The C=N⋯C–X σ-hole interaction acts as a conformational lock

Abstract

An interesting C=N⋯C–X conformation lock, which determines the linear alignment of the C=N and C–X fragments, has been found for the first time and is rationalized by density functional theory calculations. Second-order perturbation theory analysis based on the NBO method further reveals that the nature of the C=N⋯C–X interaction is mainly the lp(C=N) → σ*(C–X) interaction.

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Conformations of single molecules are primarily dominated by noncovalent interactions.^1–4 The interaction dictating molecular conformation is frequently referred to as a conformation lock. The usual type of conformation lock is hydrogen bonding.^1,2 There are also other types of noncovalent interactions^3,4 which can serve as a conformation lock, where the bridging atom is not a H but a member of group IV, V, VI or VII. These interactions usually share certain structural features: there is a positive region on the extension of the σ-bonds in the acceptor segment, which is frequently called a σ-hole,^5–8 or (and) a positive region above groups, such as C=O, C≡N etc., which is sometimes denoted as a π-hole. Whether a σ-hole or π-hole, one of the positive regions is drawn toward either a lone pair or a π-bond, thus leading to two intramolecular segments lying close to one another. Given that molecular conformation influences supramolecular assembly of any crystal, the physical properties of materials,⁹ and the reactivity and selectivity of the reactions,¹⁰ it is of vital importance to explore the molecular conformation and the conformation lock.

(E)-N′-Benzylidene-2-cyanoacetohydrazides are interesting model molecules with C=N and CH₂C≡N groups separated by rotatable chemical bonds. The former, C=N, can serve as an electron-donor (N lone pair), and the latter, C≡N, can generate two positive regions, one on the neighboring atom C2 (σ-hole), and one above itself (π-hole). Would the CH₂C≡N group generate a σ-hole interaction or a competitive π-hole interaction with the C=N group? Once one of the two interactions occurs, it would lock up the molecular conformation. Therefore, here the σ-hole (or the π-hole) interaction is expected to be an effective and reliable instrument for conformation control. As far as our knowledge extends, the C=N⋯C–CN conformation lock has not been studied in the literature. Thus, we have designed and synthesized a series of such model compounds, and examined their X-ray crystal structures. Due to the strong electron-withdrawing ability of the C≡N group, the σ-hole on C2 becomes more positive. Thus, it is probable that the imino (C=N) lone pair will approach the σ-hole of the intramolecular CH₂C≡N fragment. Interestingly, this expectation is confirmed first by the X-ray crystal structure of 1 (Fig. 1). As shown in Fig. 1, the cyanomethyl group adopts a linear alignment to the imino fragment, the conformation allows the N2 lone pair to approach the σ-hole of the CH₂C≡N group. The distance of 2.761(2) Å between C2 and N2 is significantly shorter than the sum of the van der Waals radii, 3.25 Å. The characteristic geometry suggests a C=N⋯C–CN σ-hole interaction. Molecular electrostatic potentials (Fig. 2) of 1 have further confirmed its existence. As illustrated in Fig. 2, there is a red negative region above the imino atom N2 corresponding to the N lone pair, and a blue positive region (the σ-hole) on the extension of the N≡C–C bond.

Fig. 1 Structure of 2-cyano-N′-[(1E)-(4-hydroxyphenyl)methylidene]-acetohydrazide, 1, showing both experimentally and theoretically the linear alignment of the cyanomethyl to the imino group, and the underlying C=N⋯C–CN interaction; the distances N2⋯C2 from experimental and DFT calculations are 2.761 and 2.764 Å, respectively.

Fig. 2 WB97XD/6-311+g(d,p) electrostatic potential at 0.001 a.u. isosurface of electron density for the 2-cyano-N′-[(1E)-(4-hydroxyphenyl)-methylidene]acetohydrazide, 1. The blue region represents the positive part of the electrostatic potential, and the red region is the negative part of the electrostatic potential.

Recent studies have shown the existence of N⋯C interactions.^11–13 However, the studies on this subject still remain theoretical, and the reported N⋯C interactions occur only intermolecularly. Computational study shows that the N⋯C interactions can occur between electron-donors, such as NH₃ or C≡N, and electron-acceptors CH₃X (X = CN, OH, F), and that the amino (or cyano) atom N was found to lie on the extension of X–C bond. Here the C=N⋯C–CN interaction in 1, though different in the electron-donor, is very similar to the C≡N⋯CH₃CN and H₃N⋯CH₃OH interactions.

