Synthesis and Structural Characterization of 1-Arylimidazole-2-thiones and N,N′-Aryldiethoxyethylthioureas with Electronically Diverse Substituents: A Manifold of Hydrogen Bonding Networks

Abstract

The 1-arylimidazole-2-thiones, (Hmim^Ar) [Ar = 3,4,5-C₆H₂(OMe)₃, 2,4-C₆H₃(NO₂)(OMe), 2,4,6-C₆H₂Cl₃ and 3,5-C₆H₃(CF₃)₂], which feature electronically diverse substituents, may be obtained via acid-catalyzed ring closure of the corresponding N,N′-aryldiethoxyethylthiourea derivatives, ArN(H)C(S)N(H)CH₂CH(OEt)₂, (H₂detu^Ar), which in turn are obtained via treatment of aminoacetaldehyde diethyl acetal, H₂NCH₂CH(OEt)₂, with the respective arylisothiocyanates (ArNCS). The molecular structures of all of the above N,N′-aryldiethoxyethylthioureas and 1-arylimidazole-2-thiones have been determined by X-ray diffraction, thereby demonstrating that the substituents have a profound effect on the crystal structures. For example, each of the N,N′-aryldiethoxyethylthiourea derivatives adopts a different hydrogen bonding pattern. Specifically, the hydrogen-bonding network in (i) H₂detu^ArCl₃ consists of chains of 9-membered rings, with an [ ${\mathrm{R}}_2^2$(9)] motif, that feature one N–H ⋯ O and one N–H ⋯ S interaction, (ii) H₂detu^ArOMe,NO₂ consists of chains of 6-membered rings, with an [ ${\mathrm{R}}_2^1$(6)] motif, that feature two head-to-tail N–H ⋯ S interactions, (iii) H₂detu^Ar(CF₃)₂ consists of a dimer that features two pairs of N–H ⋯ O interactions, of which each pair is a component of an 8-membered ring with an [ ${\mathrm{R}}_2^2$(8)] motif, and (iv) H₂detu^Ar(OMe)₃ consists of a chain of head-to-head dimeric rings with a basic [ ${\mathrm{R}}_2^2$(16)] motif, a notable feature of which is that sulfur does not play a role as a hydrogen bond acceptor. Each of the 1-arylimidazole-2-thiones exists as a “head-to-head” hydrogen-bonded dimer in the solid state, with an [ ${\mathrm{R}}_2^2$(8)] motif. However, while the hydrogen-bonded motifs for Hmim^ArCl₃ and Hmim^Ar(OMe)₃ are planar, those for Hmim^Ar(CF₃)₂ and Hmim^ArOMe,NO₂ are extremely puckered, with fold angles of 24.2° (mean value) and 45.7°, respectively.

Introduction

1-R-imidazole-2-thiones (Hmim^R),^1,2,3,4,5 which are often referred to in terms of their tautomeric 2-mercapto-1-R-imidazole form (Figure 1),⁶ despite the fact that the thione form is dominant,³ represent an important class of molecules that has found widespread applications in fields ranging from medicinal to coordination chemistry.

Figure 1.

Tautomers of Hmim^R.

For example, with respect to medicinal applications, the parent methyl derivative, methimazole (also known as tapazole), is a widely used antithyroid drug,^7,8 and a variety of other derivatives are potent multisubstrate inhibitors of β-hydroxylase,^2c,3d,9 octopamine agonists^3b and CCR2 antagonists.^2b,10 In addition, imidazole-2-thiones are used as reagents for the synthesis of compounds that are employed in imaging by positron emission tomography.¹¹ With respect to applications in coordination chemistry, Hmim^R derivatives have been used as ligands (in both protonated and deprotonated forms)¹² for a variety of metals. For example, in terms of mercury chemistry, coordination of Hmim^R has been shown to promote protolytic cleavage of Hg–C bonds.¹³ 1-R-imidazole-2-thiones have also been employed to construct a family of bis(mercaptoimidazolyl)hydroborato and tris(mercaptoimidazolyl)hydroborato ligands, [Bm^R] and [Tm^R], that respectively provide [S₂] and [S₃] donor arrays, of which the latter have been used to provide synthetic analogues of zinc enzymes (e.g. 5‐aminolevulinate dehydratase and the ADA DNA repair protein)^14,15 and organomercurial lyase (Mer B).^13a Furthermore, [Tm^R] ligands have also been used to afford access to metallaboratranes that feature novel retrodative M→B bonds.¹⁶ In view of the diverse applications of this class of molecules, it is surprising that only one structurally characterized 1-arylimidazole-2-thione derivative is listed in the Cambridge Structural Database,¹⁷ namely Hmim^Tol.18,19 Therefore, we report here the synthesis and structural characterization of a variety of Hmim^Ar compounds that contain electronically diverse substituents (Figure 2). In addition, we also describe the structures of the corresponding N,N⁠′-aryldiethoxyethylthiourea intermediates. Compounds of this class have not been previously structurally characterized, despite the fact that N,N′-disubstituted thioureas have varied applications.^20,21 Some examples of these applications include their use (i) as antibacterial,^22,23,24 antifungal,^24,25 antiviral,^26,27,28 anti-HIV,²⁸ antimalarial,²³ antituberculous,^28,29 antihistamine,³⁰ and anticancer²⁷ agents, (ii) in organocatalysis,^31,32,33 and (iii) in crystal engineering.^34,35

Figure 2.

Hmim^Ar ligands.

