F/¹³C, can exchange spin information through space when in van der Waals contact, regardless of the number of chemical bonds separating them. Our previous research on the conformation of F-containing molecules factored the TSC principle to differentiate between E/Z isomers. Specifically, in that study, the assignment of the ¹H-nuclear magnetic resonance (NMR) signals of N,N-dimethyl trifluoroacetamide (DMTFA) 1 was elucidated on the basis of the TSCs.

Conventionally, the relative chemical shifts of N-methyl groups in tertiary amides have often been rationalized in terms of the anisotropic effect of the carbonyl group, with the downfield-shifted methyl group frequently assigned as being cis to the amide carbonyl oxygen. However, in our previous study, the TSC arising from CF₃ was observed corresponding to the peak at a lower chemical shift, indicating that this methyl group was located on the side opposite to the amide carbonyl group. On the basis of the ¹H–¹⁹F heteronuclear Overhauser spectroscopy (HOESY) experiment for 1, we concluded that the signal at a lower magnetic field (3.14 ppm) corresponded to the trans-methyl group, and it followed that the signal at the upper magnetic field (3.05 ppm) corresponded to the cis-methyl group (Figure ). However, at that stage, we did not consider the possibility that not only TSCs but also through-bond couplings (TBCs) could contribute to the observed interactions. It was subsequently recognized that the coupling constant (⁵ J _HF) of cis-methyl/trans-methyl in compound 1 had not been adequately verified.

1.

N,N-Dimethyl trifluoroacetamide 1.

These studies prompted us to examine the stereochemical assignment of N-alkyl protons of N,N-disubstituted trifluoroacetamides on the basis of the TSCs. In this study, ¹H–¹⁹F HOESY experiments and aromatic solvent-induced shifts (ASISs) are leveraged to complement the TSC results, as extra verifications are needed to differentiate TSCs and TBCs that arise similar to TSCs. Despite the fact that these HOESY experiments are reliable, they are not commonly performed. By contrast, the ASIS-based method is a fundamental and useful method that has been utilized for over 50 years. This method is based on the well-known observation that the chemical shifts in the NMR spectra of organic molecules change depending on the solvent used. In an anisotropic solvent (e.g., C₆D₆), the NMR signals shift upfield when compared to their shifts in an isotropic solvent (e.g., CDCl₃). Such chemical shifts caused by solvents possessing different magnetic properties are defined as ASISs (Δδ): Δδ = δ_S – δ_AS, where δ_S is the position of the signal of an H atom in an isotropic solvent (e.g., CDCl₃) and δ_AS is the corresponding value for the same signal in an anisotropic solvent (e.g., C₆D₆). Considering the ASIS (Δδ) observed in ¹H NMR experiments, the position of the H atoms relative to the carbonyl group was predicted, which is known as the carbonyl planar rule. Based on this rule, cis/trans-methyl or methylene was assigned to the carbonyl group of the tertiary acetamides based on the value of Δδ.

Results and Discussion

Initially, the assignment of the ¹H NMR signals of N,N-dimethyl trifluoroacetamide (DMTFA) 1 in CDCl₃ was reexamined. Although the assignment of each methyl peak was ultimately determined, the question remained as to why a slight doublet coupling was observed for the cis-methyl peak (Figure (a)). Therefore, these peaks were reexamined more closely.

2.

(a) ¹H NMR spectrum of 1 (400 MHz, CDCl₃) and (b) ¹H NMR spectrum of 1 (400 MHz, CDCl₃) after application of the sine bell window function.

The peak of the methyl group trans to the amide carbonyl group was observed as a broad signal. Upon application of a sine bell window function, a commonly applied NMR data-processing technique to enhance spectral resolution, both methyl peaks appeared as quartets, indicating the presence of ¹H–¹⁹F couplings (Figure (b)). The coupling constant of cis-methyl (⁵ J _HF = 0.8 Hz) is smaller than that of trans-methyl (⁵ J _HF = 1.6 Hz). Considering that both protons were five bonds apart from the F in the CF₃ group, TBCs were observed. Additionally, to distinguish TSCs from TBCs, 1 was subjected to ¹H–¹⁹F HOESY experiments (Figure ).

3.

¹H–¹⁹F HOESY built-up curves (irradiation at – 69.573 ppm: ¹⁹F signal) (600/564 MHz, CDCl₃) of 1.

