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Prototropic behavior of cyclohexane substituted urethane and urea compounds. Observation of H-bond mediated 4HJH1H3 coupling constants across urea fragments
Tetrahedron 75 (2019) 130691
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Prototropic behavior of cyclohexane substituted urethane and urea compounds. Observation of H-bond mediated 4HJH1H3 coupling constants across urea fragments Maxim V. Mokeev a, Stepan A. Ostanin b, Vjacheslav V. Zuev a, b, * a b
Institute of Macromolecular Compounds of the Russian Academy of Sciences, Bolshoi pr. 31, 199004 Saint-Petersburg, Russian Federation ITMO University, Kronverkskiy pr. 49, 197101 Saint-Petersburg, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 June 2019 Received in revised form 12 October 2019 Accepted 13 October 2019 Available online 17 October 2019
Two 1-aryl-3-cyclohexylurea and two 1-aryl-3-cyclohexylurethane with and without alkyl tail in aryl fragments were synthesized and their variable-temperature 1H NMR spectra in chloroform, DMSO and DMF were recorded. The temperature dependences of chemical shift of NH protons for all compounds have been observed. The type of dependence has been explained by the aggregation of molecules and formation of ionic structures. The formation of intermolecular complexes leads to possible formation of symmetrical N1 … … H ……N3 intramolecular hydrogen bond in urea fragment. As a result,4hJH1H3 transhydrogen bond scalar coupling constants have been observed for the first time in low molecular weight compounds using a simple one-dimensional 1H NMR experiment. The formation of strong intramolecular H-bond leads to p-conjugation not only with spacer but with phenyl ring too. It support the Gilli conception that RAHB formation is a result of p-electron delocalization. The presence in urea fragment of such kind interaction leads to formation of ionic structure, which has been detected by NMR and UV spectroscopies. The formation of ionic structure can explain the catalytic activity of such compounds and the mechanism of transformation in organic and bioorganic reactions in which involved the urea compounds. © 2019 Elsevier Ltd. All rights reserved.
Keywords: NMR 1 H 13 C Prototropic behavior Cyclohexane Urea Urethane Temperature dependence
1. Introduction Organic catalysts based on H-bonding motifs are now very popular in organic and polymer synthesis [1,2]。 Considerable efforts in recent years have provided catalysts systems based on urea or thiourea that are highly active [3,4]。 The understanding of a mechanism of catalytic activity of these species is very important to address an extensive for a broad range of scientific and technological problems not only in chemistry, but also in medicine, biology, physics, and materials science [5]. One unusual observation is the fact that the catalytic activity of 1-aryl-3-cyclohexylurea with different substituents in phenyl ring is much higher than activity of diaryl analogues for the ring-opening polymerization of the lactones initiated urea/alkoxide or urea/amine catalytic systems [6]. Other motif for our investigation is comparison of urea and
* Corresponding author. Institute of Macromolecular Compounds of the Russian Academy of Sciences, Bolshoi pr. 31, 199004 Saint-Petersburg, Russian Federation. E-mail address: [email protected] (V.V. Zuev). https://doi.org/10.1016/j.tet.2019.130691 0040-4020/© 2019 Elsevier Ltd. All rights reserved.
urethane compounds because the well accepted statement believe that H-bonding in urea compounds is much stronger than in urethane analogues [7]. Therefore, can expect that the urethane also may been used as organocatalyst. This catalytic behavior can be connected with H-bond strengths into urea and urethane fragments. H-bond inside these fragments should be strong, and, therefore, be like to resonance-assisted Hbond, new type of strong H-bond where donor and acceptor are linked by a short p-conjugated fragment. We could go on to study this possibility because it is important for all H-bonds normally occurring in most chemical and biochemical systems. Here we aim to clarify how the 1-aryl-3-cyclohexylurea and 1aryl-3-cyclohexylurethane form H-bonds and makes proton exchange with surrounding solvent or the same molecules depending on the temperature and the solvent polarity and proton accepting properties. The urea and urethane are readily prepared from commercially available dicyclohexylmethane 4 40 -diisocyanate and amine or phenol with minimal workup.