Considering that the natural bond orbital (NBO) theory^14,15 is quite useful for quantitatively analyzing intramolecular interactions,¹⁶ in order to characterize the C=N⋯C–CN conformation lock via orbital interactions, the density functional theory (DFT) calculations were conducted on molecule 1 at the WB97XD¹⁷/6-311+G(d,p) levels using the crystal coordinates. The optimized geometries were further used for the NBO analysis with NBO version 3.1¹⁸ incorporated in the GAUSSIAN 09¹⁹ package. The result shows that the optimized conformation is in good agreement with crystallographically determined structure 1 (Fig. 1), suggesting that the linear orientation of the C=N to C–CN unit is caused not by crystal packing but by a certain intramolecular noncovalent interaction between imino and cyanomethyl fragments. The NBO analysis further shows that there are three intramolecular orbital interactions, A, B, C (Table 1) involved in the C=N⋯C–CN interaction, out of which only the strongest interaction, A is shown in Fig. 3. As shown in Fig. 3 and the Table 1, the lone pair on the imino atom N2 interacts with the σ*-antibonding orbital of the C2–CN bond, with a concomitant second-order stabilization energy of E(2) = 1.03 kcal mol⁻¹. The total orbital interaction energy that attributed to the C=N⋯C–CN interaction is 2.49 kcal mol⁻¹. The result has theoretically confirmed that the orbital interactions, though not strong, are the decisive factors for the linear alignment of the cyanomethyl and imino fragments.

Table 1 Stabilization energies for selected NBO pairs in 1–8, 10, as given by second-order perturbation theory analysis of the Fock matrix in the NBO basis, obtained from WB97XD/6-311+G(d,p)

Compounds	Pair name	Donor NBO	Acceptor NBO	E(2) energy (kcal mol^−1)
1	A	lp(N2)	σ*(C2–CN)	1.03
	B	lp(N2)	σ*(C2–C1)	0.76
	C	σ(C4=N2)	RY*(C2)	0.70
2	A	lp(N2)	σ*(C2–CN)	1.00
	B	lp(N2)	σ*(C2–C1)	0.75
	C	σ(C4=N2)	RY*(C2)	0.69
3	A	lp(N2)	σ*(C2–CN)	1.00
	B	lp(N2)	σ*(C2–C1)	0.75
	C	σ(C4=N2)	RY*(C2)	0.69
4	A	lp(N2)	σ*(C2–CN)	1.00
	B	lp(N2)	σ*(C2–C1)	0.75
	C	σ(C4=N2)	RY*(C2)	0.70
5	A	lp(N2)	σ*(C2–F1)	1.54
	B	lp(N2)	σ*(C2–C1)	0.54
6	A	lp(N2)	σ*(C2–Cl1)	1.52
	B	lp(N2)	σ*(C2–C1)	0.65
7	A	lp(N2)	σ*(C2–Cl1)	1.66
	B	lp(N2)	σ*(C2–C1)	0.67
8	A	lp(N2)	σ*(C2–Cl1)	1.50
	B	lp(N2)	σ*(C2–C1)	0.65
10	A	lp(N2)	σ*(C2–CN)	1.47
	B	lp(N2)	σ*(C2–C1)	1.00

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Fig. 3 Dominant orbital interaction A, lp(N2)→σ*(C2–C3≡N3), corresponding to the C=N⋯C–CN interaction in 1.