Results and Discussion

Synthesis of 1-arylimidazole-2-thiones, Hmim^Ar

The 1-arylimidazole-2-thiones, Hmim^Ar [Ar = 3,4,5-C₆H₂(OMe)₃, 2,4-C₆H₃(NO₂)(OMe), 2,4,6-C₆H₂Cl₃ and 3,5-C₆H₃(CF₃)₂], may be obtained via the two-step process illustrated in Scheme 1.^3,36 Specifically, treatment of aminoacetaldehyde diethyl acetal, H₂NCH₂CH(OEt)₂, with the respective arylisothiocyanate (ArNCS) gives the N,N′-aryldiethoxyethylthiourea derivative, ArN(H)C(S)N(H)CH₂CH(OEt)₂, (H₂detu^Ar), which is converted to the 1-arylimidazole-2-thione by acid-catalyzed ring closure. In each case, both the 1-arylimidazole-2-thione, Hmim^Ar, and the intermediate thiourea, H₂detu^Ar, can be isolated in good yields by crystallization.

Scheme 1.

Synthesis of H₂detu^Ar and Hmim^Ar.

Molecular structures of N,N′-aryldiethoxyethylthioureas, H₂detu^Ar

Despite the fact that thioureas have considerable synthetic utility^3,31-33 and applications in crystal engineering,^34,35 there are no structurally characterized examples of N,N′-aryldiethoxyethylthioureas listed in the Cambridge Structural Database.¹⁷ The structures of N,N′-aryldiethoxyethylthioureas are also of interest because the presence of multiple potential hydrogen bond acceptor groups is expected to influence the hydrogen bonding patterns in their extended structures. In this regard, X-ray diffraction studies reveal that the molecular structures of H₂detu^Ar are highly dependent on the nature of the aryl substituent, as illustrated in Figure 3 and Figure 4.

Figure 3.

Molecular structures of H₂detu^ArCl₃ (left) and H₂detu^Ar(OMe)₃ (right).

Figure 4.

Molecular structures of H₂detu^Ar(CF₃)₂ (top) and H₂detu^ArOMe,NO₂ (bottom).

With respect to the orientation of the thiourea substituents, previous studies have demonstrated that N,N′-disubstituted thioureas may exist in solution in different rotameric forms, which have been classified as trans-trans, trans-cis and cis-cis, based on their H–N–C–S dihedral angles, as illustrated in Figure 5.³⁷ Of these, the trans-trans and trans-cis rotamers typically have comparable energies, while the cis-cis has a significantly higher energy, such that the vast majority of N,N′-disubstituted thioureas exist in the solid state as either trans-trans or trans-cis rotamers;^34,38 these rotamers are also respectively referred to as syn and anti with respect to the relative positions of the N–H groups.³⁹ On this basis, H₂detu^ArCl3 and H₂detu^Ar(OMe)3 are classified as adopting a trans-cis (anti) disposition of N–H groups (Figure 3), while H₂detu^Ar(CF3)2 and H₂detu^ArOMe,NO2 adopt a trans-trans (syn) disposition (Figure 4).

Figure 5.

Rotamers of thioureas.

The C=S bond lengths in the thiourea compounds reported here are in the range 1.67 – 1.70 Å (Table 1) and are comparable to those of other thiourea derivatives (1.68 Å).⁴⁰ Furthermore, the distances pertaining to the various N ⋯ S and N ⋯ O hydrogen bonding interactions (Table 1) are also comparable to literature values (3.44 Å^40,41 and 2.95 Å,⁴² respectively).

Table 1.

Selected metrical data for H₂detu^Ar derivatives [R = CH₂CH(OEt)].

	d(N ⋯ O)/Å	d(N⋯O)/Å	d(N ⋯ S)/Å	d(NH ⋯ O)/Å	d(NH ⋯ O)/Å	d(NH ⋯ S)/Å	d(C=S)/Å	N1–C–N2/°
H2detuArCl3	3.012(2) (ArN … OEt)		3.246(2) (NR)	2.24(2) (ArN … OEt)		2.49(2) (NR)	1.691(2)	116.66(19)
H2detuAr(OMe)3	3.015(2), 2.976(2) (RN … OMe)	2.900(2), 2.882(2) (ArN … OEt)		2.32(2), 2.21(2) (RN … OMe)	2.01(2), 2.060(19) (ArN … OEt)		1.6938(17), 1.6904(17)	116.75(15), 123.40(13)
H2detuAr(CF3)2	3.141(2), 3.002(2) (RN … OEt)	2.955(2), 3.070(2) (ArN … OEt)		2.21(2), 2.31(2) (RN … OEt)	2.29(2), 2.10(2) (ArN … OEt)		1.6693(19) 1.677(2)	112.43(16), 113.06(17)
H2detuAr(CF3)2	3.070(2), 3.142(2) (RN … OEt)	3.002(2), 2.956(2) (ArN … OEt)		2.29(2), 2.32(2) (RN … OEt)	2.20(2), 2.10(2) (ArN … OEt)		1.6697(18), 1.6766(19)	112.43(15), 113.09(16)
H2detuArOMe,NO2			3.348(3) (NR) 3.541(3) (NAr)			2.52(3) (NR), 2.80(2) (NAr)	1.684(3)	113.4(3)

In addition to the syn/anti differences in the molecular structures, the compounds also exhibit significant differences with respect to their hydrogen bonding interactions, as illustrated in Figures 7 – 10.⁴³ For reference, trans-trans (syn) rotamers are typically observed to form linear⁴⁴ chains in which both N–H groups interact with a single thiocarbonyl sulfur in a bifurcated⁴⁵ manner, whereas trans-cis (anti) rotamers typically form dimers (Figure 6);³⁴ in terms of graph-set notation,⁴⁶ these networks are classified as C(4)[ $R_2^1$(6)] and [ $R_2^2$(8)], respectively. It is, therefore, evident from examination of Figures 7 – 10 that the aryldiethoxyethylthioureas reported here comprise much more varied hydrogen bonding networks than those presented in Figure 6. Specifically, the N–H groups of the thiourea moiety may interact with different combinations of hydrogen bond acceptors, such that each compound exhibits a distinctive network, as summarized in Table 1 and Table 2.

