N-Heterocyclic Carbene-Borane Adducts with Chiral (R)-Chloroethyl and Vinyl Substituents

Abstract

This research provides how chiral imidazolium salts {1,3-bis[1′-chloro-1′-phenylpropan-2′-yl]-imidazolium} (1a) and enantiopure {1,3-bis[(R)-1-chlorobutan-2-yl]-imidazolium} [1b] can be utilized in diverse synthetic pathways to obtain new carbene-borane adducts (2a–2d): {1,3-bis[1′-chloro-1′-phenylpropan-2′-yl]-imidazolyl-2-ylidene-borane} (2a), {1,3-bis[(Z)-1′-phenylpropen-2′-yl]-imidazolyl-2-ylidene-borane} (2b), {1,3-bis[(R)-1-chlorobutan-2-yl]-imidazolyl-2-ylidene-borane} (2c), and {1,3-bis[but-1-en-2-yl]-imidazolyl-2-ylidene-borane} (2d). The carbene-borane adducts were synthesized and characterized by ¹³C, ¹H, and ¹¹B nuclear magnetic resonance spectroscopy and time-of-flight mass spectrometry. The X-ray crystal analyses of compounds 2a and 2b were performed, and to understand the structure and interactions of 2a, a computational study was carried out. The effect of N-substituents in the NHC-borane adducts was clearly observed in the C–B bond lengths obtained by single-crystal X-ray diffraction, where the C–B bond is longer for adducts with N-(R)-chloroethyl substituents than for vinyl substituents. The analysis of the reduced density gradient and the bond critical point calculations of 2a showed intramolecular proton–hydride and Cl···N interactions. These chiral imidazolium salts could have applicability in the development of new materials and possibly in pharmaceutical research.

Introduction

The interest in imidazolium salts and N-heterocyclic carbenes (NHCs) arises from their wide applications in organic catalysis,¹ organometallic catalysis,² green solvents,^3,4 and therapeutic agents,⁵⁻⁸ among others.⁹⁻¹¹ Specifically, NHC–BH₃ have potential application as dual reagents for the synthesis and stabilization of metallic nanoparticles such as platinum,¹² palladium, iridium, and gold,¹³ due to their easy-to-synthesize nature and the formation of strong and covalent carbon–metal bonds. Also, NHCs can act as strong σ-donors and can coordinate metal ions to form metal NHC complexes, such as platinum, which show anticancer activities.¹⁴ Although boryl radicals were considered elusive species, the relative stability and straightforward synthesis of NHC–BH₃ adducts and NHC–boryl radicals have rapidly expanded their chemistry and synthetic applications.^15,16

On the other hand, it is well-known that N-substituents can modulate the steric effect, chirality induction, and reactivity of NHC–metal complexes and NHC organocatalysts. Particularly, N-substituents play a crucial role in the reactivity of NHC–BH₃ adducts, as in the case of 1,3-dimethylimidazole-2-ylidene-borane, which is a more reactive agent for the reduction of xanthates (and related functional groups) compared to 1,3-bis(diisopropylphenyl)imidazole-2-ylidene-borane.¹⁷ Unlike conventional bulky aromatic nitrogenous substituents used in NHC–organometallic complexes, N-alkyl substituents are regularly used in NHC–boryl radical reactions such as C–C¹⁸ or C–H¹⁹ bond formation, xanthate reduction,¹⁷ and polymerization²⁰ to name a few.^15,16 We are interested in synthesizing NHC–BH₃ adducts with chiral alkyl substituents derived from the N-β-chloroethyl imidazolium salts. In this work, we have used the diastereomeric and racemic mixture of {1,3-bis[1′-chloro-1′-phenylpropan-2′-yl]-imidazolium} (1a) and enantiopure {1,3-bis[(R)-1-chlorobutan-2-yl]-imidazolium} (1b, Figure 1).

Figure 1.

Structure of N-(R)-chloroethyl imidazolium cations. 1a was used as a diastereomeric and enantiomeric mixture, and 1b was used as an enantiopure salt.

