Noncovalent Interactions of Fluorine with Amide and CH2 Groups in N

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Noncovalent interactions of fluorine with amide and CH2 groups in N-phenyl #-lactams: Covalently identical fluorine atoms in non-equivalent chemical environments Ning Xi, Xiaohua Sun, Minxiong Li, Mingming Sun, Michael A Xi, Zeping Zhan, Jia Yao, Xu Bai, Yanjun Wu, and Min Liao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01562 • Publication Date (Web): 05 Sep 2018 Downloaded from http://pubs.acs.org on September 8, 2018

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The Journal of Organic Chemistry

Noncovalent interactions of fluorine with amide and CH2 groups in N-phenyl γ-lactams: Covalently identical fluorine atoms in non-equivalent chemical environments Ning Xi,†,‡,#,* Xiaohua Sun,† Minxiong Li,‡ Mingming Sun,‡ Michael A. Xi,# Zeping Zhan,‡ Jia Yao,‡ Xu Bai,† Yanjun Wu,‡ and Min Liao‡ † ‡ #

The School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, Jilin130021, China Sunshine Lake Pharmaceutical Co., Ltd, Dongyangguang Hi-tech Park, Dongguan, Guangdong 523871, China

Calitor Sciences LLC, PO Box 19185, Newbury Park, CA 91319-9185, USA

ABSTRACT: We designed and synthesized N-phenyl γ-lactam derivatives possesing two covalently identical ortho-F nucleus on N-phenyl group. The F nuclei sited in different chemical environments where they were spatially adjacent to amide and alkyl groups due to hindered rotation around central N-Ar bond. 19F NMR spectroscopic and X-ray crystallographic methods were used to distinguish the axially prochiral F nuclei and provide structural insights for through-space interactions between F and amide / CH2 groups. Direct spectroscopic evidences for multipolar interactions in F---amide and F---CH2 pairs were provided. INTRODUCTION The increasing uses of fluorine (F) in small molecule drugs and functional materials attracted considerable interests to study noncovalent interactions involving organic F.1 With inputs from crystallographic, spectroscopic and computational studies, we gathered much information regarding orthogonal multipolar interactions between F and amide groups, and hydrogen bonding-like interactions between F and α-CH in ligand-protein complexes. These soft and weak interactions are believed cooperative and flexible in nature, but can greatly contribute to the high affinity of fluorinated drugs in binding to targeted proteins.2 Recently, Dalvit and Vulpetti established that the preference of F to interact with amide and C-H groups depends on the chemical environments of F nuclei, which can be characterized by 19F NMR chemical shifts.3 While 19F NMR spectroscopy is capable of detecting chemical environment changes around F nuclei,4 direct spectroscopic evidence for the F---amide multipolar interactions remains elusive.5 Herein, we report our findings on noncovalent interactions between F and amide / CH2 groups based on 19F NMR spectroscopic and X-ray crystallographic studies. Evidence on amide's high fluorophilicity is revealed. Previously we reported that N-phenyl γ-lactams can form atropisomers if the ortho-substituents on the N-phenyl group were sufficiently bulky.6 In such a case, the repulsive interactions between ortho-substituents and C=O/CH2 groups from γlactam were strong enough to effectively restrict the rotation around central N-Ar bond. We discovered that the orthosubstituents engaged in close contacts with the adjacent amide and CH2 groups on the pyrrolidinone ring. Specifically, orthoF approached within the van der Waals radius of both C and O atoms from C=O group in F-substituted N-phenyl γ-lactams, as evidenced by X-ray crystal structures.6 We thus prepared di-ortho-F substituted N-phenyl γ-lactam

derivatives (compounds 1 - 8 in Table 1) to mimic noncovalent interactions between F and amides or α-CH groups in proteins. While compounds 1 - 2 contain no chiral centers, compounds (R)-3, (R)-4/(S)-4 and (R,S)-5/(S,S)-5 possess one and two carbon chiral centers, respectively. Therefore, the covalently identical ortho-F atoms in compounds 3 - 5 would be diastereotopic if rotations around central N-Ar bond were restricted, while the fluorines were enantiotopic in proatropisomeric compounds 1 and 2. As chemical shifts in 19F NMR spectra are sensitive to chemical environments, chiral di-ortho-F substituted N-phenyl γ-lactams can display two separated 19F NMR signals, and thus be used to study close interactions between F and its proximal functional groups. Table 1. Structures of compounds 1 - 8 and their chemical shifts

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F NMR

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RESULTS AND DISCUSSION N-Phenyl γ-lactams 1 - 8 were prepared according to the procedures described earlier.6,7 Enantiopure compounds (R)-3 and (S)-3 were obtained from racemic acid 3 using a chiral column chromatographic method. Enantiomers (R)-4 and (S)-4 were prepared from the corresponding acids (R)-3 and (S)-3, respectively. Compounds (R,S)-5 and (S,S)-5 were isolated from the diastereomeric mixture of 5 through a normal phase silica gel column chromatography. All the compounds were characterized by 1H, 13C and 19F NMR spectroscopy. The 1H NMR spectra of compounds (R,S)-5 and (S,S)-5 closely resembled to the related N-phenyl γ-lactams that we prepared previously.6 Accordingly, we assigned the chemical shifts of protons on γlactam ring in compounds (R,S)-5/(S,S)-5 and (R)-4/(S)-4 analogously. We next determined the single crystal structures of compounds 2, (R)-3 and (R,S)-5 by X-ray crystallography (CCDC1847236, 1510418, and 1510420, respectively, contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif). Figure 1 illustrates computer-generated drawings for the molecules with atomic numbering, and Table 2 provides structural parameters that define important distances between atoms and orientations of functional groups. Notably, C9-carbonyl groups (X-ray crystal structure numbering) in both (R)-3 and (R,S)-5 occupied pseudo-axial orientations, as confirmed by dihedral angles β1 and β2 that were in the vicinity of 90 o. Compound (R)3 displayed a large torsion angle between N-phenyl and lactam ring (ϕ1 = 76.95 o), directing one of the o-F nucleus (F2 as defined in Figure 1) on the same side with the C9-carboxylate group, and F1 on the opposite side of the lactam ring. The distance of F1 to C7 (lactam C=O, dF1-C7 = 3.19 Å) was comparable to the sum of van der Waals radii of C and F (Rw(F-C) = 3.17 Å), suggesting that there was a through-space interaction between F1 and C7. On the contrary, the torsion angle ϕ2 in compound (R,S)-5 was measured at -57.65 o, about 20 o less than that of (R)-3. An interesting structural feature in compound (R,S)-5 was that the benzyl group from chiral auxiliary pointed toward N-phenyl group, potentially causing steric interference between F2 and benzylic CH2 group.6 Hence, a smaller torsion angle was embraced in (R,S)-5 to avoid the 1,3-axial interaction between F2 and benzyl group, resulting in short distances from F2 to axial carbonyl (dF2-O2 = 3.71 Å) and benzylic CH2 (dF2-H16 = 3.92 Å). Presumably, stronger through-space interactions existed in (R,S)-5 because of small torsion angle ϕ2, as evidenced by close contacts between F1 and lactam CH2 (dF1-C8 = 2.97 Å), as well as between F2 and amide (dF2-C7 = 3.00 Å) (see Table 2). For achiral compound 2, the γ-lactam ring was almost flat and torsion angle ϕ2 (at -62.63 o) laid in the middle of ϕ values for (R)-3 and (R,S)-5. Close contacts between F and its neighbouring groups were also observed, as exemplified by the distances of F2 to lactam CH2 (dF2-C8 = 3.07 Å), and F1 to amide group (dF1-C7 = 3.05 Å).