Given that the C=N⋯C–CN conformation lock occurs in 1, it is very probable that this kind of interaction will be found in analogues, 2–8. In order to verify our expectation, we have conducted the geometry optimization on molecules 2–8 using the same method as 1. Interestingly, the optimized molecular conformations and the main geometry parameters are in perfect accordance with those in 1 (Fig. 1); each of the cyanomethyl or halogenmethyl groups in 2–8 adopts a linear alignment to the imino fragment; the distance between C2 and N2 ranges from 2.722 to 2.741 Å. Molecular electrostatic potentials show that the conformations are fixed by the C=N⋯C–X (X = CN, Cl, Br) σ-hole interaction. As typical representatives, the molecular electrostatic potentials of 7 and 8 are shown in Fig. 4. From this figure, it can be easily found that there exists a stronger C=N⋯CH₂X σ-hole interaction where the red negative region above N2 (N lone pair) interacts with the blue positive region (the σ-hole) on the atom C2. The results are in good agreement with data from the second-order perturbation theory analysis in the NBO basis. NBO analysis shows that there are three orbital interactions in 2–4 and two in 5–8 involved in the C=N⋯C–X interaction (Table 1). The total orbital interaction energy that attributed to the C=N⋯C–X interaction is in the range of 2.15–2.49 kcal mol⁻¹, which is enough strong to stabilize the molecular conformation. The results reveal that the C=N⋯C–X (X = CN, F, Cl, or Br) conformation lock does work universally in N′-[(1E)-phenylmethylidene]acetohydrazides.

Fig. 4 WB97XD/6-311+g(d,p) electrostatic potential at 0.001 a.u. isosurface of electron density for compounds N′-(4-hydroxybenzylidene)-2-bromoaceto-hydrazide, 7, and N′-benzylidene-2-chloroacetohydrazide, 8. The blue region represents the positive part of the electrostatic potential, and the red region is the negative part of the electrostatic potential.

In the C=N⋯C–X (X = CN, F, Cl, or Br) interaction, the imino unit acts as an electron-donor (lone pair), and the cyanomethyl (or halogenmethyl) as an electron-acceptor. If a strong and competitive electron-acceptor, such as the C6–OH in 9, is imported, a strong O–H⋯N=C hydrogen bond would be expected to be formed, thus probably preventing the formation of the C=N⋯C–CN interaction. Consequently, the molecular conformation should undergo a great change. Keeping our motivation in mind, we also crystallized compound 9. The crystal structure of 9 is illustrated in Fig. 5. As shown in this figure, the C6–OH group does form a strong O–H⋯N=C hydrogen bond, the O2–H2⋯N2 distance being only 1.76 Å, and the associated angle, 152°. According to NBO calculations, the total orbital interaction energy involved in the O–H⋯N=C interaction is up to 25.81 kcal mol⁻¹. Due to the formation of the strong H-bond, the relatively weak C=N⋯C–CN interaction has been prevented. As a result, the plane O1\C1\C2\C3\N3 rotates about 180° around the N1–C1 axis with respect to that in 1–4. From this point of view, the O2–H2⋯N2 hydrogen bond can be considered as an “obstacle” to the C=N⋯C–CN conformation lock.

Fig. 5 Crystal structure of 2-cyano-N′-[(1E)-(2-hydroxyphenyl)methylidene]-acetohydrazide, 9, showing the formation of the O2–H2⋯N2 hydrogen bond (the stabilization energy is 25.81 kcal mol⁻¹ according to NBO calculations), which is competitive with the C=N⋯C–CN conformation lock.

If the above “obstacle” doctrine is true, once the “obstacle” in 9 is destroyed by basification, the C=N⋯C–CN conformation lock should come into action, and are expected to be stronger than those in 1–4. In view of this, we also conducted a geometry optimization on the phenolic oxygen anion 10. Interestingly, the C=N⋯C–CN conformation lock does come back! As shown in Fig. 6, the linear alignment of the cyanomethyl and the imino is locked by the C=N⋯C–CN interaction, the distance between N2 and C2 being 2.670 Å, which is markedly shorter than the ones in 1–4. This reveals that once the O2–H2⋯N2 hydrogen bond is no longer in existence, the C=N⋯C–CN conformation lock is then in operation in the phenolic oxygen anion 10. NBO analysis shows that the stabilizing energies of the orbital interactions, A and B, involved in the C=N⋯C–CN conformation lock in 10 are 1.47 and 1.00 kcal mol⁻¹, respectively. So far, these examples from both sides have proved that the C=N⋯C–X conformation lock exists universally in N′-[(1E)-phenylmethylidene]acetohydrazides, and the lock can be opened by a strong intramolecular H-bond, such as O2–H2⋯N2 in 9. This suggests that the conformation of these compounds can be modified by pH adjustment.