Imidazolium salts with (R)-chloroethyl substituents can have three different reactive sites: (a) the nucleophilic substitution of chlorine, (b) the elimination reaction or dehydrochlorination, and (c) carbene formation by the deprotonation of the imidazolium ring (Figure 2). Nucleophilic substitutions of N-(R)-chloroethyl imidazolium or benzimidazolium salts have been reported in the synthesis of PCP complexes by nucleophilic substitution with potassium alkyl phosphides,²¹⁻²³ while the elimination reaction of N-β-chloroethyl imidazolium has only been reported by Cariou.²⁴ In addition, they also reported the formation of N-vinyl substituents via C–H activation of the N-(R)-chloroethyl group by a Ru(II) complex (Figure 2).²⁴ In our previous reports on weak nonclassical interactions (Cl···N and C–H···Ag),²⁵⁻²⁷ we have described the importance of N-(R)-chloroethyl substituents in the structure of NHC–Ag complexes. Here, we discuss the reactivity of N-substituents 1a and 1b in the preparation of four different NHC–BH₃ adducts (2a–2d). The four carbene-borane adducts were synthesized and characterized by ¹³C, ¹H, and ¹¹B NMR spectroscopy, and TOF-MS spectrometry and X-ray crystal analyses of compounds 2a and 2b were performed. To understand the structure and interactions of 2a, a computational study was carried out.

Figure 2.

Reactivity and synthesis of different ligands from imidazolium salts with β-chloroethyl substituents.

Experimental Section

All of the reagents were used as received without further purification. Standard Schlenk line, glovebox, and vacuum line techniques were employed under an atmosphere of nitrogen. THF was dried by distillation from sodium/benzophenone under an argon atmosphere. CH₂Cl₂ was dried with CaH₂. Deuterated solvents, dry CDCl₃, and THF-d₈ were purchased from Sigma-Aldrich. Imidazolium 1a and 1b were synthesized, as reported before.²⁵

The multinuclear NMR spectra were obtained with different equipment: a Jeol GSX-270 with observation frequencies of 270.16 MHz (¹H), 67.93 MHz (¹³C), and 86.68 MHz (¹¹B). A Jeol Eclipse 400 MHz with observation frequencies of 399.78 (¹H), 100.52 (¹³C), and 128.26 MHz (¹¹B). A Bruker Advance Spectrometer at 300 MHz with observation frequencies of 300.13 MHz (¹H), 75.46 MHz (¹³C), and 96.29 MHz (¹¹B). The assignment of ¹³C and ¹H NMR signals was based on HSQC 2D experiments. The Fourier transform infrared (FTIR) spectra were obtained on the KBr pellet using a PerkinElmer GX spectrometer. The spectra were obtained in the 4000–400 cm^–1 range. High-resolution mass spectra were obtained by LC/MSD TOF on an Agilent Technologies instruments with ESI as the ionization source.

1,3-Bis[(Z)-10-phenylprop-1′-en-2′-yl]-imidazolium Chloride (1c)

A suspension of compound 1a (0.95 g, 2.3 mmol) and NaHS (0.39 g, 6.9 mmol) in methanol (30 mL) was refluxed for 14 h. Then, the solvent was evaporated in vacuum, and the reaction mixture was suspended in CH₂Cl₂. The solid was filtered and discarded. The solution was evaporated. The solid was washed with acetone (3 × 10 mL). Compound 1c is a white solid (0.62 g, 80%). It was crystallized by the slow evaporation of a CH₂Cl₂ solution. Mp 240–241 °C. IR, ν(cm^–1): 1668 (C=C), 1157 (C=N), 1179 (C―N), 701 (Ph). ¹H NMR (CDCl₃, 270 MHz): δ 11.01 (s, 1H), 7.19 (m, 6H), 6.95 (s, 2H), 6.89 (m, 4H), 6.59 (s, 2H), 2.51 (s, 6H). ¹³C{¹H} NMR (CDCl₃, 270 MHz): δ 137.9, 132.5, 131.1, 129.0, 128.7, 128.3, 126.9, 122.3, 23.7. (+) TOF calcd for [C₂₁H₂₁N₂]⁺, m/z (amu): 301.1699; found 301.1702.