2 (R)-3 (R,S)-5 Figure 1. Computer-generated drawings of crystal structures of 2, (R)-3 and (R,S)-5.

Table 2. Selected atom distances, dihedral angles, and torsion angles in the crystal structures of compounds 2, (R)-3 and (R,S)-5a

a

Sum of van der Waals radii: Rw(F-C) = 3.17 Å; Rw(F-O) = 2.99 Å; Rw(F= 2.67 Å.

H)

As indicated in the crystal structures of (R)-3 and (R,S)-5, and our previous data,6 the two covalently identical ortho-F atoms encountered different chemical environments. It is understandable that the conformations of N-phenyl γ-lactams in solution may differ from those in solid states due to crystal packing effects. Nonetheless, F1 and F2 would be in anti or syn position relative to C9 carbonyl if the rotation around NAr bond was restricted. This can be conveniently monitored by 19 F NMR spectra. We carried out 19F NMR studies on these compounds, and the selected spectra are illustrated in Figure 2a. The assignments of chemical shifts to the corresponding chiral compounds, as listed in Table 1, were based on the crystal structures of compounds (R)-3 and (R,S)-5. As expected, two distinct 19F NMR peaks in chiral compounds (R)-3, (R)4/(S)-4 and (R,S)-5/(S,S)-5 were observed.7 In contrast, achiral compounds 1 and 2 showed a single peak in their NMR spectra. Racemic ester 4 (mixture of (R)-4 and (S)-4) in CDCl3 solution displayed dual signals at -117.14 and - 117.93 ppm, which were also the same for enantiomers (R)-4 and (S)-4.


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The Journal of Organic Chemistry 311++G (2df, 2p) level of theory. In the calculations, molecular energies (E) at various torsion angles (ϕ used here corresponds to ϕ2 as defined in Table 2) were obtained with γlactam conformation optimized starting from the crystal structures of 2, (R)-3 and (R,S)-5. As shown in Figure 3, the ∆E-φ2 plots for these compounds were W-shaped, with the two tops appeared at φ2 = 0 o and 180 o. The lowest energies for all three molecules appeared at the same torsion angle of 60 o. According to the shapes at the curve bottoms, we anticipated that the N-phenyl group oscillated within ϕ2 values in the range of 60 120 o (where we arbitrarily set ∆E within 1 kcal/mol). Compound (R,S)-5 displayed a more shallow valley than 2 and (R)3 around ϕ2 = 60 o, allowing N-phenyl to stay close to 60 o for longer time and thereby for ortho-F nuclei to participate in stronger contacts with amide and CH2 groups. The calculation results proved that stronger through-space interaction existed in (R,S)-5 than that in (R)-3, validating the observations from X-ray crystal structures disclosed Figure 1.

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Figure 2. (a) F NMR spectra of compounds 1, (±)-3, (±)-4, (R,S)-5 and (S,S)-5 (chemical shifts in ppm, in CDCl3 with CFCl3 as an internal reference); (b) Correlations of torsion angles φ with F distances (in Å) to C=O and CH2 groups, and with 19F NMR chemical shifts.

The chemical shifts of 19F in N-phenyl γ-lactams were greatly affected not only by the substituent structures at C9carboxylate, but also by their chirality, as seen in diasteroisomers (R,S)-5 and (S,S)-5 with double signals at -117.28/117.47 ppm and -117.10/-117.42 ppm, respectively.8 Chemical shift differences in compounds (R)-3, (S,S)-5 and (R,S)-5 decreased from 0.75, 0.32 to 0.19 ppm (∆δ in Table 1), seemingly in accordance with the decreases of torsion angle ϕ (see Table 2b and reference 6, where S,S-configured N-phenyl γlactams possessed larger ϕ than its S,S-configured counterparts). Specifically, decreased torsion angles φ led to the upfield peaks moving down-field, while the down-field peaks moving up-field. The same phenomenon was also seen in nitro-substituted N-phenyl γ-lactam derivatives 6 and 7, but not in compound 8. Para-Nitro N-phenyl γ-lactams 6 and 7 exhibited the shift difference in 19F NMR at ∆δ = 0.18 ppm (R = H) and ∆δ = 0.29 ppm (R = Me) in CDCl3. This narrowed ∆δ corresponded to small trsion angle φ ~ 58 o (in 6, R = H, as determined by X-ray crystallography). In contrast, meta-nitro N-phenyl γ-lactam 8 displayed ∆δ = 0.81 ppm (for F ortho to NO2), and 0.74 ppm (for F para to NO2). To explore the range of torsion angles (φ) that were accessible to these N-phenyl γ-lactams, we computed rotational barriertorsion angle (∆E-φ) plots using a DFT method at B3LYP/6-

Figure 3. ∆E-φ2 Profiles for 2, (R)-3 and (R,S)-5 (∆E = E - Emin). In order to show the curves at the bottoms explicitly, the middle portions of the plot were omitted. See supplementary material for the complete figure.

The ∆E-ϕ2 plots revealed that the rotation barriers for compounds 2, (R)-3 and (R,S)-5 were in the range of 11 - 12 kcal/mol, suggesting that the free rotation was hindered at ambient temperatures on an NMR timescale, but might be achievable at elevated temperatures. To assess the atropisomeric integrity of di-ortho-fluorine substituted N-phenyl γlactams, we carried out variable temperature (VT) 19F NMR experiments on compound 4 in CDCl3 solution. As shown in Figure 4a, the coalescence temperature Tc could not be reached at the highest temperature (50 oC) available for CDCl3. Instead, broadened line-shapes were observed following temperature rises from -10 to 50 oC, signifying the converging trend of the 19F NMR peaks. Apparently, large 19F chemical shift differences in CDCl3 solution required high rotation rates to unify the separated 19F NMR signals in compound 4. In such a dynamic system, faster rotation rates were generally achieved at higher temperatures.9 To attain high temperatures, we decided to use pyridine-d5 as a solvent in VT-NMR studies. Surprisingly, the two 19F NMR peaks appeared 0.39 ppm apart in pyridine-d5 at 25 oC, much smaller than the chemical shift difference seen in CDCl3 at the same temperature. We predicted a lower Tc in this polar solvent. Indeed, the chemical shift differences between the two peaks in pyridine-d5 narrowed progressively with temperature escalated from 25 to 45 oC, along with broadened peak widths. The Tc for compound 4 was estimated at 50 oC in pyridine-d5, as shown in Figure 4b. Apparently, the smaller chemical shift



difference of the two 19F nuclei in pyridine-d5 led to lowered rotation barrier for N-Ar bond, as compared to the results obtained in CDCl3.11

Figure 4. Variable temperature 19F NMR spectra of 4: (a) in CDCl3; (b) in pyridine-d5. No internal CFCl3 was added.