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2. Experimental part 4-n-hexylphenol and 4-n-hexylaniline were purchased from Aldrich (USA). Dicyclohexylmethane-4,40 -diisocyanate (Vestanate H12MDI) was purchased from Evonic Industries AG (Germany). Deuterated solvents (D2O, chloroform-d, DMF-d7, and DMSO‑d6) were purchased from Reachim (Russia). Compounds 1 (Scheme 1) were easily obtained in one step by following a standard method [8] by reaction of aniline, phenol, 4-nhexylphenol or 4-n-hexylaniline with H12MDI. As result were obtained bis-p-phenylurea 4,40 - dicyclohexylmethane 1a, bis-pphenylurethane 4,40 - dicyclohexylmethane 1b, bis-p-40 hexylphenylurea 4, 40 - dicyclohexylmethane 1c, and bis-p-40 hexylphenylurethane 4, 40 - dicyclohexylmethane 1d. Absorption spectra were recorded on an AvaSpec-ULS2048L StarLine (Avantes) UVevis spectrophotometer using a 1 cm quartz cell. The NMR experiments were carried out on a Bruker Avance-400 spectrometer (400.13 MHz for1H) equipped with variable temperature 5-mm BBI probehead. All 1D (1H, 13C) and 2D NMR(COSY, TOCSY, NOESY, HSQC) experiments were performed with standard pulse sequences supplied by spectrometer software.
signals in the 1H NMR spectrum of 4,40 -Diisocyanatodicyclohexylmethane used in this study. Polyurethanes based on commercial H12MDI are known for their excellent optical clarity, light and hydrolytic stability, and good physical and mechanical properties [10]. The commercial H12MDI is comprised of a mixture of cis-cis, cistrans and trans-trans stereoisomers (see Scheme 2). The content of
3. Results and discussion The compounds for the study were chosen to span a range of factors which affect prototropic behavior of ureas and related compounds. Firstly, were synthesized the urea and corresponding urethane to compare the prototropic behavior compounds forming the two-centered and mono-centered hydrogen bonds. Second structural motif was selected to use the aromatic ring. As part of this modification, we also elaborated one of the aromatic rings with oxy-n-hexyl groups at the para positions. Phenyl groups have been shown to enhance the hydrogen-bonding potential of the urea group [9]. Hexyl groups introduce the hydrophobic motif in the compounds under study and can promote their aggregation in different solvents. The first step of our NMR investigation was the assignment of
Scheme 1.
Scheme 2.
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stereoisomers varies in commercial products from different producers. The 1H NMR spectrum of H12MDI complicated by the presence of axial and equatorial protons in the cyclohexane ring. As results, to the best of our knowledge, full assignment of signal in the 1 H NMR spectrum of commercial H12MDI was never published before. The assignment of signals in 13C NMR spectrum is relatively simple because it is based on isolation of pure isomers by separate crystallization and liquid chromatography, and was described previously [11]. It allows us to evaluate the assignment of signals in the 13C NMR spectrum of used H12MDI (Fig. 1). A complete assignment of their 1H NMR spectrum is prevented by the fact that a commercial H12MDI is a mixture of three geometrical isomers (trans-trans, cis-cis, and cis-trans) and isomers content varies for different producers. Even with high-field spectrometer, some regions of lH NMR spectra of these molecule remain unresolved. Main problems are connected with inequivalence of equatorial and axial protons which makes the 1H NMR spectrum very complex. It is well known that, because of perturbation caused by the anisotropy of CeC bonds, the equatorial proton in a cyclohexane is generally deshielded by 0.1e0.7 ppm with respect to the corresponding axial proton [12]. Two-dimensional (2D) NMR methods have been shown to be of great help in solving the problems described above. Starting from the assignment of signals in the 13C NMR spectrum of H12MDI we use 2D 1He13C HSQC NMR to determine the signals of isomers in their 1H NMR spectrum using peak correlation plots (See Supplementary). Also, we applied the COSY-type spectra which use the J-coupling interaction to report on which proton resonances are located on the same or adjacent carbon nuclei (See Supplementary). In addition, we use the NOESY spectrum to provide information about proton resonances from protons, which are close together in space, as well as the 1He1H TOCSY spectrum which is useful for dividing the proton signals into groups or coupling networks, especially for overlapped multiplets (having very similar chemical shifts) (See Supplementary). It allows us to give a full interpretation of 1H NMR spectrum of H12MDI (Fig. 1) and to calculate the ratio of geometrical isomers. H12MDI from Evonic contains 36% trans-trans, 43% cis-cis and 21% cis-trans.