1,3-Bis[(R,R)-1′-chloro-1′-phenylpropan-2′-yl]-imidazolyl-2-ylidene-borane (2a)

Compound 1a (0.13 g, 0.31 mmol) was dissolved in nitromethane and dried with calcium hydride for 1 h. The solution was filtered and evaporated under anhydrous conditions. The white solid was dissolved in THF (20 mL) and cooled at −78 °C, and then 0.25 mL of t-butyllithium in pentane (1.3 M, 0.32 mmol) was added and stirred. After 30 min, a solution of DMS-BH₃ was added (2.65 M, 0.13 mL). The reaction mixture was evaporated under vacuum. Compound 2a is a white solid. It crystallized by slow evaporation of CDCl₃ in an NMR tube. IR, ν(cm^–1): 2929, 2866 (B–H). ¹H RMN (CDCl₃, 300 MHz): δ 7.3–6.9 (m, 10H), 6.56 (s), 6.42 (s, 2H), 5.42 (br s, 2H), 5.20 (br s, 2H), 1.25 (br s, 6H), 1.15 (br s, 3H). ¹³C{¹H} NMR (CDCl₃, 300 MHz): δ 172.7, 136.8, 136.5, 129.0, 128.6, 128.1, 128.0, 116.9, 64.2, 58.2, 16.7, 16.3. ¹¹B (CDCl₃, 300 MHz): −36.6 (q, ¹J (¹¹B, ¹H) = 81.7 Hz). (+) TOF calcd for [C₂₁H₂₄N₂BCl₂]⁺m/z (amu): 385.1404; found: 385.1406.

1,3-Bis[(Z)-1′-phenylpropen-2′-yl]-imidazolyl-2-ylidene-borane (2b)

Compound 1c (0.11 g, 0.32 mmol) was dissolved in THF (20 mL) and cooled at −78 °C. Then, 0.20 mL of n-butyllithium in hexane (1.6 M, 0.32 mmol) was added and stirred. After 30 min, a solution of DMS-BH₃ was added (2.65 M, 0.13 mL). The reaction mixture was evaporated under vacuum. Compound 2b is a white solid. It was crystallized by the slow evaporation of CDCl₃ in an NMR tube. IR, ν(cm^–1): 2344, 2300 (B–H). ¹H RMN (CDCl₃, 400 MHz): δ 7.19–6.93 (m, 10H), 6.57 (s, 2H), 6.50 (s, 2H), 2.34 (s, 6H), 1.30–1.20 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 400 MHz): δ 172.9, 134.1, 134.0, 128.3, 128.2, 127.7, 126.7, 120.1, 23.5. ¹¹B NMR (CDCl₃, 400 MHz): – 36.4 [q, ¹J(¹¹B,¹H) = 86.91 Hz]. (+) TOF calcd for [C₂₁H₂₀N₂B]⁺, m/z (amu): 311.1714; found 311.1719.

1,3-Bis[(R)-1-chlorobutan-2-yl]-imidazolyl-2-ylidene-borane (2c)

Compound 1b (0.18 g, 0.32 mmol) was dissolved in acetonitrile and dried with calcium hydride for 1 h. The solution was filtered and evaporated in anhydrous conditions. The white solid was dissolved in THF (20 mL) and cooled at −78 °C. Then, 0.25 mL of t-butyllithium in pentane (1.3 M, 0.32 mmol) was added and stirred, and after 30 min, a solution of DMS-BH₃ was added (2.65 M, 0.13 mL). The reaction mixture was evaporated under vacuum. Compound 2c is a white solid. IR, ν(cm^–1): 2346, 2284 (B–H). ¹H RMN (CDCl₃, 300 MHz): δ 6.91 (br s, 2H, H4, H5), 5.10 (br s, 2H, H7), 3.81 (br s, 2H, H6a), 3.76 (br s, 2H, H6b), 1.97 (m, 4H, H8), 1.30–1.20 (s, 3H) 0.91 (t, ³J(¹H,¹H) = 6.7 Hz, 6H, H9). ¹³C{¹H} NMR (CDCl₃, 300 MHz): δ 167.7 (C2), 117.2 (C4, C5), 59.3 (C7), 46.9 (C6), 24.8 (C8), 10.4 (C9). ¹¹B NMR (CDCl₃, 300 MHz): −37.4 (q, ¹J(¹¹B,¹H) = 87.2 Hz). (+) TOF calcd for [C₁₁H₂₀N₂Cl₂B]⁺m/z (amu): 261.1091; found: 261.1088.