The marked solvent effects on the splits of the 19F NMR peaks can be originated from either the solvent’s ability to solvate F nuclei (i.e., F solvation) or the solvent’s influence on molecule configurations (such as changes of ϕ values and γ-lactam conformations), or the combination of both. Nonetheless, the impacts of different solvents on 19F NMR signals reflected chemical environment fluctuations around F nuclei, which were related to the noncovalent interactions between F nuclei and amide/CH2 groups. Hence, we decided to examine 19F NMR spectra of compound 4 in various deuterated solvents, together with prototype molecule 1 as a reference. The chemical shifts of compounds 1 and 4 (δ1, δ4down and δ4up), the averages of the two 19F chemical shifts in compound 4 [δ4, ave = (δ4down + δ4up)/2], and the differences between the average chemical shifts of 4 and the chemical shift of 1 (∆δ4-1 = δ4, ave - δ1) are listed in Table 3. Table 3. Solvent effects on 19F NMR chemical shiftsa

a The concentration of compounds 1 and 4 were ~15 mg/mL in all solvents except in D2O, where the concentration of compound 1 was 3.6 mg/mL and 4 was 1.2 mg/mL. CFCl3 was added as an internal reference. See Supporting Information for chemical shifts in deuterated solvents without CFCl3.

As shown in Table 3, the 19F NMR chemical shifts of compounds 1 and 4 did not vary significantly in assorted solvents, ranging from -117.05 ppm in pyridine-d5 to -118.29 ppm in MeOD-d4 for compound 1, and from -116.57 to -118.07 ppm

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for compound 4.10 Notably, the values of ∆δ4-1 stayed in a narrow range of 0.22 to 0.32 ppm. We attributed the deshielding shifts ∆δ4-1 to the electron withdrawal effects of C9-ester, which were governed by torsion angle ϕ and the conformation of γ-lactam. Since ∆δ4-1 varied modestly in different solvents, the conformation changes of N-phenyl γ-lactam 4 appeared minimal. To calibrate the solvent’s effects on 19F NMR signals, we tabulated the chemical shift differences in compound 4 (∆δ4 = δ4down - δ4up), and the chemical shift changes between 4 and 1 for each F nucleus (∆δdown = δ4down - δ1 and ∆δup = δ4up - δ1). Also listed in Table 4 are solvents’ relative polarities and dipole moments. ∆δ4 measured the ability of a solvent to shelter a F nucleus from its chemical surroundings. While ∆δ4 altered significantly in different solvents,11 it revealed no apparent correlation with solvent’s relative polarity, or hydrogen bonding ability. Instead, an overt linear relationship between ∆δ4 and dipole moments (µ) was observed, as shown in Figure 5a. Obviously, less polar solvents generally promoted large disparity between the two 19F NMR peaks, as seen in benzene-d6 and CDCl3 solutions. ∆δ4 values shrank (i.e., the two 19F NMR signals converged) when dipole moments µ increased. Therefore, a solvent’s ability to shield a F nucleus from interacting with its proximal groups improved with the rise of solvent’s dipole moment. In fact, the impacts of neighbouring amide and CH2 groups on 19F chemical shifts diminished in DMF-d7 (∆δ4 = 0 ppm), establishing DMF as the most fluorophilic solvent among those we examined. DMF's strong solvating ability for organic F atoms has implications in fluorinated drugs binding to proteins since the amide bond in DMF resembles peptide bonds. It is often observed that binding potency increases when F atoms are incorporated into the drugs.13 Likely, the abundance of amide bonds in protein’s binding sites creates a fluorophilic environment to favourably accommodate drugs incorporated with F atoms. On the other hand, the nature of noncovalent interactions between F and its neighboring groups is diversified. Diederich et al in their landmark paper on fluorine in pharmaceuticals suggested that F participates in orthogonal multipolar interactions with C=O group,2a while the interactions between F and H may involve various mechanisms, such as F---H hydrogen bonding,3b,14 steric interactions (i.e., jousting interactions),16a as well as multipolar interactions.2a By inspecting 19F NMR chemical shifts and the X-ray structures of fluorinated molecules, Dalvit and Vulpetti established empirical correlations between the fluorine isotropic chemical shifts and the types of fluorine-protein interactions. Thus, deshielded F nuclei, i.e., with decreased electron density, were found preferentially in close contacts with the carbon of the carbonyl, while shielded F nuclei were observed favourably to interact with hydrogen bond donors of the protein. Applying this rule of “local environment of the fluorine” to our model molecules, we can assign the down-field 19F NMR signals (δ4down) to the F nucleus that engaged in noncovalent interactions with the amide, and the up-field signals (δ4up) to the F nucleus that involved in close contacts with the CH2 group. Accordingly, chemical shift differences ∆δdown and ∆δup compared the variations of F---amide and F---CH2 contacts in compounds 1 and 4. As illustrated in Figure 5b, ∆δdown displayed good linear relationship with dipole moments (µ), suggesting that the close contacts between F and amide were most likely multipolar interactions. Meanwhile, the ∆δup-µ linear


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curve exhibited poorer R2 value than ∆δdown-µ curve, signifying that there might be additional factors besides dipole components in affecting 19F chemical shifts.2a, 14, 16a It is interesting to note that the two linear curves possessed similar absolute slope (~0.117), but opposite direction trends with the changes of dipole moments, further supporting the notion that the two F nuclei participated in different types of noncovalent interactions (vide supra). The assignments of 19F NMR signals (δdown and δup) in Nphenyl γ-lactams were corroborated with the close contact information observed in the crystal structures of (R)-3 and (R,S)-5. For example, we can assign F1((R)-3) at -117.12 ppm and F2((R,S)-5) at -117.28 ppm, as F2((R,S)-5) engaged in closer contacts with the amide group than F1((R)-3). 19F signal at 117.87 ppm in compound (R)-3 was assigned to F2((R)-3), similar to the one in compound 1 (-117.82 ppm), as F2((R)-3) was not participated in any through-space interactions. F1((R,S)-5) was in close contacts with CH2 group, and its signal moved down-field at -117.47 ppm, as compared to F2((R)-3). Table 4. Relationships between 19F NMR chemical shift differences and solvent’s physical propertiesa

a The values of dipole moment (in Debye) and relative polarity were obtained from Christian Reichardt, "Solvents and Solvent Effects in Organic Chemistry", Wiley-VCH Publishers, 3rd ed., 2003. Deuteration effects were not accounted for in these solvents.