Figure 7.

Hydrogen bonding network for H₂detu^Ar(CF₃)₂.

Figure 10.

Hydrogen bonding network for H₂detu^Ar(OMe)₃.

Figure 6.

Typical hydrogen bonding networks in thioureas.

Table 2.

Hydrogen bonding networks for H₂detu^Ar derivatives.

	Unitary Network	Binary Network
H2detuArCl3	C(4)C(7)	${\mathrm{C}}_2^2(11)[{\mathrm{R}}_2^2(9)]$
H2detuAr(OMe)3	DDDD	${\mathrm{C}}_2^2(14){\mathrm{R}}_2^2(16){\mathrm{R}}_4^4(22){\mathrm{R}}_4^4(22){\mathrm{R}}_4^4(30){\mathrm{R}}_4^4(30)$
H2detuAr(CF3)2	DDDD	${\mathrm{R}}_2^2(8){\mathrm{R}}_2^2(8){\mathrm{R}}_2^2(10){\mathrm{R}}_2^2(12){\mathrm{R}}_2^2(12){\mathrm{R}}_2^2(14)$
H2detuArOMe,NO2	C(4)C(4)	${\mathrm{C}}_2^2(8)[{\mathrm{R}}_2^1(6)]$

For example, rather than adopt the chain-like structure that is typical for trans-trans (syn) rotamers (Figure 6), H₂detu^Ar(CF₃)₂ exists as a discrete dimeric species with approximate C₂ symmetry (Figure 7). Thus, rather than hydrogen bond with the sulfur, the N–H groups of each thiourea moiety form intermolecular N–H ⋯ O hydrogen bonds with two oxygen atoms of a single diethoxyethyl group, CH₂CH(OEt)₂, thereby resulting in an 8-membered ring with an [ $R_2^2$(8)] motif.

In contrast, H₂detu^ArOMe,NO₂, which also possesses a syn disposition of N–H groups, does not exhibit any intermolecular N–H ⋯ O hydrogen bonding interactions with either the CH₂CH(OEt)₂, OMe or NO₂ groups.⁴⁷ Instead, the pair of N–H groups exhibit intermolecular “head-to-tail” hydrogen bonding interactions with a single sulfur atom, thereby resulting in a chain of a 6-membered rings, each one of which possesses an [ $R_2^1$(6)] motif (Figure 8). The overall hydrogen bonding network is described by the binary graph set $C_2^2$(8)[ $R_2^1$(6)] and is well-precedented for thioureas that possess a syn disposition of N–H groups (Figure 6).⁴⁸

Figure 8.

Hydrogen bonding network for H₂detu^ArOMe,NO₂.

H₂detu^ArCl₃ exists as a trans-cis (anti) rotamer, but rather than form a simple dimer by the centrosymmetric interaction of two thiourea [S/NH] pairs (Figure 6), H₂detu^ArCl₃ forms a structure that results from an interaction between a pair of [S/NH] and [O/NH] moieties, thereby resulting in a 9-membered ring with an [ $R_2^2$(9)] motif that features one N–H ⋯ O and one N–H ⋯ S interaction. In addition to the oxygen atom of the ethoxy groups allowing for an unusual type of ring structure, it also provides a means to create an extended chain structure by virtue of there being an additional hydrogen bond acceptor present. Thus, whereas the dimeric structures observed for other trans-cis (anti) rotamers utilize only one N–H bond per urea (Figure 6), both N–H bonds are utilized for H₂detu^ArCl₃, such that the hydrogen bonding network is described by the binary graph set $C_2^2$(11)[ $R_2^2$(9)].

The extended structure of H₂detu^Ar(OMe)₃ is unique because, in contrast to the other derivatives that form chains (H₂detu^ArCl₃ and H₂detu^ArOMe,NO₂), it does not utilize sulfur as a hydrogen bond acceptor.⁴⁹ Rather, each thiourea moiety of H₂detu^Ar(OMe)₃ exhibits two intermolecular N–H ⋯ O hydrogen bonding interactions, one with an oxygen atom of the diethoxyethyl group and one with an oxygen atom of a methoxy group (Figure 10). The overall result may be described as a polymeric chain of “head-to-head” H₂detu^Ar(OMe)₃ dimeric units, each of which is composed of a 16-membered ring with a basic [ $R_2^2$(16)] motif.

Molecular structures of 1-arylimidazole-2-thiones

The molecular structures of Hmim^Ar [Ar = 3,4,5-C₆H₂(OMe)₃, 2,4-C₆H₃(NO₂)(OMe), 2,4,6-C₆H₂Cl₃ and 3,5-C₆H₃(CF₃)₂] have been determined by X-ray diffraction, as illustrated in Figures 11 – 14.

Figure 11.

Molecular structure of hydrogen bonded Hmim^ArCl₃.

Figure 14.

Molecular structure of hydrogen bonded Hmim^ArOMe,NO₂.

Each of the compounds exists as a “head-to-head” hydrogen bonded dimer in the solid state, with an [ $R_2^2$(8)] motif, which is common for this class of compound.⁵⁰ However, while the hydrogen-bonded dimers of Hmim^ArCl₃ and Hmim^Ar(OMe)₃ are planar, those of Hmim^Ar(CF₃)₂ and Hmim^ArOMe,NO₂ are extremely puckered, as illustrated for the latter in Figure 15.

Figure 15.

View of the non-planar hydrogen bonded [ $R_2^2$(8)] motif in Hmim^ArOMe,NO₂.