1,3-Bis[but-1-en-2-yl]-imidazolyl-2-ylidene-borane (2d)

Compound 1b (0.18 g, 0.32 mmol) was dissolved in acetonitrile and dried with calcium hydride for 1 h. The solution was filtered and evaporated in anhydrous conditions. The white solid was dissolved in THF (20 mL) and cooled at −78 °C; then 0.60 mL of n-butyllithium in hexane (1.6 M, 0.96 mmol) was added and stirred, and after 30 min, a solution of DMS-BH₃ was added (2.65 M, 0.13 mL). The reaction mixture was evaporated under vacuum. Compound 2d is a white solid. IR, ν(cm^–1): 2344, 2299 (B–H). ¹H NMR (CDCl₃, 300 MHz): δ 6.74 (s, 2H), 5.25 (s, 2H), 5.16 (s, 2H), 2.58 (q, ³J(1H,1H) = 7.3 Hz, 4H), 1.30–1.20 (s, 3H), 1.08 (t, ³J(¹H,¹H) = 7.3 Hz). ¹³C{¹H} NMR (CDCl₃, 300 MHz): δ 147.8, 120.2, 111.8, 28.1, 11.1. ¹¹B NMR (CDCl₃, 300 MHz): – 36.5 (q, ¹J(¹¹B,¹H) = 86.2 Hz). (+) TOF calcd for [C₁₁H₁₆N₂B]⁺, m/z (amu): 187.1409; found: 187.1401.

Computational Methodology

Conformational analysis was performed in N-heterocyclic carbene-borane 2a to obtain its conformers distribution using the semiempirical method PM3, which is well-known to predict correct conformations for organic molecules. Then, the minimal energy conformer and performed optimization calculations were chosen using the hybrid method B3LYP functional with the 6 311++G(2d,2p) basis set. The same hybrid method was employed to obtain optimized structures and NBO partial charges of the structures using the pseudopotential LANL2DZ with diffuse functions. All these calculations were done using the Gaussian 03 package. Subsequently, Bader analysis of the electronic density was performed with AIMAll software version 17.01.25, which allowed the visualization of bond paths, critical points, and maps of the reduced gradient of the electronic density.

Crystallographic Data

Crystal size, low temperature, long exposure times, and collection strategy were considered to acquire the best possible data set.²⁵ Crystals 2a and 2b were obtained in CDCl₃ and measured using a Bruker D8 VENTURE instrument with a PHOTON 100 area detector using graphite monochromatic MoK/a radiation (λ = 0.71073 Å). Even though crystal data were collected up to 0.70 Å resolution, the crystal diffracted quite weakly at high angles, so the data set was cut off for sin(θ)/λ > 0.458 to eliminate noisy, weak data. Crystal structures were solved by direct methods, using SHELXT 2018/2, and refined by full-matrix least-squares methods based on F2 using SHELXL-2019/2. All atoms (except hydrogen atoms) were refined anisotropically. Number CCDC of structures: 2413415 and 1542474 (2a) and 2301429 (2b) contain the related crystallographic data, which can be obtained free of charge from the Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures/.

Results and Discussion

In order to study the reactivity of chiral imidazolium salts N-(R)-chloroethyl-imidazoliums 1a and 1b were prepared as previously reported.²⁶ The reactivity of the imidazolium was investigated under different reaction conditions, in the presence of (a) lithium diphenylphosphide (LiPPh₂) to form PCP ligands, (b) sodium hydrosulfide (NaSH) to form thiols, and (c) nBuLi or tBuLi as strong bases to give the corresponding carbenes. In the first attempt to form PCP ligands by a nucleophilic substitution reaction between lithium diphenylphosphide and imidazolium 1a, a mixture of compounds was obtained. The analysis of the ³¹P NMR spectrum of the reaction mixture showed diphenylphosphine (Ph₂PH, ³¹P = −40 ppm), indicating a deprotonation reaction of the imidazolium. Meanwhile, TOF-MS analysis showed dehydrochlorination [M⁺–HCl, m/z (amu): 373.12, 337.14, and 301.17] and degradation of the imidazolium cations.