Figure 5. Plots of solvents’ dipole moment µ with 19F chemical shift difference: (a) down-field signals versus up-field signals, ∆δ4; and (b) upfield and down-field signals versus the reference signal, ∆δup and ∆δdown, respectively. Reference chemical shifts are from compound 1 in corresponding solvents; Chemical shift data from D2O were not used to generate the linear plots.15

Our 19F NMR spectroscopic data divulged that 19F signals were deshielded when F nuclei participated in close contacts with CH2 group. Such a signal shifting was well-documented for F nuclei that participated in close contacts with C-H groups, regardless of the interactions tracking weak hydrogen bonding3,12 or steric deshielding mechanisms.14,16a 19F NMR signals reflect the behavior of its p-electrons, and the deshielding effects imply that the p-electron cloud in F is either shared or restricted.10 Stronger interactions between F and CH2 group led to larger 19F down-field shift, however, such contacts may not be entirely attractive interactions.14,16 19 F NMR signals also shifted downfield when F nuclei engaged in noncovalent interactions with amide groups. We observed that smaller torsion angle φ led to smaller down-field shift (see Figure 2b). A 19F NMR signal can be compressive deshielded when a F nucleus and a carbonyl group were forced into proximity. For example, in a conformationally confined molecule where the C=O group and proximal F were sterically compressed, the 19F NMR peak manifested a downfield shift of 6.74 ppm.16b Similarly, the F nuclei in compound (R,S)-5 may experience compressive deshielding, as the auxiliary’s benzyl group pressed the ortho-F nuclei toward amide and CH2 groups. Presumably, short dF2-O1(amide) value led to repulsive interaction between F and C=O group, and reduced multipolar interactions. In flexible compounds such as (R)-3 and 4, attractive, multipolar interactions between F and amide may play important roles in shifting 19F NMR signals down-field, where the compressive deshielding effects diminished due to increased distances between F and amide groups. Thus, the differences of 19F NMR chemical shifts in (R)-3 and (R,S)-5 may be originated from different mechanisms, and were responsible for the observed relationship between φ and ∆δ.17 CONCLUSIONS In summary, we designed and synthesized N-phenyl lactam derivatives to study noncovalent interactions between F and amide/CH2 groups. X-ray crystal structures of compounds (R)3 and (R,S)-5 unambiguously demonstrated that the two o-F atoms sited in different chemical environments and engaged in close contacts with C=O and/or CH2 groups. 19F NMR spectra allowed us to distinguish covalently identical, but spatially



differentiated F nuclei in chiral compounds (R)-3 and (R,S)-5. More importantly, we found that the chemical shifts of F nuclei were greatly affected by various solvents. Our 19F NMR spectroscopic data suggested that the close contacts between F and amide groups were predominately multipolar interactions, the strengths of which were correlated with milieu’s dipole moments. Solvents with larger dipole moments (µ) such as DMF showed higher fluorophilic propensity than those with smaller µ such as benzene and CHCl3. Further studies to elucidate the strength and bonding nature of such noncovalent interactions are underway and will be reported in due course.

EXPERIMENTAL SECTION General Information Unless otherwise stated, all the reactions were carried out under atmosphere conditions. Anhydrous tetrahydrofuran (THF) was obtained by distillation over sodium benzophenone under nitrogen atmosphere. All other chemical reagents were purchased from commercial sources and used without further purification. Flash column chromatography was performed with Agilent Technologies Claricep FlashSilica. All 1H- and 13 C NMR experiments were carried out using a Bruker AVANCE 400 spectrometer or a Bruker AVANCE III 600 spectrometer at 298 K. Room temperature (at 298 K) 19F NMR data were recorded using a Bruker AVANCE 400 spectrometer and variable temperature 19F NMR experiments were undertaken with a Bruker AVANCE III 600 spectrometer. Chemical shifts in 1H, 19F and 13C NMR spectra are reported in parts per million (ppm). The residual solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl3: δ (H) = 7.26 ppm, δ (C) = 77.16 ppm) for 1H and 13C NMR spectra. For 19F NMR experiments at 298 K, CFCl3 was added as an internal reference (0.5% CFCl3). No internal standard was used in variable temperature 19F NMR experiments. All coupling constants (J values) were reported in Hertz (Hz). Multiplicities are reported as follows: singlet (s), doublet (d), doublet of doublets (dd), doublet of doublet of doublets (ddd), doublet of triplets (dt), triplet (t), triplet of doublets (td), quartet (q), and multiplet (m). High resolution mass spectra (HRMS) were obtained from an Agilent 6200 series TOF/6500 series spectrometer, using electrospray ionization (ESI) as an ion source. The purity of synthesized compounds and their MS spectra were assessed with an Agilent 1260 – 6120 spectrometer with an electrospray ionization (ESI) source, equipped with an Agilent SB-C18 (2.1*30 mm, 3.5 um) column. Purity assessments of compounds 3 and 5 were also carried out using Agilent 1260 HPLC spectrometer. Separations of chiral compound 3 to (R)-3 and (S)-3, diasteroisomer mixture of (R,S)-5 and (S,S)-5 to optical active compound (R,S)-5 and (S,S)-5 were performed using an Agilent 1260 HPLC spectrometer equipped with a chiral (Chiralpak, IC 10*250 mm,5 um) column. Specific rotation, [α]20D , was measured with Rudolph Research Analytical Autopol VI, serial number 90010. Single crystal X-ray diffraction data were collected with an Agilent Technologies Gemini A Ultra system (Cu Kα radiation, λ = 1.5418 Å). Melting point was measured with a Mettler-Toledo MP70. Compound Characterization

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1-(2,6-difluorophenyl)pyrrolidin-2-one (Compound 1): To a solution of 2, 6-difluoroaniline (533.4 mg, 4.13 mmol) and Et3N (613.8 mg, 6.01 mmol) in CH2Cl2 (8 mL) was added 4chlorobutanoyl chloride (1 mL, 8.94 mmol) dropwise at 0 oC. The reaction mixture was stirred at 25 oC for 3 h, quenched with water (30 mL) and extracted with CH2Cl2 (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 3/7) to give 4-chloro-N-(2,6difluorophenyl)butanamide (compound 1a) (886.8 mg, 92%) as a white solid. mp. 98.4 – 99.4 oC; MS (ESI, pos. ion) m/z: 234.0 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.217.16 (m, 1H, Ph), 7.08 (br. s, 1H, NH), 6.93 (t, J = 8.0 Hz, 2H, Ph), 3.65 (t, J = 6.0 Hz, 2H, CH2Cl), 2.60 (s, 2H, COCH2), 2.22-2.17 (m, 2H, CH2); 19F NMR (376 MHz, CDCl3): δ (ppm) -118.44 (s); 13C NMR (100 MHz, CDCl3): δ (ppm) 170.9 (s), 159.3 (d, J = 4.5 Hz), 156.8 (d, J = 4.5 Hz), 127.8 (s), 113.9 (t, J = 16.5 Hz), 111.7 (d, J = 22.9 Hz), 44.3 (s), 32.9 (s), 28.1 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C10H11ClF2NO 234.0497; Found: 234.0496. To a solution of compound 1a (2.24 g, 9.59 mmol) in DMF (20 mL) was added DBU (2.30 g, 15.11 mmol) at room temperature. The reaction mixture was heated at 100 oC and stirred overnight. The reaction was quenched with water (50 mL) and extracted with CH2Cl2 (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/5) to give compound 1 (1.66 g, 88%) as a pale yellow solid. mp. 49.6 – 52.8 oC; MS (ESI, pos. ion) m/z: 198.0 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.24-7.16 (m, 1H, Ph), 6.90 (t, J = 8.2 Hz, 2H, Ph), 3.69 (t, J = 7.0 Hz, 2H, CH2N), 2.49 (t, J = 8.1 Hz, 2H, COCH2), 2.23-2.16 (m, 2H, CH2); 19F NMR (376 MHz, CDCl3): δ (ppm) -117.82 (s); 13 C NMR (150 MHz, CDCl3): δ (ppm) 174.8 (s), 159.7 (d, J = 4.8 Hz), 158.0 (d, J = 5.4 Hz), 128.8 (t, J = 10.0 Hz), 115.5 (t, J = 16.4 Hz), 112.0 (dd, J = 19.6, 4.0 Hz), 49.2 (s), 30.2 (s), 19.2 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C10H10F2NO 198.0730; Found: 198.0732. 1-(2,6-difluoro-4-methylphenyl)pyrrolidin-2-one (Compound 2): To a solution of 2,6-difluoro-4-methylaniline (1.38 g, 9.64 mmol) and Et3N (3.91 g, 38.64 mmol) in CH2Cl2 (20 mL) was added 4-chlorobutanoyl chloride (3.6 mL, 32.17 mmol) dropwise at 0 oC. The reaction mixture was stirred at 25 oC for 6 h, quenched with water (50 mL) and extracted with CH2Cl2 (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 3/8) to give 4-chloro-N-(2,6-difluoro-4-methylphenyl)butanamide (compound 2a) (2.39 g, 100%) as a white solid. MS (ESI, pos. ion) m/z: 248.3 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.00 (br. s, 1H, NH), 6.74 (d, J = 8.7 Hz, 2H, Ph), 3.65 (t, J = 5.6 Hz, 2H, CH2Cl), 2.59 (s, 2H, COCH2), 2.32 (s, 3H, CH3), 2.23-2.14 (m, 2H, CH2); 19F NMR (376 MHz, CDCl3): δ (ppm) -119.69 (s). 13C NMR (100 MHz, CDCl3): δ (ppm)