Fig. 6 Structure of 2-((2-(2-cyanoacetyl)hydrazono)methyl)phenol oxygen anion, 10, optimized at WB97XD/6-311+G(d,p) level, showing the existence of the C=N⋯C–CN conformation lock; the distance N2⋯C2 is 2.670 Å.

In addition to the C=N⋯C–CN conformation lock, there are four intermolecular hydrogen bonds involved in the crystal packing of 1, one of N–H⋯O, one of O–H⋯N, and two of C–H⋯O type (Fig. 7). The distances N1–H1⋯O1, O2–H2⋯N3, C2–H2B⋯O1 and C2–H2A⋯O2 are 1.96, 1.86, 2.33 and 2.58 Å, respectively, and the corresponding angles 171, 171, 168 and 127°, respectively. These hydrogen bonds synergistically constitute a complicated 3D structure, the formation of which can be easily understood in the following way (Fig. 7). The molecules related by an n-glide plane form a zig–zag [101] chain via a strong O–H⋯N hydrogen bond; antiparallel chains of this type are laterally linked into a (−301) sheet by N–H⋯O and C2–H2A⋯O2 hydrogen bonds; these parallel sheets are finally interconnected into a 3D structure via a C2–H2B⋯O1 hydrogen bond.

Fig. 7 The part packing diagram of 1, showing the formation of a (−301) sheet. Symmetry codes: (i) −3/2 + x, 3/2 − y, −1/2 + z; (ii) 1/2 − x, −1/2 + y, 3/2 − z; (iii) 2 − x, 1 − y, 2 − z; (iv) −1 + x, y, z.

In conclusion, the work has revealed an interesting σ-hole C=N⋯C–X conformation lock existing universally in N′-[(1E)-phenylmethylidene]acetohydrazides. Ab initio calculations provided effective support for the interaction; second-order perturbation theory analysis of the Fock matrix on the NBO basis has confirmed that the conformation lock is in nature intramolecular charge transfer from the C=N lone pair into the σ*(C–X) antibonding orbital. We believe that the present work may be the first study on the conformation effect of the C=N⋯C–X σ-hole interaction.

Experimental

Synthesis of 1 and 9

To a solution of ethyl cyanoacetate (0.2 mol) in anhydrous ethanol (50 mL), was added hydrazine (80%, 0.25 mol), the reaction mixture was stirred at room temperature. The precipitate was filtered off, washed with anhydrous ethanol and dried to give pure cyanoacetohydrazide (12 g). As an intermediate, cyanoacetohydrazide (0.1 mol) was dissolved in anhydrous ethanol (50 mL), and then 4-hydroxy or 2-hydroxybenzaldehyde (0.1 mol) was added. The reaction mixture was refluxed for 20 min, and then cooled to room temperature. The solid was collected by filtration, washed with ethanol, and dried to yield compound 1 or 9 (15 g) as a crystalline solid. Crystals 1 and 9 suitable for an X-ray analysis were obtained by slow cooling of a hot acetonitrile solution of the corresponding product.

Crystal data of compounds 1 and 9

1 . C₁₀H₉N₃O₂, M = 203.20, monoclinic, P21/n, a = 4.7366(4), b = 11.1769(10), c = 18.9660(18) Å, α = 90, β = 97.015(2), γ = 90°, V = 996.55(15) ų, Z = 4, T = 296(2) K, D_c = 1.354 g cm⁻³; 5454 reflections collected, 1767 unique (R_int = 0.026), 1289 observed with I > 2σ(I); final R = 0.0345, wR₂ = 0.0866, goodness-of-fit S = 1.01.

9 . C₁₀H₉N₃O₂, M = 203.20, monoclinic, P21/n, a = 4.5944(3), b = 9.3525(4), c = 22.972(3) Å, α = 90, β = 94.883(2), γ = 90°, V = 983.50(15) ų, Z = 4, T = 296(2) K, D_c = 1.372 g cm⁻³; 14 740 reflections collected, 2971 unique (R_int = 0.035), 1796 observed with I > 2σ(I); final R = 0.0496, wR₂ = 0.1400, goodness-of-fit S = 1.01.

Acknowledgements

We gratefully acknowledge the support from the High Performance Computing Center of Henan Normal University.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1447696 and 1447697. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6nj02622b

‡ L. Wang and Z. Zhang contributed equally to this work.

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