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By using the same approach we made the assignment of signals in the 1H and 13C NMR spectra of compounds 1a-d (See Supplementary). The ratio of geometrical isomers in compounds 1ad differs from corresponding value for H12MDI due to purification procedure because each isomer have different solubility. However, fractions of geometric isomers in compounds 1a-d are very similar to those in H12MDI, for example, 1b contains 36% trans-trans, 52% cis-cis and 12% cis-trans. We recorded the variable-temperature 1H NMR spectra of compounds 1a-d in polar solvents which are capable (DMSO‑d6 and DMF-d7) or not (CDCl3) to form the intermolecular hydrogen bonds. The variable-temperature 1H NMR spectra of compound 1b in CDCl3 in the temperature range from 30 to 25 C for NH of urethane group are given in Fig. 2. As one can see, the signals from all three geometrical isomers are present in the spectra. The temperature dependences of NH proton resonances are given on Fig. 2. This dependence for all isomers is usual for protons participating in the formation of hydrogen bonds: chemical shift increases with decreasing temperature; the signal of NH proton moves downfield as the temperature decreases. As a matter of fact, a linear relationship between 1H NMR chemical shift and temperature has been observed. The slopes of dependences are the same for cc and tt isomers (0.00223 for cc and 0.00242 for tt) and increases in two time for ct isomers (0.00441). At this point we note that a similar inverse dependence of the chemical shift as a function of the temperature was previously found experimentally by Kato et al. [13] for the proton forming the hydrogen bond in the hexabenzyloxymethyl- XDK [m-xylidenediamine-bis(Kemp’s triacid)imide] monoanion in apolar organic media, a symmetric hydrogen bond (in the sense that the proton-donor and the protonacceptor groups are identical) that turns out to be a low-barrier hydrogen bond. However, the temperature dependence of signal shape is different for each isomers. For cis-cis isomer the shape of signal did not depend on the temperature both for protons 1H of cyclohexane and NH of urethane group. For trans-trans isomer the normal dependence on the temperature of signal shape is observed both for protons 1H of cyclohexane and NH of urethane group. With
Fig. 1. 1H NMR spectrum of commercial H12MDI.
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Fig. 2. The variable-temperature 1H NMR spectra of compound 1b (region of NH resonance) in CDCl3 (a; slope -0.00223) for cc and 0.00242 for tt; (0.00441 for ct), DMSO‑d6(b; slope 0.00640), and DMF-d7(c; slope 0.00838) and correspondence dependence NH resonance on temperature.
temperature decreasing the signals are becoming sharper and 1HeNH coupling splitting are observed. For trans-cis isomer the opposite temperature dependence was observed. Such anomalous behavior can be explained only by the formation of intermolecular hydrogen bond as result of formation of dimer or more complex aggregation of molecules 1b. Indeed, the urethane or urea groups sometimes have been introduced into organic molecules to stimulate their aggregation. In the case of formation of intramolecular hydrogen bond in the OOCNH fragments their properties should not depend from isomeric form of molecules as a whole. To proof this suggestion we recorded the variable-temperature 1 H NMR spectra of 1b in DMSO‑d6, in the solvent which can form intermolecular hydrogen bonds with urethane groups and prevent aggregation of 1b molecules. According to Linas and Klein [14], comparing the chemical shift of this NH resonance in DMSO‑d6 to the position of the resonance in CDCl3 can give an insight into how
“solvent accessible” the NH group is. If the NH is strongly intramolecular hydrogen bonded, it will have minimal interaction with solvent and thus a downfield shift should not be observed on moving to a more strongly coordinating system. The spectra are given on Fig. 2b. We observed the downfield shift of 1H NMR signal of NH groups (from about 5.5 ppm to 7.8 ppm). However, the temperature dependence is also normal, i.e., with increasing the temperature the signal shifts upfield. The signals of isomers are unresolved. With increase of temperature the peak broadening is observed regarding to increasing of proton exchange in these complexes. The temperature dependence of chemical shift are cooler addiction (slope is 0.00640). Similar experiment was performed in DMF-d7 solution (Fig. 2c). The result are very similar to that in DMSO solution and slope is 0.00838. Hence, the temperature dependence of chemical shift is cooler addiction. However, a precise investigation of 1H NMR
Fig. 3. The variable-temperature 1H NMR spectra in DMF-d7(region of azomethine proton resonance) of compound 1b (a; slope 0.00212), 1a (b; 0.00207), 1d (c; 0.00198), 1c (d; 0.00200) and correspondence dependence azomethine proton resonance on temperature.
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spectra in DMF shows one peculiarities. In these spectra we observed minor signals at about 8.3 ppm (Fig. 3a). Their temperature dependence have slope of 0.00212. To explain the inverse dependence of the chemical shift on the temperature found for the phenolic proton of 4-(dimethylamino)2¢-hydroxychalcone Wachter-Jurcsak and Detmer [15] hypothesized that the ground electronic state of this molecule has a significant contribution from the zwitterionic resonance. We suggest that in our case in dimers formation of ionic structure is also possible.