170.7 (s), 159.0 (d, J = 4.4 Hz), 156.6 (d, J = 4.4 Hz), 139.2 (s), 112.3 (d, J = 22.0 Hz), 110.9 (t, J = 18.2 Hz), 44.4 (s), 33.0 (s), 28.2 (s), 21.4 (s). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H12ClF2NO 248.0654; Found: 248.0663.


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To a solution of compound 2a (2.61 g, 10.54 mmol) in DMF (20 mL) was added DBU (2.42 g, 15.90 mmol) at room temperature. The reaction mixture was heated at 100 oC and stirred overnight. The reaction was quenched with water (30 mL) and extracted with CH2Cl2 (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/PE (v/v) = 1/10 to 1/5) to give the crude product, which was beeten with EtOAc (5 mL) for 1 h and filtered to give compound 2 (1.39 g, 62%) as a white solid. MS (ESI, pos. ion) m/z: 212.3 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 6.90 (d, J = 8.8 Hz, 2H, Ph), 3.72 (t, J = 7.0 Hz, 2H, CH2N), 2.55 (t, J = 8.1 Hz, 2H, COCH2), 2.29-2.19 (m, 2H, CH2).19F NMR (376 MHz, CDCl3): δ (ppm) -119.21 (s).13C NMR (150 MHz, CDCl3): δ (ppm) 174.9 (s), 159.4 (d, J = 6.1 Hz), 157.7 (d, J = 6.1 Hz), 140.2 (t, J = 9.6 Hz), 112.6 (dd, J = 19.4, 3.8 Hz), 49.4 (s), 30.3 (s) , 21.4 (s), 19.2 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H12F2NO 212.0887; Found: 212.0885. 1-(2,6-difluorophenyl)-5-oxopyrrolidine-3-carboxylic acid. (Compound 3): A mixture of 2, 6-difluoroaniline (1.31 g, 10.11 mmol) and 2-methylenesuccinic acid (1.30 g, 9.99 mmol) was heated at 180 oC for 7 h in a sealed tube. The reaction vessel was then cooled to room temperature, and the crude product (yellow oil) was purified by a flash column chromatography (EtOAc/hexanes (v/v) = 1/2 to 2/1) to give compound 3 (1.14 g, 47%) as a yellow solid, which was separated by chiral stationary phase HPLC to give compound (R)-3 and compound (S)-3 as yellow solids. Slow diffusion of heptane into a saturated solution of compound (R)-3 in CHCl3 afforded single crystals suitable for X-ray diffraction experiments. Compound 3: mp. 140.8 – 141.9 oC; MS (ESI, pos. ion) m/z: 242.2 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.337.28 (m, 1H, Ph), 6.98 (t, J = 8.5 Hz, 2H, Ph), 4.04-3.95 (m, 2H, CH2N), 3.56-3.48 (m, 1H, CH), 2.92 (ABX, J = 17.5, 7.6, 9.7 Hz, 2H, COCH2); 19F NMR (376 MHz, CDCl3): δ (ppm) 117.11 (s), -117.86 (s); 13C NMR (100 MHz, CDCl3): δ (ppm) 176.4 (s), 172.76 (s), 160.3 (d, J = 4.9 Hz), 157.8 (d, J = 4.9 Hz), 129.6 (t, J = 9.9 Hz), 114.7 (t, J = 16.3 Hz), 112.3 (dd, J = 20.1, 2.6 Hz), 50.9 (s), 37.2 (s), 33.3 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H10F2NO3 242.0629; Found: 242.0627. Compound (R)-3: mp. 174.6 – 176.4 oC; MS (ESI, pos. ion) m/z: 242.0 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.34-7.28 (m, 1H, Ph), 6.99 (t, J = 8.6 Hz, 2H, Ph), 4.05-3.96 (m, 2H, CH2N), 3.57-3.49 (m, 1H, CH), 2.92 (ABX, J = 17.4, 7.6, 9.7 Hz, 2H, COCH2); 19F NMR (376 MHz, CDCl3): δ (ppm) -117.12 (s), -117.87 (s); 13C NMR (100 MHz, CDCl3): δ (ppm) 176.1 (s), 172.3 (s), 160.4 (d, J = 4.7 Hz), 157.8 (d, J = 4.6 Hz), 129.6 (t, J = 9.9 Hz), 114.8 (t, J = 16.7 Hz), 112.4 (dd, J = 20.3, 3.0 Hz), 50.7 (s), 37.1 (s), 33.2 (s); HRMS (ESITOF) m/z: [M + H]+ Calcd for C11H10F2NO3 242.0629; Found: 242.0631; [α]20D = -10.278o (c 0.515, CH3CN). Compound (S)-3: mp. 174.9 – 176.7 oC; MS (ESI, pos. ion) m/z: 242.0 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.34-7.28 (m, 1H, Ph), 6.99 (t, J = 8.6 Hz, 2H, Ph), 4.05-3.96 (m, 2H, CH2N), 3.57-3.49 (m, 1H, CH), 2.92 (ABX, J = 17.4, 7.6, 9.7 Hz, 2H, COCH2); 19F NMR (376 MHz, CDCl3): δ (ppm) -117.12 (s), -117.87 (s); 13C NMR (100 MHz, CDCl3): δ