In Figure , trans-methyl (3.14 ppm), which has a steeper slope than that of cis-methyl (3.05 ppm), is spatially closer to CF₃. This result confirms that trans-methyl exhibits TSCs, cis-methyl exhibits TBCs, and the coupling constant of TSC (⁵ J _HF = 1.6 Hz) is larger than that of TBC (⁵ J _HF = 0.8 Hz). This suggests that the ⁵ J _HF coupling depends on the spatial distance dependence. To clarify this point, DFT calculations were performed to determine the most stable conformation of compound 1, and the distances between the F atoms of CF₃ and the hydrogen atoms of the cis- and trans-methyl groups were calculated (Supporting Information Figure S23). The H···F distance between cis-methyl H and CF₃ F was 4.543 Å, and the H···F distance between trans-methyl H and CF₃ F was 2.431 Å. These results indicate that the trans-methyl group, which is closer to the F atom, exhibits stronger TSC coupling. Notably, the peak of cis-methyl, which is located close to the carbonyl oxygen, appears corresponding to the upper magnetic field as opposed to that of trans-methyl.

As part of our further investigations of the ASIS on 1, cis-methyl and trans-methyl peaks were observed in C₆D₆ at 2.24 and 2.12 ppm (Supporting Information Figure S1), with ASIS (Δδ) values of 0.81 and 1.02, respectively. Evidently, the ASIS (Δδ) value of trans-methyl is larger than that of cis-methyl (Figure ). This result is consistent with the carbonyl planar rule, which states that anisotropic solvent shifts of methyl protons trans to the carbonyl oxygen atom are larger than those oriented cis to the oxygen.

4.

ASIS (Δδ) of the methyl groups of 1. Chemical shifts: up in CDCl₃, down in C₆D₆ Δδ values: 0.81 (cis), 1.02 (trans).

Subsequently, we investigated the ¹H NMR spectra of N,N-diethyl trifluoroacetamide 2. However, the methylene proton signals of cis/trans ethyl groups in CDCl₃ could not be distinguished because of overlap, although the methyl signals were distinctly separated (Supporting Information Figure S3). The methylene protons of the cis/trans ethyl groups in C₆D₆ were well separated (Supporting Information Figure S5), and applying a sine bell window function enabled the calculation of the Δδ values (Figure ).

5.

¹H NMR spectrum of 2 (400 MHz, C₆D₆) after sine bell window function processing. Δδ values: 0.55 (A), 0.68 (B), 0.44 (C), 0.65 (D).

Signal (A) (2.89 ppm) was observed as a simple quartet with a lower chemical shift than signal (B) (2.76 ppm), which was observed as a quartet of quartets. These signals correspond to the methylene protons of the ethyl groups. Signal (A) was split into a simple quartet owing to coupling with the adjacent methyl group, and no TSC/TBC with the F of CF₃ was observed. By contrast, the signal (B) was observed as a quartet of quartets (⁵ J _HF = 1.2 Hz) because of the TSC from CF₃. For the methyl protons, signal (C) (0.76 ppm) was observed as a simple triplet with a chemical shift lower than that of signal (D) (0.59 ppm), which appeared as a doublet of triplets. Because the methyl protons are six bonds from the F of the CF₃ group, a TBC between them would be impossible. Given this consideration, the upperfield methyl signal (D) was assumed to be that of the trans-methyl group, which is close to CF₃, with a small TSC.

The origin of the small couplings observed in signals (B) and (D) was further verified via HOESY spectroscopy; the slope of (B) was observed to be the steepest, followed by those of (D), (A), and (C) (Figure ). From these results, it was concluded that the small couplings of signals (B) and (D) were due to TSC; thus, signal (B) at the upper magnetic field corresponded to the trans-methylene group, and signal (A) at the lower magnetic field corresponded to the cis-methylene group. Similarly, the signal (D) at the upper magnetic field corresponded to the trans-methyl group and the signal (C) at the lower magnetic field corresponded to the cis-methyl group.

6.

¹H–¹⁹F HOESY built-up curves (irradiation at –69.377 ppm: ¹⁹F signal) (600/564 MHz, C₆D₆) of 2.

Contrary to the case of N,N-dimethyl trifluoroacetamide 1, signals (B) and (D), which were trans to the carbonyl oxygen, were observed at a magnetic field higher than those cis to the oxygen. Notably, however, the spectrum of 2 in Figure was obtained using C₆D₆ as the solvent.

Next, we investigated ASIS on 2. For the cis-methylene group (A), the ASIS (Δδ) was 0.55, and that of the trans-methylene group (B) was 0.68, indicating a larger ASIS (Δδ) value of the trans-methylene group than that of the cis-methylene group. Similarly, the ASIS (Δδ) value of the cis-methyl group was 0.44, and that of the trans-methyl group was 0.65, indicating a larger ASIS (Δδ) value of the trans-methyl group than that of the cis-methyl group (Figure ). This result is consistent with the carbonyl planar rule, which states that the anisotropic solvent shifts of the protons trans to the carbonyl oxygen atom are greater than those of the cis protons.