At low temperatures molecular motions of solvent would decrease in such a way that the polarization of the solvent would grow, thus amplifying the fraction of that ionic form. For the signals of azomethine protons also observed the dependence of the chemical shift on the temperature. The downfield signal connected with trans-trans isomer is more intensive then signals of other geometrical isomers. Probably, this isomer have a conformation, which favors the aggregation. The compounds 1a is practically not soluble in chloroform. Therefore, we recorded its variable-temperature 1H NMR spectra only in DMSO and DMF.
In these solvents both NH protons of urea group give common signal for cis-cis and trans-trans geometrical isomers and separate signal for cis-trans isomer. In DMSO‑d6 the normal temperature dependence of chemical shift was observed for both NH protons for all geometrical isomers (Fig. 4). The slopes of these dependences are the same for both urea protons and all geometrical isomers (0.00212; 0.00207; 0.00198;-0.00200). However, the slopes are similar to those for slopes of temperature dependence of chemical shifts of urethane 1b in chloroform. The of variable-temperature 1H NMR spectra of compound 1a in DMF-d7 and DMSO‑d6 gives similar results with 1b (Fig. 4). We observed the normal temperature dependence of chemical shifts of both protons of urea unit. The cis-cis and trans-trans isomers give the common signal. The slopes of these dependences a less steep than for urethane 1b but in DMF-d7 this differences are minimal (the slopes are 0.00755; 0.00537; 0.00511; 0.00676). To proof the suggestion about the aggregation of compounds 1a-b we synthesized the compounds 1 c-d with aliphatic tail. These compounds should be more prone to aggregation in polar solvents. The compounds 1d have similar isomer content as 1b. Their variable-temperature 1H NMR spectra are also very similar (Fig. 5).
Fig. 4. The variable-temperature 1H NMR spectra of compound 1a (region of NH resonance) in DMSO‑d6(a; slope 0.00263, 0.00303, 0.00330, 0.00254), and DMFd7(b; 0.00755, 0.00537, 0.00511, 0.00676) and correspondence dependence NH resonances on temperature.
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Fig. 5. The variable-temperature 1H NMR spectra of compound 1d (region of NH resonance) in CDCl3 (a; slope 0.00255 (tt), 0.00174 (cc), 0.00227 (ct)), DMSO‑d6(b; 0.00648), and DMF-d7(c; 0.00756) and corresponding dependences of NH resonance on temperature.
However, one can be hypothesized that the compound 1d is more prone to aggregation. This is supported by its variabletemperature spectra in CDCl3 (Fig. 5a). The broad signals of NH proton are observed for all three isomers (Fig. 5) at 30 C (not only for trans-trans as for 1b). Hence, this supports their higher tendency towards aggregation. It is more clear from analysis of variable-temperature 1H NMR spectra in DMF-d7. The behavior of proton of NH group in region 7.3e7.8 ppm is very similar to its behavior in compounds 1b (although the slope of temperature dependence is less pronounced (0.00756)). This is seen even better from the spectra in the region 8.0e8.35 ppm (Fig. 3c). Similar to compound 1b the signals observed in the spectra characteristic of the ionic structure. However, their relative fraction measured with respect to the side-band of solvent is much higher (more than
in 3 times). Hence, the introduction of aliphatic tails contributes to aggregation that leads to formation of ionic structure. More interesting is the temperature behavior of compound 1c in DMF (Fig. 6). At low temperature (40 C) the NH(2) proton gives common signal for all geometric isomers. With increasing temperature its start to separate from common signal, and difference in their chemical shifts increases with temperature. The signals of NH(1) protons of cis-trans and (cis-cis and trans-trans) isomers are separated at all temperatures. However, the signal of NH(1) proton of cis-trans ispmer is broad at high temperature (70 C) and convert to doublet with temperature decrease. This behavior can be explained as before by aggregation of compound 1a. In this situation the formation of ionic structure can also be expected. Likewise to compound 1d, we found in these spectra the signal
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Fig. 6. The variable-temperature 1H NMR spectra of compound 1c (region of NH resonance) DMSO‑d6(a; slope 0.00755, 0.00537, 0.00511, 0.00675), and DMFd7(b; 0.00254, 0.00303, 0.00328, 0.00283) and correspondence dependence NH resonance on temperature.