For example, the fold angle about the S ⋯ S vector for Hmim^ArOMe,NO₂ is 45.7° (Table 3). Nevertheless, despite the varying deviations from planarity among the Hmim^Ar compounds reported here, their N–H ⋯ S hydrogen bond distances do not vary dramatically (Table 3). Although a possible explanation for the large deviation for Hmim^ArOMe,NO₂ could be attributed to the presence of an ortho NO₂ substituent, it should be recognized that the methyl derivative, Hmim^Me, also exhibits a highly bent [ $R_2^2$(8)] ring, with a fold angle of 58.2°,⁵¹ which indicates that steric factors are not likely responsible. Thus, it is evident that the nonplanarity of the 8-membered hydrogen bond rings in this system is dictated by packing forces rather than any electronic effect that influences the N–H ⋯ S hydrogen bonding interactions.

Table 3.

Selected metrical data for Hmim^Ar derivatives.

	d(C=S)/Å	N1–C–N2/°	d(N ⋯ S)/Å	d(H ⋯ S)Å	N–H ⋯ S/°	Fold Angle/°a	Ar twist/°b
HmimArCl3	1.6881(12)	104.96(10)	3.2511(11)	2.413(19)	174.1(17)	0.00	89.13
HmimAr(OMe)3	1.6896(17)	104.94(14)	3.2662(15)	2.36(2)	171.2(17)	0.00	56.77
HmimAr(CF3)2	1.692(2), 1.692(2)	105.23(18), 104.87(18)	3.278(2), 3.284(2)	2.50(1), 2.45(3)	178(3), 168(3)	22.87	43.65, 45.94
	1.692(2), 1.689(2)	104.85(19), 104.72(18)	3.291(2), 3.260(2)	2.46(3), 2.43(3)	178(3), 160(3)	23.47	42.28, 49.09
	1.692(2), 1.690(2)	105.19(19), 105.5(2)	3.370(2), 3.206(2)	2.54(4), 2.39(4)	167(4), 170(3)	26.19	44.52, 58.72
HmimArOMe,NO2	1.698(2)	105.1(2)	3.292(2)	2.39(3)	173(3)	45.72	68.07

^(a)angle between planes defined by S₁–C₁–N₁ ⋯ S₂ and S₂–C₂–N₂ ⋯ S₁.

^(b)angle between planes defined by the 5-membered heterocycle and 6-membered aryl rings.

Conclusions

In summary, the structures of imidazole-2-thiones that feature electronically diverse 1-aryl substituents, namely Hmim^Ar [Ar = 3,4,5-C₆H₂(OMe)₃, 2,4-C₆H₃(NO₂)(OMe), 2,4,6-C₆H₂Cl₃ and 3,5-C₆H₃(CF₃)₂], have been determined by X-ray diffraction and shown to exist as “head-to-head” hydrogen-bonded dimers in the solid state, with [ $R_2^2$(8)] motifs. The N,N′-aryldiethoxyethylthiourea precursors (H₂detu^Ar) have also been analyzed by X-ray diffraction, thereby demonstrating that the structures are strongly influenced by the nature of the aryl substituents, especially with respect to intermolecular hydrogen bonding interactions. For example, H₂detu^Ar(CF₃)₂ is a dimer that features 8-membered rings, H₂detu^ArOMe,NO₂ consists of chains of 6-membered rings, H₂detu^ArCl₃ consists of chains of 9-membered rings, and H₂detu^Ar(OMe)₃ consists of chains of 16-membered rings. In addition to these different hydrogen bonding networks, the substituents also influence the trans-trans (syn) and trans-cis (anti) preferences. Thus, H₂detu^ArCl₃ and H₂detu^Ar(OMe)₃ adopt a trans-cis (anti) disposition of N–H groups, whereas H₂detu^Ar(CF₃)₂ and H₂detu^ArOMe,NO₂ adopt a trans-trans (syn) disposition. N,N′-aryldiethoxyethylthioureas have not been previously structurally characterized and the variety of hydrogen bonding networks observed here have ramifications with respect to the use of such compounds in crystal engineering.

Experimental Section

General Considerations

NMR spectra were measured on Bruker 400 DRX and Bruker Avance 500 DMX spectrometers. ¹H NMR spectra are reported in ppm relative to SiMe₄ (δ = 0) and were referenced internally with respect to the protio solvent impurity (δ 7.16 for C₆D₅H and 2.50 for Me₂SO-d₅).^{52 13}C NMR spectra are reported in ppm relative to SiMe₄ (δ = 0) and were referenced internally with respect to the solvent (δ 39.52 for Me₂SO-d₅).^{52 19}F NMR spectra are reported in ppm relative to CFCl₃ (δ = 0) and were obtained by using the Ξ/100% value of 94.094011.⁵³ Coupling constants are given in hertz. All chemicals were purchased from Sigma-Aldrich.

X‐ray structure determinations

Single crystal X-ray diffraction data were collected on a Bruker Apex II diffractometer and crystal data, data collection and refinement parameters are summarized in Table 4. All data were corrected for absorption (SADABS) and the structures were solved using direct methods and standard difference map techniques, and were refined by full‐matrix least‐squares procedures on F² with SHELXTL (Version 6.12).⁵⁴ Hydrogen atoms attached to carbon were refined in calculated positions (AFIX 43 for sp CH groups, AFIX 23 for sp² CH₂ groups, AFIX 13 for sp³ CH groups, and AFIX 137 for methyl groups) with a displacement parameter of U_iso(H) = 1.2U_iso(C) for CH and CH₂ groups and U_iso(H) = 1.5U_iso(C) for CH₃ groups. The positional parameters of hydrogen atoms attached to nitrogen were refined freely, while the displacement parameters were either freely refined or assigned values of U_iso(H) = 1.2U_iso(N). The CF₃ groups of H₂detu^Ar(CF₃)₂ and Hmim^Ar(CF₃)₂ were disordered and were modeled by using SADI, SIMU, ISOR and RIGU commands for the disordered components. Molecular structures were viewed using SHELXTL⁵⁴ and Mercury.⁵⁵

Table 4.