(ppm) 176.1 (s), 172.3 (s), 160.4 (d, J = 5.1 Hz), 157.8 (d, J = 4.9 Hz), 129.6 (t, J = 9.9 Hz), 114.8 (t, J = 16.2 Hz), 112.4 (dd, J = 20.1, 3.0 Hz), 50.7 (s), 37.1 (s), 33.2 (s); HRMS (ESITOF) m/z: [M + H]+ Calcd for C11H10F2NO3 242.0629; Found: 242.0617; [α]20D = 11.687o (c 0.520, CH3CN). General procedure for methyl 1-(2,6-difluorophenyl)-5oxopyrrolidine-3-carboxylate (compound 4), (R)-4 and (S)4: To a solution of compound 3 in MeOH (5 mL) was added concentrated sulfuric acid (0.1 mL, 1.84 mmol). The reaction mixture was refluxed for 4 h and then concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/hexanes (v/v) = 1/10 to 1/2) to give compound 4. Compound 4: pale yellow solid, 504.2 mg, 81% yield; mp. 66.2 – 69.7 oC; MS (ESI, pos. ion) m/z: 256.2 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.30-7.23 (m, 1H, Ph), 6.96 (t, J = 8.5 Hz, 2H, Ph), 3.99-3.90 (m, 2H, CH2N), 3.76 (s, 3H, Me), 3.51-3.43 (m, 1H, CH), 2.85 (ABX, J = 17.3, 7.7, 9.6 Hz, 2H, COCH2); 19F NMR (376 MHz, CDCl3): δ (ppm) -117.14 (s), -117.93 (s); 13C NMR (100 MHz, CDCl3): δ (ppm) 172.6 (s), 172.2 (s), 160.3 (d, J = 4.9 Hz), 157.8 (d, J = 4.9 Hz), 129.4 (t, J = 9.9 Hz), 114.9 (t, J = 16.4 Hz), 112.2 (dd, J = 20.1, 3.1 Hz), 52.6 (s), 50.8 (s), 37.3 (s), 33.3 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H12F2NO3 256.0785; Found: 256.0800. Compound (R)-4: pale yellow oil, 90.1 mg, 89% yield; MS (ESI, pos. ion) m/z: 256.1 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.32-7.25 (m, 1H, Ph), 6.98 (t, J = 8.6 Hz, 2H, Ph), 4.01-3.91 (m, 2H, CH2N), 3.78 (s, 3H, Me), 3.53-3.44 (m, 1H, CH), 2.87 (ABX, J = 17.3, 7.8, 9.6 Hz, 2H, COCH2); 19 F NMR (376 MHz, CDCl3): δ (ppm) -117.14 (s), -117.94 (s); 13 C NMR (100 MHz, CDCl3): δ (ppm) 172.7 (s), 172.2 (s), 160.4 (d, J = 5.0 Hz), 157.8 (d, J = 4.8 Hz), 129.4 (t, J = 9.9 Hz), 115.0 (t, J = 16.3 Hz), 112.3 (dd, J = 19.9, 2.9 Hz), 52.7 (s), 50.9 (s), 37.4 (s), 33.4 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H12F2NO3 256.0785; Found: 256.0783; [α]20D = -8.647o (c 0.504, CH3CN). Compound (S)-4: pale yellow oil, 91.9 mg, 93% yield; MS (ESI, pos. ion) m/z: 256.0 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.32-7.25 (m, 1H, Ph), 6.98 (t, J = 8.5 Hz, 2H, Ph), 4.01-3.92 (m, 2H, CH2N), 3.78 (s, 3H, Me), 3.53-3.45 (m, 1H, CH), 2.87 (ABX, J = 17.3, 7.8, 9.6 Hz, 2H, COCH2); 19 F NMR (376 MHz, CDCl3): δ (ppm) -117.14 (s), -117.94 (s); 13 C NMR (100 MHz, CDCl3): δ (ppm) 172.7 (s), 172.2 (s), 160.4 (d, J = 4.9 Hz), 157.8 (d, J = 5.0 Hz), 129.4 (t, J = 10.0 Hz), 115.0 (t, J = 16.4 Hz), 112.3 (dd, J = 20.1, 2.9 Hz), 52.7 (s), 50.9 (s), 37.4 (s), 33.4 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H12F2NO3 256.0785; Found: 256.0776; [α]20D = 10.188o (c 0.525, CH3CN). (S)-4-benzyl-3-((R)-1-(2,6-difluorophenyl)-5-oxopyrrolidine-3-carbonyl)oxazolidin-2-one (Compound (R,S)-5) and (S)-4-benzyl-3-((S)-1-(2,6-difluorophenyl)-5oxopyrrolidine-3-carbonyl)oxazolidin-2-one (Compound (S,S)-5): To a solution of compound 3 (2.54 g, 10.5 mmol) in a mixture of CH2Cl2 (21 mL) and DMF (1 mL) was added oxalyl dichloride (3.6 mL, 43 mmol) dropwise at 0 oC. The reaction mixture was stirred at 25 oC overnight and concentrated in vacuo to give 1-(2,6-difluorophenyl)-5oxopyrrolidine-3-carbonyl chloride as yellow oil. The product was used in the next step without further purification.