at about 8.4e8.5 ppm (Fig. 3d). Hence, this finding support the formation of ionic structure containing azomethine unit. If this hypothesis is correct, such observation should be more pronounced for compound 1c. We recorded its variabletemperature 1H NMR spectra in DMSO and DMF. During the testing of compound 1c we observed some unusual behavior. Common signal of NH(2) proton of cis-cis and trans-trans isomers in DMSO‑d6 solution splits with coupling constant about 2 Hz which decreases with temperature increase. As shown in COSY experiment coupling is possible only with aromatic protons. Hence, the aggregation of 1c molecules in the case of cis-cis and transtrans isomers leads to restrictions of the range of motions of aromatic rings that allows direct coupling of aromatic and urea protons. The slope of temperature dependence of chemical shifts of urea protons are practically the same as for all other compounds under study. Therefore, it indicates the similar nature of hydrogenbonded molecular complexes. Much more interesting are the variable-temperature 1H NMR spectra recorded in DMF-d7 (Fig. 3d). Firstly, the resonances connected with formation of ionic structure are much more intensive at all temperatures (about in one order of magnitude). Hence, the aggregation and, therefore, the formation of ionic structure are more pronounced. However, the NMR spectra show the complex behavior of NH protons. At 30 C the NH(2) protons produce the common signal for all isomers. NH(1) protons give separate signals for cis-cis/trans-trans and cis-trans isomers. Unexpectedly, the signal for cis-cis/trans-trans isomers is doublet. With temperature increase the coupling constant decreases up to transformation of resonance to singlet at 50 C (Fig. 6b). The slopes of temperature
dependences of NH(1) resonances for geometric isomers are different, and they with temperatures change places. NH(2) resonance for cis-trans isomer is doublet coupled with H1 proton of cyclohexane and its coupling constant did not depends on temperature (Fig. 6b). The NH(2) resonance for cis-cis/trans-trans isomers have complex shape. It can be deconvoluted into two doublets (Fig. 7) one of which has the same scalar constant with NH(2) resonance as cis-trans isomer (coupling with H1 proton of cyclohexane) and another one has the same coupling constant of NH(1) protons as cis-cis/trans-trans isomers and also has the same dependence on temperature (Fig. 7). Hence, NH(1) and NH(2) protons of cis-cis/trans-trans isomers are scalar coupled. Therefore, we observed indirect spinespin coupling constants across intramolecular hydrogen bond (4hJH1H3). The number of such observations is very limited [16], and observation of 4hJH1H3 scalar coupling constants, to the best of our knowledge, is for the first time. The value of this constant increases from 2 Hz at 40 C to 10 Hz at 40 C. Hence, the strength of hydrogen bond also increases in this direction. It is known that the dielectric constant of solvents increases considerably when the temperature is lowered and this, in turn, affects the stability of charge-separated species such as 2. Therefore, that also stabilizes the formed aggregates. These observations suggest that this hydrogen bond has geometric features that deviate from those typically observed in small molecules and brings it close to those observed in proteins. These results suggest that hydrogen bonds within the aggregates are conformationally coupled with cyclohexane unit. The formation of aggregates is strongly supported by additional observations described below, although we note that the central
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complex or ion-free radical structure. The latter suggestion may be supported by the following observation. All our attempt to received 1 H NMR spectrum of compounds 1c of the urea fragment region in chloroform failed. The observed spectra (Fig. 9) confirm the presence of paramagnetic species near urea unit near urea unit. Thus, we propose that catalytic activity of urea unit substituted phenyl and cyclohexyl fragments is due to the structural rearrangements upon aggregation in solution and active role of hydrogen bonds in these processes. Indeed, the structural rearrangements we observed in response to mutations within the hydrogen bond network support this view. The aggregation of molecules under study is sensitive to isomer geometry. The importance of H-bonds in chemistry and biology leads to growth a study in explaining their nature. Unlike normal chemical bonds, H-bonds characteristically feature binding energies and contact distances that do not simply depend on the donor and acceptor nature. For strong H-bonds. Gilli et al. [17] introduced a concept of resonance-assisted hydrogen bonding (RAHB). RAHB occurring when the donor and the acceptor are connected by a short p-conjugated fragment. According to this concept of RAHB, a mechanism of synergetic interplay is assumed between the resonance of p-electrons in the spacer and the H-bond formation. It
Fig. 7. Dependence scalar coupling constants J compound 1c on temperature.