Crystal, intensity collection and refinement data.

	H2detuArCl3	H2detuAr(OMe)3	H2detuAr(CF3)2	H2detuArOMe,NO2
crystal system	Monoclinic	Triclinic	Monoclinic	Monoclinic
formula	C13H17Cl3N2O2S	C16H26N2O5S	C15H18F6N2O2S	C14H21N3O5S
formula weight	371.70	358.45	404.37	343.40
space group	P21/c	P1̄	P21/n	P21/c
a/Å	6.769(2)	10.344(3)	12.5507(13)	13.241(4)
b/Å	23.886(8)	12.952(4)	13.4265(14)	15.160(4)
c/Å	10.834(4)	13.814(4)	21.715(2)	8.398(2)
α/°	90	95.357(4)	90	90
β/°	90.947(5)	95.836(4)	98.920(2)	101.009(4)
γ/°	90	92.996 (4)	90	90
V/Å3	1751.4(10)	1829.5(9)	3615.0(6)	1654.7(8)
Z	4	4	8	4
temperature (K)	150(2)	150(2)	150(2)	150(2)
radiation (λ, Å)	0.71073	0.71073	0.71073	0.71073
ρ (calcd.) g cm-3	1.410	1.301	1.486	1.378
μ (Mo Kα), mm-1	0.646	0.204	0.250	0.224
θ max, deg.	30.67	30.36	30.03	28.28
no. of data collected	27726	28972	55289	8040
no. of data	5411	10893	10539	4104
no. of parameters	200	458	713	219
R1 [I > 2ω(I)]	0.0505	0.0498	0.0509	0.0558
wR2 [I > 2ω(I)]	0.0986	0.1144	0.1153	0.0641
R1 [all data]	0.0991	0.1013	0.0844	0.1648
wR2 [all data]	0.1151	0.1356	0.1331	0.0834
Rint	0.0703	0.0547	0.0412	0.1117
GOF	1.015	1.027	1.019	1.003

	HmimArCl3	HmimAr(OMe)3	HmimAr(CF3)2	HmimArOMe,NO2
crystal system	Monoclinic	Monoclinic	Orthorhombic	Monoclinic
formula	C9H5Cl3N2S	C12H14N2O3S	C11H6F6N2S	C10H9N3O3S
formula weight	279.56	266.31	312.24	251.26
space group	P21/c	P21/c	P212121	C2/c
a/Å	7.4408(8)	7.2383(6)	8.4302(5)	13.747(5)
b/Å	20.454(2)	7.9459(7)	23.8152(15)	12.625(4)
c/Å	7.1759(8)	22.324(2)	36.666(2)	13.632(5)
α/°	90	90	90	90
β/°	91.0376(14)	93.0750(10)	90	106.496(5)
γ/°	90	90	90	90
V/Å3	1091.9(2)	1282.12(19)	7361.4(8)	2268.7(14)
Z	4	4	24	8
temperature (K)	130(2)	150(2)	130(2)	130(2)
radiation (λ, Å)	0.71073	0.71073	0.71073	0.71073
ρ (calcd.) g cm-3	1.701	1.380	1.690	1.471
μ (Mo Kα), mm-1	0.993	0.254	0.329	0.285
θ max, deg.	30.51	30.61	32.63	26.37
no. of data collected	17407	7575	117976	12681
no. of data	3337	3945	22429	2330
no. of parameters	139	170	1247	158
R1 [I > 2ω(I)]	0.0276	0.0426	0.0381	0.0449
wR2 [I > 2ω(I)]	0.0722	0.0914	0.0882	0.1128
R1 [all data]	0.0283	0.0745	0.0358	0.0550
wR2 [all data]	0.0728	0.1042	0.0872	0.1182
Rint	0.0327	0.0417	0.0256	0.0670
GOF	1.128	1.049	1.082	1.120
Flack parameter	–	–	0.34(4)	–

Syntheses

H₂detu^ArCl₃

Aminoacetaldehyde diethyl acetal (6.5 g, 49 mmol) was added via syringe over a period of 1 minute to a rapidly stirred solution of 2,4,6-trichlorophenyl isothiocyanate (13.1 g, 55 mmol) in EtOH (250 mL). The mixture was refluxed for 3 hours under an inert atmosphere. After this period, the solvent was removed in vacuo and the residue obtained was dissolved in CH₂Cl₂ (100 mL). Pentane (100 mL) was added to the solution, thereby resulting in the formation of a suspension that was placed overnight at −15°C. The mixture was filtered and the precipitate was dried in vacuo to give H₂detu^ArCl₃ as a white solid (17.7 g, 98%). Colorless crystals of H₂detu^ArCl₃ suitable for X-ray diffraction were obtained via slow diffusion of hexanes into a solution in CH₂Cl₂. Anal. calcd. for H₂detu^ArCl₃: C, 42.0; H, 4.6; N, 7.5. Found: C, 42.0; H, 4.3; N, 7.5. ¹H NMR (Me₂SO-d⁶): δ 1.14 [br s, 6H of C(H)(OCH₂CH₃)₂], 3.53 [br s, 4H of C(H)(OCH₂CH₃)₂], 3.64 [br s, 2H of NCH₂C(H)(OCH₂CH₃)₂], 4.70 [br s, 1H of C(H)(OCH₂CH₃)₂], 7.71 [br s, 2H of C₆H₂Cl₃], 7.87 [br s, 1H of NH], 9.27 [br s, 1H of NH]. ¹³C{¹H} NMR (Me₂SO-d⁶): δ 15.3 [CH₃ of C(H)(OCH₂CH₃)₂], 46.9 [CH₂ of NCH₂C(H)(OCH₂CH₃)₂], 62.0 [CH₂ of C(H)O(CH₂CH₃)₂], 99.7 [CH of C(H)(OCH₂CH₃)₂], 128.2 [CH of C₆H₂Cl₃], 128.4 [CH of C₆H₂Cl₃], 132.4 [C of C₆H₂Cl₃], 136.0 [C of C₆H₂Cl₃], not observed [C=S].