To a solution of (4S)-4-benzyloxazolidin-2-one (1.55 g, 8.75 mmol) in dry THF (20 mL) was added LiHMDS (1 M in THF solution, 10 mL, 10 mmol) dropwise at -78 oC under a nitrogen atmosphere. The reaction mixture was continued to stir for 0.5 h and a solution of 1-(2,6-difluorophenyl)-5oxopyrrolidine-3-carbonyl chloride in dry THF (20 mL) was added. After addition, the reaction mixture was stirred for 1 h at -78 oC and for an additional hour at 25 oC. The reaction was then quenched with water (30 mL) and extracted with CH2Cl2 (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/hexanes (v/v) = 1/10 to 2/3) to give a yellow solid, which was separated by chiral stationary phase HPLC to give compound (R,S)-5 (1.46 g, 42%) and compound (S,S)-5 (0.72 g, 20%) as yellow solids. Slow diffusion of heptane into a saturated solution of compound (R,S)-5 in CHCl3 afforded single crystal suitable for X-ray diffraction experiments. Compound (R,S)-5: mp. 143.4 – 145.7 oC; MS (ESI, pos. ion) m/z: 401.2 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.30-7.26 (m, 4H, CH2Ph), 7.20 (d, J = 6.8 Hz, 2H, Ph-F2), 6.99 (t, J = 8.6 Hz, 2H, Ph-F2), 4.76-4.71 (m, 1H, CO2CH2), 4.48-4.41 (m, 1H, CO2CH2), 4.32-4.24 (m, 2H, CONCH2), 4.14 (t, J = 9.2 Hz, 1H, CH2Ph), 3.91 (dd, J = 9.8, 4.8 Hz, 1H, CH2Ph), 3.30 (dd, J = 13.3, 2.6 Hz, 1H, CHCH2Ph), 3.03 (dd, J = 17.2, 5.5 Hz, 1H, CHCONCO2), 288-2.81 (m, 2H, NCH2CH); 19F NMR (376 MHz, CDCl3): δ (ppm) -117.28 (s), -117.47 (s); 13C NMR (150 MHz, CDCl3): δ (ppm) 172.3 (s), 171.8 (s), 159.9 (d, J = 5.1 Hz), 158.2 (d, J = 5.1 Hz), 153.3 (s), 134.9 (s), 129.5 (s), 129.4 (t, J = 9.9 Hz), 129.1 (s), 127. 7 (s), 114.9 (t, J = 16.3 Hz), 112.3 (dd, J = 20.0, 2.5 Hz), 66.8 (s), 55.5 (s), 51.1 (s), 37.8 (s), 37.4 (s), 32.8 (s); HRMS (ESITOF) m/z: [M + H]+ Calcd for C21H19F2N2O4 401.1313; Found: 401.1325; [α]20D = 81.744o (c 0.542, CH3CN). Compound (S,S)-5: mp. 47.4 – 50.9 oC; MS (ESI, pos. ion) m/z: 401.2 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.37-7.24 (m, 4H, CH2Ph), 7.20 (d, J = 7.0 Hz, 2H, Ph-F2), 6.98 (t, J = 8.5 Hz, 2H, Ph-F2), 4.77-4.71 (m, 1H, CO2CH2), 4.55-4.47 (m, 1H, CO2CH2), 4.30-4.23 (m, 2H, CONCH2), 4.02 (d, J = 7.0 Hz, 2H, CH2Ph), 3.30 (dd, J = 13.4, 3.1 Hz, 1H, CHCH2Ph), 3.01-2.83 (m, 3H, NCH2CH); 19F NMR (376 MHz, CDCl3): δ (ppm) -117.10 (s), -117.42 (s); 13C NMR (150 MHz, CDCl3): δ (ppm) 172.0 (s), 171.9 (s), 159.9 (d, J = 4.6 Hz), 158.2 (d, J = 4.7 Hz), 153.2 (s), 134.8 (s), 129.5 (s), 129.3 (t, J = 9.9 Hz), 129.2 (s), 127.7 (s), 114.9 (t, J = 16.2 Hz), 112.3 (dd, J = 20.0, 3.1 Hz), 66.7 (s), 55.4 (s), 50.4 (s), 37.8 (s), 37.3 (s), 33.4 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H19F2N2O4 401.1313; Found: 401.1326; [α]20D = 53.110o (c 0.502, CH3CN). 1-(2,6-difluoro-4-nitrophenyl)-5-oxopyrrolidine-3carboxylic acid. (Compound 6): A mixture of 2,6-difluoro-4nitroaniline (872.4 mg, 5.01 mmol) and 2-methylenesuccinic acid (655.8 mg, 5.04 mmol) was heated at 150 oC for 44 h in a sealed tube. The reaction vessel was then cooled to room temperature, and the crude product (yellow oil) was purified by a flash column chromatography (EtOAc/hexanes (v/v) = 1/10 to 1/2) to give compound 6 (715.2 mg, 50%) as a beige solid. MS (ESI, pos. ion) m/z: 287.0 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.91 (d, J = 7.9 Hz, 2H, Ph), 4.12 – 4.00

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(m, 2H, CH2N), 3.60 – 3.48 (m, 1H, CH), 3.02 – 2.83 (m, 2H, COCH2); 19F NMR (376 MHz, CDCl3): δ (ppm) -110.65 (s), -110.83 (s); 13C NMR (100 MHz, CDCl3 and CD3OD): δ (ppm) 173.8 (s), 172.8 (s), 159.5 (d, J = 5.5 Hz), 157.0 (d, J = 5.5 Hz), 147.0 (t, J = 10.4 Hz), 121.3 (t, J = 16.4 Hz), 108. 5 (dd, J = 25.7, 3.6 Hz), 50.7 (s), 37.3 (s), 33.2 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H12F2NO 287.0480; Found: 287.0475. methyl 1-(2,6-difluoro-4-nitrophenyl)-5-oxopyrrolidine-3carboxylate. (Compound 7): To a solution of compound 6 (808.2 mg, 2.82 mmol) in MeOH (10 mL) was added concentrated sulfuric acid (0.2 mL, 3.68 mmol). The reaction mixture was refluxed for 5 h and then concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/hexanes (v/v) = 1/10 to 1/6) to give compound 7 (465.0 mg, 55%) as a yellow solid. MS (ESI, pos. ion) m/z: 301.0 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.90 (d, J = 8.0 Hz, 2H, Ph), 4.11 – 3.95 (m, 2H, CH2N), 3.79 (s, 3H, Me), 3.58 – 3.45 (m, 1H, CH), 2.89 (ABX, J = 17.6, 7.6, 9.6 Hz, 2H, COCH2); 19F NMR (376 MHz, CDCl3): δ (ppm) -110.62 (s), -110.91 (s); 13C NMR (150 MHz, CDCl3): δ (ppm) 172.3 (s), 172.0 (s), 159.2 (d, J = 5.5 Hz), 157.4 (d, J

= 5.6 Hz), 147.0 (t, J = 10.3 Hz), 121.4 (t, J = 16.3 Hz), 108.7 (dd, J = 25.5, 3.2 Hz), 52.9 (s), 50.5 (s), 37.5 (s), 33.2 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H12F2NO 301.0636; Found: 301.0637. methyl 1-(2,6-difluoro-3-nitrophenyl)-5-oxopyrrolidine-3carboxylate. (Compound 8): A mixture of 2,6-difluoro-3nitroaniline (873.5 mg, 5.02 mmol) and 2-methylenesuccinic acid (789.8 mg, 6.07 mmol) was heated at 120 oC for 44 h in a sealed tube. The reaction vessel was then cooled to room temperature, and the crude product (yellow oil) was purified by a flash column chromatography (EtOAc/hexanes (v/v) = 1/10 to 1/2) to give 1-(2,6-difluoro-3-nitrophenyl)-5-oxopyrrolidine-3carboxylic acid (164.1 mg, 11%) as a yellow-green solid. To a solution of 1-(2,6-difluoro-3-nitrophenyl)-5oxopyrrolidine-3-carboxylic acid in MeOH (5 mL) was added concentrated sulfuric acid (0.1 mL, 1.84 mmol). The reaction mixture was refluxed for 5 h and then concentrated in vacuo. The residue was purified by a flash column chromatography (EtOAc/hexanes (v/v) = 1/10 to 1/6) to give compound 8 (93.0 mg, 54%) as pale yellow oil. MS (ESI, pos. ion) m/z: 301.0 ([M + H]+); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.15 – 8.09

(m, 1H, o-NO2Ph), 7.19 – 7.09 (m, 1H, m-NO2Ph), 4.01 – 3.95 (m, 2H, CH2N), 3.78 (s, 3H, Me), 3.57 – 3.45 (m, 1H, CH), 2.88 (ABX, J = 17.5, 7.4, 9.5 Hz, 2H, COCH2); 19F NMR (376 MHz, CDCl3): δ (ppm) -103.70 (s), -104.51 (s), 118.09 (s), -118.83 (s); 13C NMR (100 MHz, CDCl3): δ (ppm) 172. 3 (s), 172. 2 (s), 163.4 (d, J = 4.0 Hz), 160.8 (d, J = 4.1 Hz), 154.8 (d, J = 6.1 Hz), 152.2 (d, J = 5.9 Hz), 134.8 (s), 126.3 (d, J = 10.6 Hz), 117.4 (dd, J = 16.9, 15.8 Hz), 112.3 (dd, J = 22.2, 3.8 Hz), 52.8 (s), 50.6 (s), 37.4 (s), 33.1 (s); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H12F2NO 301.0636; Found: 301.0634.