Notably, in the ¹³C­{¹H} NMR spectrum (and contrary to the ¹H NMR spectrum), each peak of the trans-methylene/methyl group, assigned based on the heteronuclear single quantum coherence (HSQC) spectrum (Supporting Information Figure S7), appeared at a magnetic field lower than that for peaks shown by the cis-methylene/methyl group (Figure ). Furthermore, the signal of trans-methylene was observed as a broad quartet (⁴ J _CF = 3.4 Hz) considering the TSC between C and F.

7.

¹³C­{¹H} NMR spectrum of 2 (100 MHz, C₆D₆).

Additionally, the assignment of the ¹H NMR signals of N-benzyl-N-methyl trifluoroacetamide 3 in CDCl₃ was examined. In this case, compound 3 was observed to exist as an equilibrium mixture of E/Z amide rotamers (3-I and 3-II) in a 2:1 ratio (Figure (a)). Moreover, the benzyl methylene protons of both E/Z amide rotamers were observed as broad signals. On the contrary, of the signals corresponding to the methyl groups, the one at a lower magnetic field was observed as a clear quartet, and the other appeared as a slightly broad signal. Upon application of the sine bell window function, signals (A), which corresponded to the methylene group of 3-I, and signal (B), which corresponded to the methylene group of 3-II, remained broad. However, signal (C), which corresponded to the methyl group of the major isomer (3-I), and signal D, which corresponded to the minor isomer (3-II), were observed as well-defined quartets (Figure S8).

8.

(a) ¹H NMR spectrum of 3 (400 MHz, CDCl₃). (b) ¹⁹F-decoupled ¹H NMR spectra of 3 (400 MHz, CDCl₃). Δδ values: 0.55 (A), 0.73 (B), 0.79 (C), 0.57 (D).

To confirm that the splitting of signals C and D was due to the F atoms, ¹⁹F-decoupled ¹H NMR experiments were performed. As shown in Figure (b), irradiation of ¹⁹F resulted in the simplification of their signal patterns to singlets; moreover, these experiments facilitated the calculation of the H–F coupling constants of signals C and D as 1.6 and 0.8 Hz, respectively. To confirm whether the couplings were due to TSC or TBC, we performed one-dimensional (1D) HOESY ¹H–¹⁹F experiments again.

Figure (a) shows the ¹H–¹⁹F HOESY built-up curves of 3-I observed in CDCl₃; the slope of C (methyl group) is evidently steeper than that of A (methylene group). Therefore, it is clear that the coupling of signal C is due to TSC. Thus, the major isomer of 3-I is Z-amide, in which the methyl group is close to CF₃. Similarly, Figure (b) shows that the slope of B (methylene group) is steeper than that of D (methyl group); thus, the minor isomer 3-II is E-amide, in which the methylene group is close to CF₃. To improve the reliability of these assignments, we examined the proton-decoupled ¹³C­{¹H} NMR spectrum of 3 (Supporting Information Figure S9), in which the signals were assigned according to the HSQC spectrum of 3 (Supporting Information Figure S10). The CH₂ of 3-II (52.9 ppm) and CH₃ of 3-I (34.2 ppm) were observed as broad quartets, whereas the CH₂ of 3-I (52.3 ppm) and CH₃ of 3-II (34.0 ppm) were observed as singlets. These results confirmed that each coupling observed in CH₂ of 3-II and CH₃ of 3-I was caused by TSC.

9.

¹H–¹⁹F HOESY built-up curves of 3. (a) Irradiation of major isomers 3-I at –69.52 ppm (¹⁹F). (b) Irradiation of minor isomers 3-II (600/564 MHz, CDCl₃) at –67.95 ppm (¹⁹F).

Subsequently, we investigated the ASISs on 3-I and 3-II ( Figure (a)). The ¹H NMR spectrum of 3 in C₆D₆ is shown in the Supporting Information (Figure S11). For 3-I, the value of ASIS (Δδ) of the methylene group was 0.55, and that of the methyl group was 0.79, indicating that the methyl trans to the amide carbonyl group had a larger ASIS (Δδ) value than that of the methylene group cis to the amide carbonyl group. Similarly, for 3-II, the ASIS (Δδ) value of the methylene group (0.73) was larger than that of the methyl group (0.57). Thus, the ASIS (Δδ) value of the methylene protons trans to the amide carbonyl group was larger than that of the methyl group cis to the amide carbonyl group. This result was consistent with the carbonyl planar rule (vide supra).