Hmim^ArCl₃

A rapidly stirred solution of H₂detu^ArCl₃ (16.7 g, 45 mmol) in a mixture of EtOH:H₂O (250 mL, 9:1) was treated with HCl_aq (3.4 mL of 12.1 M, 41 mmol) and the mixture was refluxed for 3 hours under an inert atmosphere, resulting in the slow formation of a white precipitate. After this period, the mixture was filtered and the precipitate was dried in vacuo to give Hmim^ArCl₃ as a white solid (13.4 g, 94%). Colorless crystals of Hmim^ArCl₃ suitable for X-ray diffraction were obtained via slow evaporation of a solution in Me₂SO on a watch glass. Anal. calcd. for Hmim^ArCl₃: C, 38.7; H, 1.8; N, 10.0. Found: C, 38.3; H, 1.7; N, 9.8. ¹H NMR (Me₂SO-d⁶): δ 7.11 [t, ³J_H-H = 2, 1H of C₃H₃N₂S], 7.15 [t, ³J_H-H = 2, 1H of C₃H₃N₂S], 7.91 [s, 2H of C₆H₂Cl₃], 12.5 [s, 1H of NH]. ¹³C{¹H} NMR (Me₂SO-d⁶): δ 116.3 [CH of C₃H₃N₂S], 118.7 [CH of C₃H₃N₂S], 128.7 [CH of C₆H₂Cl₃], 132.7 [C of C₆H₂Cl₃], 134.9 [C of C₆H₂Cl₃], 135.1 [C of C₆H₂Cl₃], 162.9 [C=S].

H₂detu^Ar(OMe)₃

Aminoacetaldehyde diethyl acetal (1.8 g, 14 mmol) was added via syringe over a period of 1 minute to a rapidly stirred solution of 3,4,5-trimethoxyphenyl isothiocyanate (3.3 g, 15 mmol) in EtOH (200 mL). The mixture was refluxed for 2 hours under an inert atmosphere. After this period, the solvent was removed in vacuo and the residue obtained was dissolved in dichloromethane (100 mL). Pentane (100 mL) was added to the solution, thereby resulting in the formation of a suspension. The mixture was filtered and the precipitate was dried in vacuo to give H₂detu^Ar(OMe)₃ as a white solid (4.5 g, 93%). Colorless crystals of H₂detu^Ar(OMe)₃ suitable for X-ray diffraction were obtained via slow diffusion of hexanes into a solution in CH₂Cl₂. Anal. calcd. for H₂detu^Ar(OMe)₃: C, 53.6; H, 7.3; N, 7.8. Found: C, 53.4; H, 7.1; N, 7.7. ¹H NMR (Me₂SO-d⁶): δ 1.13 [t, ³J_H-H = 7, 6H of C(H)(OCH₂CH₃)₂], 3.50 [m, 2H of NCH₂C(H)(OCH₂CH₃)₂], 3.59 [m, 4H of C(H)(OCH₂CH₃)₂], 3.64 [s, 3H of para-C₆H₂(OCH₃)₃], 3.75 [s, 6H of meta-C₆H₂(OCH₃)₃], 4.71 [t, ³J_H-H = 5, 1H of C(H)(OCH₂CH₃)₂], 6.75 [s, 2H of C₆H₂(OCH₃)₃], 7.49 [s, 1H of NH], 9.60 [s, 1H of NH]. ¹³C{¹H} NMR (Me₂SO-d⁶): δ 15.3 [CH₃ of C(H)(OCH₂CH₃)₂], 46.3 [CH₂ of NCH₂C(H)(OCH₂CH₃)₂], 55.8 [CH₃ of C₆H₃(OCH₃)₃], 60.0 [CH₃ of C₆H₃(OCH₃)₃], 61.6 [CH₂ of C(H)(OCH₂CH₃)₂], 99.7 [CH of C(H)(OCH₂CH₃)₂], 101.1 [CH of C₆H₂(OCH₃)₃], 134.5 [C of C₆H₃(OCH₃)₃], 134.6 [C of C₆H₂(OCH₃)₃], 152.7 [C of C₆H₂(OCH₃)₃], 180.3 [C=S].