ASSOCIATED CONTENT Supporting Information The Supporting Information contains variable temperature 19F NMR spectra of compound 4, and X-ray crystallographic data as


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well as the calculations of the rotational barrier at each torsion angle (∆E-φ) for compounds 2, (R)-3 and (R,S)-5. The Supporting Information is available free of charge on the ACS Publications website.

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AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] (Ning Xi)

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ACKNOWLEDGMENT The work was supported by the National Major Scientific and Technological Special Project for “Significant new drugs Development” during the Twelfth Five-year Plan Period (No. 2015ZX09101013), China; the Introduction of Innovative R & D Team Program of Guangdong Province (No. 2009010048), and the State Key Laboratory of Anti-Infective Drug Development (Sunshine Lake Pharma Co., Ltd) (No. 2015DQ780357), China.

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(a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315-8359. (b) Panini, P.; Chopra, D. In "Hydrogen Bonded Supramolecular Structures." Li, Z.; Wu, L. (Eds.), Springer Berlin Heidelberg, 2015. (a) Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881-1886. (b) Zhou, P.; Zou, J.; Tian, F.; Shang, Z. Fluorine Bonding s How Does It Work In Protein-Ligand Interactions? J. Chem. Inf. Model. 2009, 49, 23442355. (a) Dalvit, C.; Vulpetti, A. Fluorine-protein interactions and 19F NMR isotropic chemical shifts: An empirical correlation with implications for drug design. ChemMedChem. 2011, 6, 104-114. (b) Dalvit, C.; Vulpetti, A. Intermolecular and Intramolecular Hydrogen Bonds Involving Fluorine Atoms: Implications for Recognition, Selectivity, and Chemical Properties. ChemMedChem. 2012, 7, 262-272. Espinet, P.; Albéniz, A. C.; Casares, J. A.; Martínez-Ilarduya, J. M. 19 F NMR in organometallic chemistry Applications of fluorinated aryls. Coordination Chemistry Reviews. 2008, 252, 2180-2208. (a) Hof, F.; Scofield, D. M.; Schweizer, W. B.; Diederich, F. A Weak Attractive Interaction between Organic Fluorine and an Amide Group. Angew. Chem. Int. Ed. Engl. 2004, 43, 5056-5059. (b) Fischer, F. R.; Schweizer, W. B.; Diederich, F. Molecular Torsion Balances: Evidence for Favorable Orthogonal Dipolar Interactions Between Organic Fluorine and Amide Groups. Angew. Chem. Int. Ed. Engl. 2007, 46, 8270-8273. Sun, X.; Li, M.; Sun, M.; Li, X.; Xi, B. J.; Wu, Y.; Yao, J.; Zhan, Z.; Bai, X.; Xi, N. Studies on structural requirements for atropisomerism in N-phenyl γ-lactams. Tetrahedron, 2018, 74, 2991-2998. Xi, N.; Arvedson, S.; Eisenberg, S.; Han, N.; Handley, M.; Huang, L.; Huang, Q.; Kiselyov, A.; Liu, Q.; Lu, Y.; Nunez, G.; Osslund, T.; Powers, D.; Tasker, A. S.; Wang, L.; Xiang, T.; Xu, S.; Zhang, J.; Zhu, J.; Kendall, R.; Dominguez, C. N-Aryl-γ-lactams as integrin αvβ3 antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 2905-2909. All 19F NMR spectra at 298K were recorded with 0.5% CFCl3 as an

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internal reference. The chemical shift of 19F in CFCl3 was assigned to zero. No internal CFCl3 was added for VT 19F NMR studies. Yang, G.; Han, X.; Zhang, W.; Liu, X.; Yang, P.; Zhou, Y.; Bao, X. J. Study on Conformation Interconversion of 3-Alkyl-4-acetyl-3,4dihydro-2H-1,4-benzoxazines from Dynamic NMR Experiments and ab Initio Density Functional Calculations. Phys. Chem. B. 2005, 109, 18690-18698. Dolbier, W. Guide to fluorine NMR for organic chemists, Wiley, 2009. Struble, M. D.; Scerba, M. T.; Siegler, M.; Lectka, T. Evidence for a Symmetrical Fluoronium Ion in Solution. Science 2013, 340, 57-60. Dunitz, J. D.; Taylor, R. Organic Fluorine Hardly Ever Accepts Hydrogen Bonds. Chem. Eur. J. 1997, 3, 89-98. (a) Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst Sander, U.; D'Arcy, A.; Stihle, M.; Muller, K.; Diederich, F. A Fluorine Scan of Thrombin Inhibitors to Map the Fluorophilicity/Fluorophobicity of an Enzyme Active Site: Evidence for C-F···C=O Interactions. Angew. Chem. Int. Ed. Engl. 2003, 42, 2507-2511. (b) Pollock, J.; Borkin, D.; Lund, G.; Purohit, T.; Dyguda-Kazimierowicz, E.; Grembecka J.; Cierpicki, T. Rational design of orthogonal multipolar interactions with fluorine in protein-ligand complexes. J. Med. Chem. 2015, 58, 7465-7474.

14 (a) Struble, M. D.; Kelly, C.; Siegler, M. A.; Lectka, T. Search for a Strong, Virtually “No-Shift” Hydrogen Bond: A Cage Molecule with an Exceptional OH···F Interaction. Angew. Chem. Int. Ed. Engl. 2014, 53, 8924-8928. (b) Struble, M. D.; Guan, L.; Siegler, M. A.; Lectka, T. A C-F Bond Directed Diels-Alder Reaction. J. Org. Chem. 2016, 81, 8087-8090. 15 ∆δ4 value measured in D2O was considerably deviated from the linear curve. The 19F NMR chemical shifts are sensitive to sample concentrations, and that the much lowered concentrations of compounds 1 and 4 in D2O was the reason for the observed deviation. This deviation coincided with the lower ∆δ4-1 for D2O than those for other solvents. 16 (a) Struble, M. D.; Strull, J.; Patel, K.; Siegler, M. A.; Lectka, T. Modulating “Jousting” C−F---H−C Interactions with a Bit of Hydrogen Bonding. J. Org. Chem. 2014, 79, 1-6. (b) Holl, M. G.; Struble, M. D.; Siegler, M. A.; Lectka, T. The close interaction of a C-F bond with a carbonyl π–system: Attractive, repulsive, or both? J. Fluorine Chem. 2016, 188, 126-130. (c) Pitts, C. R.; Holl, M. G.; Lectka, T. Spectroscopic Characterization of a [C-F-C]+ Fluoronium Ion in Solution. Angew. Chem. Int. Ed. 2018, 57, 1924-1927. 17 (a) Paulini, R.; Muller, K.; Diederich, F. Orthogonal Multipolar Interactions in Structural Chemistry and Biology. Angew. Chem. Int. Ed. Engl. 2005, 44, 1788-1805. (b) Holl, M. G.; Pitts, C. R.; Lectka T. Fluorine in a C−F Bond as the Key to Cage Formation. Angew. Chem. Int. Ed. Engl. 2018, 57, 2758-2766.



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