The results of ¹H NMR experiments on the tertiary trifluoroacetamide derivatives (1–3) are summarized as follows: (1) In compound 1 in CDCl₃, TSC was observed at the trans-methyl group close to the trifluoromethyl group, which was observed at a lower magnetic field, and the peak of the cis-methyl was observed at the upper magnetic field. (2) In compound 2 in C₆D₆, TSC was observed at the trans-methyl and trans-methylene groups close to the trifluoromethyl group; however, each peak was observed at a magnetic field higher than those of the peaks of the cis-methyl and methylene. (3) In CDCl₃, between the methyl groups of 3-I and 3-II, the trans-methyl group of 3-I, which exhibited TSC owing to the trifluoromethyl group, was observed at a lower magnetic field than that of the cis-methyl group of 3-II. By contrast, the cis-methylene group of 3-I was observed at a magnetic field lower than that of the trans-methylene group of 3-II. Considering the above results (1) and (3), for some cases of tertiary trifluoroacetamide derivatives, such as compound 1 in CDCl₃, the trans-methyl was observed at a lower magnetic field than that of the cis-methyl; in other cases, such as for compound 2 in C₆D₆, the trans-methyl and trans-methylene were observed at a higher field than that of the cis-methyl and cis-methylene, respectively. Overall, the assignment of the ¹H NMR signals of N,N-dialkyl trifluoroacetamide and the distinction of cis/trans rotamers based on the conventional anisotropic effect of the carbonyl group are not reliable. In contrast, the TSC is based on spatial distance and therefore appears to be useful to consider. However, TBC should also be factored if the protons are five bonds apart from F in the CF₃ group. As we have shown, the HOESY measurements can distinguish between TBC and TSC; however, these experiments are somewhat sophisticated and therefore less commonly utilized. When both TSC and TBC were observed, such as in the cis/trans-methyl groups of compound 1 (Figure (b)) and compound 3 (Figure (a)), the coupling constant of TSC being larger than that of TBC should aid the differentiation between TSC and TBC. Additionally, examining the classical ASIS proves helpful. For compounds 1–3, the ASIS-based assignment was reliable, consistent with the general carbonyl planar rule (vide supra).

Therefore, we decided to distinguish between cis/trans rotamers of trifluoroacetamide derivatives 4–8 using two methods: (1) Classical ASIS and (2) comparison of the coupling constants derived from the TSC and TBC. First, the NMR spectra of CDCl₃ and C₆D₆ were measured for each compound (Figures S13–S22) to determine ASIS. For all the cis/trans rotamers of compounds 4–8 (N-Me and N-CH₂−), the ASIS (Δδ) value of the methyl/methylene group trans to the amide carbonyl group was expected to be larger than that of the group cis to the amide carbonyl group. Given this expectation, the cis and trans isomers were estimated by comparing the ASIS (Δδ) values for the protons (α/α’), which were five bonds apart from F in the CF₃ group (Figure (a), Table S1). N-Methyl-N-propyl trifluoroacetamide 4, N-ethyl-N-benzyl trifluoroacetamide 5, N-benzyl-N-propyl trifluoroacetamide 6, N-ethyl-N-propyl trifluoroacetamide 7, and N-allyl-N-methyl trifluoroacetamide 8 in C₆D₆/CDCl₃ exist as equilibrium mixtures of cis/trans rotamers (4-I/4-II, 5-I/5-II, 6-I/6-II, 7-I/7-II, and 8-I/8-II) in various ratios.

10.

(a) ASIS (CDCl₃/C₆D₆) spectrum of compounds 4–8. Δδ values for 4-I: 0.86 (α), 0.56 (α′), Δδ values for 4-II: 0.65 (α), 0.70 (α′), Δδ values for 5-I: 0.56 (α), 0.42 (α′), Δδ values for 5-II: 0.40 (α), 0.59 (α′), Δδ values for 6-I: 0.44 (α), 0.37 (α′), Δδ values for 6-II: 0.28 (α), 0.52 (α′), Δδ values for 7-I: 0.67 (α), 0.46 (α′), Δδ values for 7-II: 0.54 (α), 0.60 (α′), Δδ values for 8-I: 0.80 (α), 0.59 (α′), Δδ values for 8-II: 0.61 (α), 0.77 (α′). (b) ASIS (CDCl₃/C₆F₆) of compounds 4–8. Δδ values for 4-I: −0.23 (α), −0.10 (α′), Δδ values for 4-II: −0.11 (α), −0.22 (α′), Δδ values for 5-I: −0.20 (α), −0.03 (α′), Δδ values for 5-II: −0.08 (α), −0.15 (α′), Δδ values for 6-I: −0.18 (α), −0.02 (α′), Δδ values for 6-II: −0.03 (α), −0.13 (α′), Δδ values for 7-I: −0.23 (α), −0.11 (α′), Δδ values for 7-II: −0.11 (α), −0.22 (α′), Δδ values for 8-I: −0.23 (α), −0.07 (α′), Δδ values for 8-II: −0.10 (α), −0.19 (α′).