Hmim^Ar(OMe)₃

A rapidly stirred solution of H₂detu^Ar(OMe)₃ (4.8 g, 13 mmol) in a mixture of EtOH:H₂O (200 mL, 9:1) was treated with HCl_aq (1.4 mL of 12.1 M, 17 mmol) and the mixture was refluxed for 3 hours under an inert atmosphere. After this period, the volatile components were removed in vacuo from the resulting yellow solution. The residue obtained was dissolved in EtOH (ca. 50 mL) and placed overnight at −15°C, thereby depositing a white precipitate. The mixture was filtered and the precipitate was dried in vacuo to give Hmim^Ar(OMe)₃ as a white solid (2.3 g, 65%). Colorless crystals of Hmim^Ar(OMe)₃ suitable for X-ray diffraction were obtained via slow diffusion of hexanes into a solution in CH₂Cl₂. Anal. calcd. for Hmim^Ar(OMe)₃: C, 54.1; H, 5.3; N, 10.5. Found: C, 53.9; H, 5.3; N, 10.2. ¹H NMR (Me₂SO-d⁶): δ 3.70 [s, 3H of para-C₆H₂(OCH₃)₃], 3.80 [s, 6H of meta-C₆H₂(OCH₃)₃], 7.00 [s, 2H of C₆H₂(OCH₃)₃], 7.05 [d, ³J_H-H = 2, 1H of C₃H₃N₂S], 7.29 [d, ³J_H-H = 2, 1H of C₃H₃N₂S], 12.36 [br s, 1H of NH]. ¹³C{¹H} NMR (Me₂SO-d⁶): δ 56.1 [CH₃ of C₆H₂(OCH₃)₃], 60.1 [CH₃ of C₆H₂(OCH₃)₃], 103.7 [CH of C₆H₂(OCH₃)₃], 115.2 [CH of C₃H₃N₂S], 119.7 [CH of C₃H₃N₂S], 133.5 [C of C₆H₂(OCH₃)₃], 136.6 [C of C₆H₂(OCH₃)₃], 152.6 [C of C₆H₂(OCH₃)₃], 161.5 [C=S].

H₂detu^Ar(CF₃)₂

Aminoacetaldehyde diethyl acetal (4.6 g, 35 mmol) was added via syringe over a period of 1 minute to a rapidly stirred solution of 3,5-bis(trifluoromethyl)phenyl isothiocyanate (8.8 g, 32 mmol) in EtOH (250 mL). The mixture was refluxed for 2 hours under an inert atmosphere. After this period, the solvent was removed in vacuo and the residue obtained was dissolved in Me₂CO (100 mL) to give a pale yellow solution. Pentane (ca. 100 mL) was added to the solution until the onset of precipitation was observed. At this point, the mixture was placed at -15°C for 2 days, after which the resulting suspension was filtered to give H₂detu^Ar(CF₃)₂ as colorless crystals, suitable for X-ray diffraction, that were dried in vacuo (9.7 g, 74%). Anal. calcd. for H₂detu^Ar(CF₃)₂: C, 44.6; H, 4.5; N, 6.9. Found: C, 44.8; H, 4.4; N, 7.0. ¹H NMR (Me₂SO-d⁶): δ 1.15 [t, ³J_H-H = 7, 6H of C(H)(OCH₂CH₃)₂], 3.53 [m, 2H of NCH₂C(H)(OCH₂CH₃)₂], 3.64 [m, 4H of C(H)(OCH₂CH₃)₂], 4.71 [t, ³J_H-H = 5, 1H of C(H)(OCH₂CH₃)₂], 7.71 [s, 1H of para-C₆H₃(CF₃)₂], 8.10 [br s, 1H of NH], 8.27 [s, 2H of ortho-C₆H₃(CF₃)₂], 10.21 [br s, 1H of NH]. ¹³C{¹H} NMR (Me₂SO-d⁶): δ 15.2 [CH₃ of C(H)(OCH₂CH₃)₂], 46.4 [CH₂ of NCH₂C(H)(OCH₂CH₃)₂], 61.7 [CH₂ of C(H)(OCH₂CH₃)₂], 99.4 [CH of C(H)(OCH₂CH₃)₂], 116.1 [CH of C₆H₃(CF₃)₂], 121.8 [CH of C₆H₃(CF₃)₂], 123.2 [q, ¹J_C-F = 273, C₆H₃(CF₃)₂], 130.2 [q, ²J_C-F = 33, C-CF₃ of C₆H₃(CF₃)₂], 141.8 [C of C₆H₃(CF₃)₂], 180.8 [C=S]. ¹⁹F{¹H} NMR (Me₂SO-d⁶): δ -61.8.

Hmim^Ar(CF₃)₂

A rapidly stirred solution of H₂detu^Ar(CF₃)₂ (5.6 g, 14 mmol) in a mixture of EtOH:H₂O (200 mL, 9:1) was treated with HCl_aq (1.4 mL of 12.1 M, 17 mmol) and the mixture was refluxed for 2 hours under an inert atmosphere. After this period, the solvent was removed in vacuo and the residue obtained was dissolved in EtOAc (100 mL). Pentane (100 mL) was added to the solution, which was placed overnight at −15°C, thereby depositing colorless crystals of Hmim^Ar(CF₃)₂, which were suitable for X-ray diffraction (3.0 g, 69%). Anal. calcd. for Hmim^Ar(CF₃)₂: C, 42.3; H, 1.9; N, 9.0. Found: C, 42.3; H, 1.8; N, 8.9. ¹H NMR (Me₂SO-d⁶): δ 7.16 [t, ³J_H-H = 2, 1H of C₃H₃N₂S], 7.58 [t, ³J_H-H = 2, 1H of C₃H₃N₂S], 8.15 [s, 1H of para-C₆H₃(CF₃)₂], 8.52 [s, 2H of ortho-C₆H₃(CF₃)₂], 12.62 [br s, 1H of NH]. ¹³C{¹H} NMR (Me₂SO-d⁶): δ 116.0 [CH of C₃H₃N₂S], 119.2 [CH of C₃H₃N₂S], 121.1 [septet, ³J_C-F = 4, para-CH of C₆H₃(CF₃)₂], 122.9 [q, ¹J_C-F = 273, C₆H₃(CF₃)₂], 126.5 [q, ³J_C-F = 4, ortho-CH of C₆H₃(CF₃)₂], 130.5 [q, ²J_C-F = 33, C-CF₃ of C₆H₃(CF₃)₂], 139.1 [C-N of C₆H₃(CF₃)₂], 162.2 [C=S]. ¹⁹F{¹H} NMR (Me₂SO-d⁶): δ -61.4.