On the other hand, the reaction of the enantiomeric and diastereomeric mixture of imidazolium 1a with NaSH produces the complete dehydrochlorination of the N-substituents (Figure 3). ¹³C NMR spectra analysis shows the formation of substituents with only one alkene isomer (C6 and C7, δ¹³C = 131.1 and 126.9 ppm, respectively). The diastereomeric selectivity of the reaction allows us to propose an E2 mechanism that produces Z-alkenyl substituents (compound 1c), driven by the antiperiplanar position of the C–H and C–Cl bonds, allowing an antiperiplanar arrangement between the C–Me and C–Ph bonds (Figure 3b). The formation of 1c was confirmed by single-crystal X-ray diffraction. These results suggest that in contrast to the nucleophilic substitutions reported in the literature for (R)-chloroethyl imidazolium,²¹⁻²³ the elimination reaction is favored in 1a and 1b compounds.

Figure 3.

(A) Dehydrochlorination of imidazolium 1a and the capped stick representation of 1c. (B) Antiperiplanar arrangement of 1a for the E2 reaction.

To evaluate the different steric effects, the dehydrochlorination reaction and carbene formation from 1a and 1b were studied with different equivalents of strong bases such as n-butyllithium (nBuLi) and t-butyllithium (tBuLi), and to obtain the corresponding NHC-BH₃ adducts, DMS–BH₃ was added. The reaction of different nBuLi equivalents (1.2, 2.4, or 3) with 1a gave in high yield a mixture of compound 2a and traces of 2b (Figure 4). The reactions of 1.2 equiv of nBuLi with 1a showed regioselectivity deprotonation of C2 with respect to the C6 position, and the presence of nBuLi in excess (3 equiv) kept the yield of carbene-borane adduct 2a above 90%. For the identification of compound 2b, obtained in traces, it was selectively synthesized from compound 1c, which was isolated from the mixture reaction of 1a with NaSH (see above). The reaction to obtain 2b was carried out in the presence of nBuLi and borane.

Figure 4.

Synthesis of NHC-BH₃ adducts 2a and 2b in the presence of different base equivalents.

To gain insights into the steric effects of the N-substituent, we synthesized imidazolium 1b with a higher degree of conformational freedom. In contrast to compound 1a, the reaction of 3 equiv of nBuLi with 1b followed by borane addition produces in quantitatively yields the carbene-borane adducts with vinyl substituents (compound 2d). On the other hand, the addition of only 1 equiv of nBuLi afforded to carbene-borane adducts 2c and 2d in a ratio of 2.4:1 (Figure 5). A possible reaction mechanism for compounds 2a–2d, based on previous reports of a ruthenium(II) compound is proposed.²⁴ First, without removing the chlorine atom from 1a or 1b, the base would abstract the H-2 proton, and then the carbene would bind to BH₃ to form 2a or 2c, respectively. In the case of the formation of 2b or 2d, there would first be dehydrochlorination and then the abstraction of the H-2 proton from compound 1a or 1b, leading to vinyl carbene, followed by coordination to boron. We assume that the conformational freedom of both N-substituents and nBuLi allows the dehydrochlorination of N-substituents and carbene formation. Meanwhile, selective cyclic deprotonation to form 2c was achieved with tBuLi, revealing the strong influence of the steric hindrance of the base.

Figure 5.

Synthesis of NHC–BH₃ adducts 2c and 2d with different base equivalents.

The obtention of compounds 2c and 2d with different equivalents of nBuLi or tBuLi and the subsequent DMS-borane addition were monitored by ¹¹B NMR, as shown in Figure 6.

Figure 6.

Proton-decoupled ¹¹B{¹H} NMR spectra (−34.0 to −40.0 ppm) of the reaction products (2c and 2d) obtained of 1b with different base equivalents: (A) 1 equiv nBuLi, (B) 3 equiv nBuLi, and (C) 1 equiv tBuLi. The green signal corresponds to compound 2d and the red one to compound 2c.

The NMR shifts of ¹¹B{¹H} of 2a–2d (36.6, 36.4, 37.4, and 36.5 ppm) corresponded to adducts of cNH–BH₃, where boron was tetracoordinated with a tetrahedral structure.^15,28 The displacements show a slight tendency of unprotection of boron, 2b > 2d > 2a > 2c, where unsaturated imidazolium species (2b and 2d) are slightly more unprotected than saturated ones (2a and 2c); they also contain chlorine. It seems that when there is no steric impediment, the chlorines move closer to the boron atom, protecting it slightly, as in 2c.