For each isomer, the proton exhibiting the larger ASIS (Δδ) value was assigned a trans configuration to the amide carbonyl group. This assignment allowed us to estimate the cis/trans ratios of the rotamers of 4–8. To further verify this, the coupling constant of ¹H–¹⁹F coupling in C₆D₆ was determined for the protons (α/α′), which are five bonds apart from the F in CF₃ (Table ). In compound 4-II, the α′-protons closer to the trifluoromethyl groupwhich is trans-methylene to the amide carbonyl grouphad a larger coupling constant (1.2 Hz) than that of the α-protons (0.4 Hz). Similarly, in compounds 8-II, the α′-protons, trans-methylene to the amide carbonyl group, closer to the trifluoromethyl group, showed a larger coupling constant (1.2 Hz) than that of the α-protons (0.8 Hz). For all other isomers except compounds 5-II and 6-II, ¹H–¹⁹F couplings (0.8–1.6 Hz) derived from TSC were observed for the protons spatially close to the trifluoromethyl group but not for the protons cis to the amide carbonyl group; this implies that no TBC was observed in these protons either. These results are consistent with the fact that the coupling constant of TSC is larger than that of TBC. For compounds 5-II and 6-II, in which TSC-derived ⁵ J _HF couplings were not observed, stable conformations were determined by DFT calculations, and the distances between the F atom of the trifluoromethyl group and the H atom at the benzyl position were calculated (Supporting Information Figures S24–S25). As a result, the distances between the F atom and the H atom at the benzyl position in compounds 5-II and 6-II were found to be almost the same as the distance between the F atom of the trifluoromethyl group and the H atom of the methyl group in compound 1. Therefore, in this case, TSCs may not be observed due to the influence of the electronic effects of the benzene ring. Further consideration of this point is required.

1. ¹H–¹⁹F Coupling Constants of Compounds 4–8 in C₆D₆ .

	1H–19F coupling constants (Hz)
compound	trans	cis
4-I	α: 1.6	α′: not observed
4-II	α′: 1.2	α: 0.4
5-I	α: 1.2	α′: not observed
5-II	α′: not observed	α: not observed
6-I	α: 0.8	α′: not observed
6-II	α′: not observed	α: not observed
7-I	α: 1.2	α′: not observed
7-II	α′: 1.2	α: not observed
8-I	α: 1.6	α′: not observed
8-II	α′: 1.2	α: 0.8

Furthermore, the ASIS was calculated by considering C₆F₆ instead of C₆D₆. Protons at the positive end of the dipole are shielded in C₆D₆ and deshielded in C₆F₆, whereas the opposite occurs for protons at the negative end. Consequently, the direction of the C₆F₆-induced shift is opposite that of the C₆D₆-induced shift. The carbonyl planar rule also reportedly holds true for ASIS with both C₆F₆ and C₆D₆, although the value of ASIS (Δδ) in this case: Δδ = δ_CDCl3 – δ_C6F6 is negative. The ASIS values of the α- and α′-protons of the compounds 4–8 exhibit a general trend, i.e., the ASIS phenomena are reversed for the C₆F₆ effects (Figure (b)). Additionally, the ASIS values of all of the protons of compounds 1–8 also show a general trend for the C₆F₆ effects (Supporting Information Table S2). Ultimately, as mentioned earlier, the configuration of cis/trans rotamers of trifluoroacetamide derivatives 4–8 was determined based on TSC in addition to ASIS.

Conclusion

For the assignment of N,N-dialkyl trifluoroacetamides (1–3), a conventional method based on the anisotropic effect of the carbonyl group was proven to be unreliable. Therefore, a combination of TSC and ASIS for determining the assignment was investigated in this study. Notably, TSC and TBC could be observed for protons that were five bonds apart from F in the CF₃ group. In such cases, the observed ¹H–¹⁹F coupling constants for TSC being larger than those of TBC proved to be useful for the analyses, and the additional 1D ¹H–¹⁹F HOESY experiments provided solid evidence for verification. We confirmed that for compounds 2–8, the observed TSCs were always larger than the TBCs, and the additional 1D ¹H–¹⁹F HOESY experiments provided further evidence to verify this observation. Additionally, the ASIS (CDCl₃/C₆D₆) in compounds 1 −3 supported the assignments deduced from the TSC. These experiments clarified that methyl/methylenes, which are trans to the amide carbonyl groups, have larger ASIS (Δδ) values than those cis to the amide carbonyl groups. The stereochemistry of the cis/trans rotamers of trifluoroacetamide derivatives 4–8 was also verified by considering the ASIS (CDCl₃/C₆D₆). Additionally, the ASIS (CDCl₃/C₆F₆) of compounds 4–8 also supported the aforementioned conclusion.