H₂detu^ArOMe,NO₂

Aminoacetaldehyde diethyl acetal (15.8 g, 118 mmol) was added via syringe over 1 minute to a rapidly stirred solution of 4-methoxy-2-nitrophenyl isothiocyanate (24.7 g, 118 mmol) in EtOH (300 mL). The mixture was refluxed for 90 minutes under an inert atmosphere. After this period, the solvent was removed in vacuo and the residue obtained was dissolved in CH₂Cl₂ (100 mL). Pentane (ca. 100 mL) was added to the solution until the onset of precipitation was observed. At this point, the mixture was placed at -15°C overnight, after which the resulting bright yellow suspension was filtered and dried in vacuo to give H₂detu^ArOMe,NO₂ as flocculent, yellow crystals (28.4 g, 70%). Yellow crystals suitable for X-ray diffraction were obtained via slow diffusion of hexanes into a solution in CH₂Cl₂. Anal. calcd. for H₂detu^ArOMe,NO₂: C, 49.0; H, 6.2; N, 12.2. Found: C, 49.1; H, 6.1; N, 12.3. ¹H NMR (Me₂SO-d⁶): δ 1.15 [t, ³J_H-H = 7, 6H of C(H)(OCH₂CH₃)₂], 3.54 [m, 4H of C(H)(OCH₂CH₃)₂], 3.64 [m, 2H of NCH₂C(H)(OCH₂CH₃)₂], 3.85 [s, 3H of C₆H₃(NO₂)(OCH₃)], 4.66 [t, ³J_H-H = 5, 1H of C(H)(OCH₂CH₃)₂], 7.27 [dd, ³J_H-H = 9, ⁴J_H-H = 3, 1H of C₆H₃(NO₂)(OCH₃)], 7.49 [d, ⁴J_H-H = 3, 1H of C₆H₃(NO₂)(OCH₃)], 7.57 [d, ³J_H-H = 9, 1H of C₆H₃(NO₂)(OCH₃)], 8.13 [m, 1H of NH], 9.51 [s, 1H of NH]. ¹³C{¹H} NMR (Me₂SO-d⁶): δ 15.3 [CH₃ of C(H)(OCH₂CH₃)₂], 46.8 [CH₂ of NCH₂C(H)(OCH₂CH₃)₂], 56.0 [CH₃ of C₆H₃(NO₂)(OCH₃)], 61.9 [CH₂ of C(H)(OCH₂CH₃)₂], 99.7 [CH of C(H)(OCH₂CH₃)₂], 108.6 [CH of C₆H₃(NO₂)(OCH₃)], 119.7 [CH of C₆H₃(NO₂)(OCH₃)], 126.1 [C of C₆H₃(NO₂)(OCH₃)], 131.6 [CH of C₆H₃(NO₂)(OCH₃)], 145.1 [C of C₆H₃(NO₂)(OCH₃)], 156.8 [C of C₆H₃(NO₂)(OCH₃)], 182.5 [C=S].

Hmim^ArOMe,NO₂

A rapidly stirred solution of H₂detu^ArOMe,NO₂ (27.1 g, 79 mmol) in a mixture of EtOH:H₂O (300 mL, 9:1) was treated with HCl_aq (6.0 mL of 12.1 M, 73 mmol). The mixture was refluxed for 3 hours under an inert atmosphere, resulting in the formation of a light orange precipitate. The mixture was allowed to cool to room temperature and filtered. The precipitate was washed with EtOH (ca. 50 mL) and dried in vacuo to give Hmim^ArOMe,NO₂ as a yellow-orange solid (18.4 g, 93%). Orange crystals suitable for X-ray diffraction were obtained via slow evaporation of a solution in Me₂SO on a watch glass. Anal. calcd. for Hmim^ArOMe,NO₂: C, 47.8; H, 3.6; N, 16.7. Found: C, 47.4; H, 3.3; N, 16.3. ¹H NMR (Me₂SO-d⁶): δ 3.92 [s, 3H of C₆H₃(NO₂)(OCH₃)], 7.08 [t, ³J_H-H = 2, 1H of C₃H₃N₂S], 7.24 [t, ³J_H-H = 2, 1H of C₃H₃N₂S], 7.43 [dd, ³J_H-H = 9, ⁴J_H-H = 3, 1H of C₆H₃(NO₂)(OCH₃)], 7.51 [d, ³J_H-H = 9, 1H of C₆H₃(NO₂)(OCH₃)], 7.67 [d, ⁴J_H-H = 3, 1H of C₆H₃(NO₂)(OCH₃)], 12.37 [s, 1H of NH]. ¹³C{¹H} NMR (Me₂SO-d⁶): δ 56.4 [C₆H₃(NO₂)(OCH₃)], 110.3 [CH of C₆H₃(NO₂)(OCH₃)], 115.6 [CH of C₃H₃N₂S], 119.8 [CH of C₃H₃N₂S], 119.9 [CH of C₆H₃(NO₂)(OCH₃)], 123.6 [C of C₆H₃(NO₂)(OCH₃)], 131.5 [CH of C₆H₃(NO₂)(OCH₃)], 146.4 [C of C₆H₃(NO₂)(OCH₃)], 159.4 [C of C₆H₃(NO₂)(OCH₃)], 162.9 [C=S].

Figure 9.

Hydrogen bonding network for H₂detu^ArCl₃.

Figure 12.

Molecular structure of hydrogen bonded Hmim^Ar(OMe)₃.

Figure 13.

Molecular structure of hydrogen bonded Hmim^Ar(CF₃)₂. Only two of the six crystallographically independent molecules are shown.