In addition, the substituents’ effect in the NHC–BH₃ bond was analyzed. Crystals of compounds 2a and 2b were suitable for X-ray diffraction (Figures 7 and 8). It is noteworthy that the B–C_carbene bond lengths between 2a {1.609(3)} and 2b {1.5667(14)} crystal structures are different.

Figure 7.

Crystalline structure of 2a.

Figure 8.

Crystalline structure of 2b.

The difference between the two B–C_carbene distances is attributed to the N-substituents, confirming their importance in the NHC–BH₃ adducts. In Figure 9, the comparison of BH₃–C_carbene bond lengths of 2a, 2b, and other reported structures is shown (see Table S3 in the Supporting Information (SI)).²⁹⁻³¹ Compound 2a has similar bond distances to other chiral NHC-BH₃ compounds (1.604–1.623 Å),²⁹ while the bond length of 2b is even shorter than NHC-BH₃ adducts with aromatic N-substituents (1.585–1.596 Å; Figure 10).^30,31

Figure 9.

C–B bond lengths of 2a, 2b, and N-heterocyclic carbene adducts.

Figure 10.

(A) Distances between the α-hydrogen of the N-substituents and the borane hydride atom in the crystalline structure of 2a. (B) Reduced gradient maps and bond critical points of 2a, showing H^δ+···H^δ− interactions.

Furthermore, the crystal structure of 2a shows that the hydrogens of the N-substituents are directed to borane. The distances between the hydrogen of the N-substituents and the hydrogens attached to the boron were found to be 2.10, 2.26, and 2.52 Å, smaller than the sum of the van der Waals radii [∑r_vdW(H^δ+···H^δ−) = 2.65 Å], indicative of hydride–proton interactions (Figure 10A).³² To better understand the structure and interactions, we performed a computational study using the crystal structure of 2a as the initial geometry for the calculations. The analysis of the reduced density gradient and the bond critical point calculations show intramolecular proton–hydride interactions (Figure 10B). Cl···N interactions were also observed. These types of interactions have been previously described in R-chloroethyl imidazolium and diimines.²⁵

The conformation in which the hydrogens of the N-substituents are directed toward borane is not only observed in 2a but also observed in other crystalline structures reported previously. We assume that the inductive effect of nitrogen and the cationic heterocycle increases the hydrogen acidity of the N-substituent. The acidity of hydrogen directs the dehydrochlorination of the substituents and even directs the conformation of the adducts in the solid state.

Conclusions

In summary, we have reported four NHC-borane adducts with alkyl and vinyl substituents. The effect of the N-substituents in the NHC-borane adducts is clearly observed in the C–B bond lengths obtained by single-crystal X-ray diffraction, where the C–B bond is longer for adducts with N-(R)-chloroethyl substituents compared to vinyl substituents. It is noteworthy that the reactivity of the N-substituents allowed us to obtain carbene-borane adducts with different structures synthesized from the same imidazolium salt. Our work opens the way to integrating reactive N-substituents to diversify structures and properties of N-heterocyclic carbene complexes.

Data Availability Statement

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

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.4c00088.

• Additional experimental and calculation details; methods and copies of NMR and IR spectra of all products; and crystallographic data of compounds 2a and 2b (PDF)

Author Contributions

The project was conceptualized, supervised, administrated, and analyzed by F.-P. The manuscript was written through contributions of all authors. R.-L.: investigation, formal analysis, and methodology. V.-G.: software and investigation. S.-R.: methodology and NMR spectroscopy. E.-R.: investigation, formal analysis, and X-ray analysis. All authors have given approval to the final version of the manuscript. CRediT: Germán Rodríguez-López formal analysis, investigation, methodology; Tayde O. Villaseñor-Granados investigation, software; Sonia Sánchez-Ruiz methodology; Adriana Esparza-Ruiz formal analysis, investigation, software, writing - original draft, writing - review & editing; Angelina Flores-Parra conceptualization, formal analysis, project administration, supervision.

The authors declare no competing financial interest.