For the assignments of N,N-dialkyl trifluoroacetamides, the TSC supported by ¹H–¹⁹F HOESY experiments proved to be reliable, although the HOESY experiments require specialized measurements. In contrast, TSC and ASIS can be more easily obtained using conventional 1D techniques. However, there are cases where TSC is not observed; in such cases, it will be necessary to verify with a larger number of compounds if it is acceptable to determine the stereochemistry of N,N-dialkyl trifluoroacetamides using ASIS alone. Despite the phenomena of both TSC and ASIS being known for a long time, they have not been exploited significantly in recent years. Our method, which combines TSC and ASIS, is therefore expected to be applicable to the determination of cis/trans configurations in other tertiary trifluoroacetamides. Improvements to this method will be reported in the future.

Experimental Section

Materials

Compounds 1–8 were purchased and used.

General Methods

The NMR spectra were recorded on a spectrometer at 400 MHz for ¹H NMR, and at 100 MHz for ¹³C­{¹H} NMR; additionally, ¹⁹F NMR spectra were recorded at 564 MHz. The chemical shifts were expressed in parts per million (ppm) downfield from tetramethylsilane as the internal standard, and the coupling constants (J) were reported in hertz (Hz). The splitting patterns are abbreviated herein as follows: singlet (s), doublet (d), triplet (t), quartet (q), sextet (sext), doublet of quartet (dq), triplet of quartet (tq), quartet of quartet (qq), and multiplet (m). The structural assignments were performed using additional information obtained from correlation spectroscopy (COSY), nuclear Overhauser effect spectroscopy (NOESY), and HSQC experiments. NMR measurements were performed by dissolving 3 mg of the substrate in 0.6 mL of a deuterated solvent at 23 °C.

N,N-Dimethyltrifluoroacetamide (1) ,

Colorless oil

¹H NMR (400 MHz, CDCl₃) δ 3.14 (q, ⁵ J _HF = 1.6 Hz, 3H), 3.05 (q, ⁵ J _HF = 0.8 Hz, 3H).

¹H NMR (400 MHz, C₆D₆) δ 2.24 (q, ⁵ J _HF = 0.8 Hz, 3H), 2.12 (q, ⁵ J _HF = 1.6 Hz, 3H).

N,N-Diethyltrifluoroacetamide (2) ,

Colorless oil

¹H NMR (400 MHz, CDCl₃) δ 3.44 (q, J = 7.2 Hz, 2H), 3.44 (qq, J = 7.2, ⁵ J _HF = 1.2 Hz, 2H) 1.24 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H).

¹H NMR (400 MHz, C₆D₆) δ 2.89 (q, J = 7.2 Hz, 2H), 2.76 (qq, J = 7.2, ⁵ J _HF = 1.2 Hz, 2H), 0.76 (t, J = 7.2 Hz, 3H), 0.59 (t, J = 7.2 Hz, 3H).

N-Benzyl-N-methyltrifluoroacetamide (3) ,

Colorless oil

¹H NMR (400 MHz, CDCl₃) E-isomer: δ 7.41–7.30 (m, 3H), 7.22–7.20 (m, 2H), 4.63 (s, 2H), 2.92 (q, ⁵ J _HF = 0.8 Hz, 3H); Z-isomer: δ 7.41–7.30 (m, 3H), 7.27–7.23 (m, 2H), 4.64 (s, 2H), 3.05 (q, ⁵ J _HF = 1.6 Hz, 3H).

¹H NMR (400 MHz, C₆D₆) E-isomer: δ 7.04–6.98 (m, 3H), 6.73–6.69 (m, 2H), 3.90 (s, 2H), 2.35 (q, ⁵ J _HF = 0.4 Hz, 3H); Z-isomer: δ 7.04–6.98 (m, 3H), 6.95–6.91 (m, 2H), 4.09 (s, 2H), 2.26 (q, ⁵ J _HF = 1.6 Hz, 3H).

N-Methyl-N-propyltrifluoroacetamide (4)

Colorless oil

¹H NMR (400 MHz, CDCl₃) E-isomer: δ 3.36 (tq, J = 7.6 Hz, ⁵ J _HF = 1.2 Hz, 2H), 3.02 (q, ⁵ J _HF = 0.4 Hz, 3H), 1.63 (sext, J = 7.6 Hz, 2H), 0.93 (t, J = 7.6 Hz, 3H); Z-isomer: δ 3.41 (t, J = 7.6 Hz, 2H), 3.12 (q, ⁵ J _HF = 1.6 Hz, 3H), 1.66 (sext, J = 7.6 Hz, 2H), 0.93 (t, J = 7.6 Hz, 3H).

¹H NMR (400 MHz, C₆D₆) E-isomer: δ 2.66 (tq, J = 7.6 Hz, ⁵ J _HF = 1.2 Hz, 2H), 2.37 (q, ⁵ J _HF = 0.4 Hz, 3H), 0.96 (sext, J = 7.6 Hz, 2H), 0.41 (t, J = 7.6 Hz, 3H); Z-isomer: δ 2.85 (t, J = 7.6 Hz, 2H), 2.26 (q, ⁵ J _HF = 1.6 Hz, 3H), 1.09 (sext, J = 7.6 Hz, 2H), 0.55 (t, J = 7.6 Hz, 3H).

¹H NMR (400 MHz, C₆F₆) E-isomer: δ 3.58 (tq, J = 7.6 Hz, ⁵ J _HF = 1.2 Hz, 2H), 3.13 (q, ⁵ J _HF = 0.4 Hz, 3H), 1.93 (sext, J = 7.6, 2H), 1.17 (t, J = 7.6 Hz, 3H); Z-isomer: δ 3.51 (t, J = 7.6 Hz, 2H), 3.35 (q, ⁵ J _HF = 1.6 Hz, 3H), 1.80 (sext, J = 7.6 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H).

N-Benzyl-N-ethyltrifluoroacetamide (5)

Colorless oil

¹H NMR (400 MHz, CDCl₃) E-isomer: δ 7.40–7.28 (m, 3H), 7.26–7.21 (m, 2H), 4.62 (s, 2H), 3.37 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H); Z-isomer: δ 7.40–7.28 (m, 3H), 7.26–7.21 (m, 2H), 4.66 (s, 2H), 3.41 (qq, J = 7.2 Hz, ⁵ J _HF = 1.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H).

¹H NMR (400 MHz, C₆D₆) E-isomer: δ 7.06–6.98 (m, 3H), 6.79–6.77 (m, 2H), 4.03 (s, 2H), 2.97 (q, J = 7.2 Hz, 2H), 0.69 (t, J = 7.2 Hz, 3H); Z-isomer: δ 7.06–6.98 (m, 5H), 4.24 (s, 2H), 2.85 (qq, J = 7.2 Hz, ⁵ J _HF = 1.2 Hz, 2H), 0.59 (t, J = 7.2 Hz, 3H).

¹H NMR (400 MHz, C₆F₆) E-isomer: δ 7.40–7.20 (m, 5H), 4.77 (s, 2H), 3.44 (q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H); Z-isomer: δ 7.40–7.20 (m, 5H), 4.69 (s, 2H), 3.61 (qq, J = 7.2 Hz, ⁵ J _HF = 1.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H).

N-Benzyl-N-propyltrifluoroacetamide (6)

Colorless oil

¹H NMR (400 MHz, CDCl₃) E-isomer: δ 7.40–7.28 (m, 3H), 7.26–7.19 (m, 2H), 4.62 (s, 2H), 3.27 (t, J = 7.2 Hz, 2H), 1.56 (sext, J = 7.2 Hz, 2H), 0.86 (t, J = 7.2 Hz, 3H); Z-isomer: δ 7.40–7.28 (m, 3H), 7.26–7.19 (m, 2H), 4.66 (s, 2H), 3.27 (t, J = 7.2 Hz, 2H), 1.65 (sext, J = 7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H).

¹H NMR (400 MHz, C₆D₆) E-isomer: δ 7.07–6.99 (m, 3H), 6.82–6.79 (m, 2H), 4.10 (s, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.21 (sext, J = 7.6 Hz, 2H), 0.52 (t, J = 7.6 Hz, 3H); Z-isomer: δ 7.07–6.99 (m, 5H), 4.29 (s, 2H), 2.83 (tq, J = 7.6 Hz, ⁵ J _HF = 0.8 Hz, 2H), 1.10 (sext, J = 7.6 Hz, 2H), 0.41 (t, J = 7.6 Hz, 3H).

¹H NMR (400 MHz, C₆F₆) E-isomer: δ 7.39–7.19 (m, 5H), 4.75 (s, 2H), 3.33 (t, J = 7.6 Hz, 2H), 1.69 (sext, J = 7.6 Hz, 2H), 1.02 (t, J = 7.6 Hz, 3H); Z-isomer: δ 7.39–7.19 (m, 5H), 4.68 (s, 2H), 3.45 (t, J = 7.6 Hz, 2H), 1.91 (sext, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H).

N-Ethyl-N-propyltrifluoroacetamide (7)

Colorless oil

¹H NMR (400 MHz, CDCl₃) E-isomer: δ 3.45 (q, J = 7.2 Hz, 2H), 3.32 (tq, J = 7.2 Hz, ⁵ J _HF = 1.2 Hz, 2H), 1.64 (sext, J = 7.2 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H); Z-isomer: δ 3.45 (q, J = 7.2 Hz, 2H), 3.34 (t, J = 7.2 Hz, 2H), 1.64 (sext, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H).

¹H NMR (400 MHz, C₆D₆) E-isomer: δ 2.91 (t, J = 7.6 Hz, 2H), 2.72 (tq, J = 7.2 Hz, ⁵ J _HF = 1.2 Hz, 2H), 1.24 (sext, J = 7.2 Hz, 2H), 0.78 (t, J = 7.6 Hz, 3H), 0.45 (t, J = 7.6 Hz, 3H); Z-isomer: δ 2.88 (q, J = 7.2 Hz, 2H), 2.78 (qq, J = 7.2 Hz, ⁵ J _HF = 1.2 Hz, 2H), 1.04 (sext, J = 7.6 Hz, 2H), 0.59 (t, J = 7.2 Hz, 3H), 0.58 (t, J = 7.2 Hz, 3H).

¹H NMR (400 MHz, C₆F₆) E-isomer: δ 3.56 (q, J = 7.2 Hz, 2H), 3.54 (tq, J = 7.2 Hz, ⁵ J _HF = 1.2 Hz, 2H), 1.91 (sext, J = 7.2, 2H), 1.32 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H); Z-isomer: δ 3.68 (qq, J = 7.2 Hz, ⁵ J _HF = 0.4 Hz, 2H), 3.45 (t, J = 7.2 Hz, 2H), 1.76 (sext, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H).

N-Allyl-N-methyltrifluoroacetamide (8)

Colorless oil

¹H NMR (400 MHz, CDCl₃) E-isomer: δ 5.81–5.71 (m, 1H), 5.33–5.20 (m, 2H), 4.01 (dq, J = 6.0 Hz, ⁵ J _HF = 1.2 Hz, 2H), 3.00 (q, ⁵ J _HF = 0.8 Hz, 3H); Z-isomer: δ 5.81–5.71 (m, 1H), 5.33–5.20 (m, 2H), 4.05 (d, J = 6.0 Hz, 2H), 3.09 (q, ⁵ J _HF = 1.6 Hz, 3H).

¹H NMR (400 MHz, C₆D₆) E-isomer: δ 5.19–5.08 (m, 1H), 4.85–4.61 (m, 2H), 3.24 (dq, J = 6.0 Hz, ⁵ J _HF = 1.2 Hz, 2H), 2.39 (q, ⁵ J _HF = 0.8 Hz, 3H); Z-isomer: δ 5.34–5.23 (m, 1H), 4.85–4.61 (m, 2H), 3.46 (d, J = 6.0 Hz, 2H), 2.29 (q, ⁵ J _HF = 1.6 Hz, 3H).

¹H NMR (400 MHz, C₆F₆) E-isomer: δ 6.04–5.86 (m, 1H), 5.48–5.43 (m, 2H), 4.20 (dq, J = 6.0 Hz, ⁵ J _HF = 1.2 Hz, 2H), 3.10 (q, ⁵ J _HF = 0.8 Hz, 3H); Z-isomer: δ 6.04–5.86 (m, 1H), 5.40–5.34 (m, 2H), 4.12 (d, J = 6.0 Hz, 2H), 3.32 (q, ⁵ J _HF = 1.6 Hz, 3H).

The data underlying this study are available in the published article and Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.5c02877.

• ¹H NMR spectrum of 1 in C₆D₆, ¹³C­{¹H} NMR spectrum of 1 in C₆D₆, ¹H NMR spectra of 2 in CDCl₃, ¹³C­{¹H} NMR spectrum of 2 in CDCl₃, ¹H NMR spectrum of 2 in C₆D₆, ¹³C­{¹H} NMR spectrum of 2 in C₆D₆, HSQC spectrum of 2 in C₆D₆, ¹H NMR spectra of 3 in CDCl₃, ¹³C­{¹H} NMR spectrum of 3 in CDCl₃, HSQC spectrum of 3 in CDCl₃, ¹H NMR spectrum of 3 in C₆D₆, ¹³C­{¹H} NMR spectrum of 3 in C₆D₆, ¹H NMR spectrum of 4 (C₆D₆, CDCl₃), ¹H NMR spectrum of 5 (C₆D₆, CDCl₃), ¹H NMR spectrum of 6 (C₆D₆), ¹H NMR spectrum of 7 (C₆D₆), ¹H NMR spectrum of 8 (C₆D₆), ASIS of compounds 1–8 (ASIS (Δδ): Δδ = δCDCl₃ – δC₆D₆), ASIS of compounds 1–8 (ASIS (Δδ): Δδ = δCDCl₃ – δC₆F₆), NMR spectra of 4, NMR spectra of 5, NMR spectra of 6, NMR spectra of 7, NMR spectra of 8, calculation method, conformational search of 1, conformational search of 5-II, and conformational search of 6-II (PDF)

The authors declare no competing financial interest.