NH1CH1
and
4h
JH1H3 (slope 0.10995) of
conclusions of our study do not depend on this assignment. For this purpose we used UV spectroscopy (Fig. 8). UV absorbance spectra of 1c in DMSO and DMF confirmed that this compound does indeed bind ionized azomethine structures (absorbance around 440 nm). This observation is supported by solvatochromic effect (See Supplementary). The color of DMSO solution is yellow and DMF solution is rose. However, the chloroform solution of 1c has violet color. In UV absorbance spectrum of this solution is absence of absorbance band around 440 nm is absent, and a new one appears around 700 nm. This absorbance can be due to formation of charge-transfer
Fig. 9. 1H NMR spectra of compound 1c in CDCl3 at room temperature.
Fig. 8. UV/vis absorption spectra of compound 1c.
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Fig. 10. COSY spectrum of 1с in DMF-d7.
should to be mentioned that the original concept of RAHB was l criticized by some authors working with NMR method [18e20]. According to this criticism the stronger H-bonds in RAHB models result from steric effects and not from the p-electron delocalization, as it was proposed by Gilli. These statements were based on study of magnetic properties of coupling constants (2hJOeO and 2h JNeN) and proton chemical shifts of the hydrogen-bonded protons. However, numerous papers described the direct relation between the p-electron structure and the parameters of RAHB [21e26]. Our study give a possibility to contribute in this discussion. The formation of ionic fragment 2 assist to strong intramolecular Hbond. This fragment is p-conjugate. Our studies attested to the covalent nature of these strong H-bond because spinespin coupling constants across intramolecular hydrogen bond (4hJH1H3) possible only at covalent bonding. The covalent contribution in Hbond increases with decreasing temperature as relived by increasing of 4hJH1H3 (Fig. 7). We applied the COSY-type spectra which use the J-coupling interaction to compound 1c in DMF-d7 solution. These spectra shown that NH protons interact also with protons of phenyl ring (Fig. 10). Hence, the formation of strong intramolecular H-bond leads to p-conjugation not only with spacer but with phenyl ring too. It support the Gilli conception that RAHB formation is a result of pelectron delocalization.
formation of intermolecular complexes makes possible formation of symmetrical N1 … …H ……N3 intramolecular hydrogen bond in urea fragment. As a result, 4hJH1H3 trans-hydrogen bond scalar coupling constants have been observed for the first time in low molecular compounds using a simple one-dimensional 1H NMR experiment. It is known, that the magnitude of the coupling constants depends mainly on H-bond length and strength, but can also vary with changes in intermolecular complex geometry. The dependence of the 4hJH1H3 hydrogen bond scalar coupling constant on temperature was recorded. Such behavior has been explained by the aggregation of molecules and formation of ionic structures. We propose that catalytic activity of urea unit substituted phenyl and cyclohexyl fragments is due to the structural rearrangements upon aggregation in solution and active play of hydrogen bonds in these processes. The formation of strong intramolecular H-bond leads to p-conjugation not only with spacer but with phenyl ring too. It support the Gilli conception that RAHB formation is a result of pelectron delocalization. The presence in urea fragment of such kind interaction leads to formation of ionic structure, which has been detected by NMR and UV spectroscopies. The formation of ionic structure can explain the catalytic activity of such compounds and the mechanism of transformation in organic and bioorganic reactions in which involved the urea compounds. The evidence of spontaneous formation of ionic structure in substituted ureas in polar solvents is important for understanding biochemical transformation of biomolecules.
4. Conclusions Declaration of competing interest In this paper we have studied the prototropic behavior of phenyl and cyclohexyl disubstituted urea and urethanes using the variable-temperature 1H NMR spectra in polar solvents such as chloroform, DMSO and DMF. For all cases under study the usual temperature dependence of chemical shift of proton participating in formation hydrogen bond have been observed, e.g. with temperature decreasing their resonances shifted downfield. The
Authors have not any conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tet.2019.130691.
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Prototropic behavior of cyclohexane substituted urethane and urea compounds. Observation of H-bond mediated 4HJH1H3 coupling constants across urea fragments Maxim V. Mokeev a, Stepan A. Ostanin b, Vjacheslav V. Zuev a, b, * a b
Institute of Macromolecular Compounds of the Russian Academy of Sciences, Bolshoi pr. 31, 199004 Saint-Petersburg, Russian Federation ITMO University, Kronverkskiy pr. 49, 197101 Saint-Petersburg, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 June 2019 Received in revised form 12 October 2019 Accepted 13 October 2019 Available online 17 October 2019
Two 1-aryl-3-cyclohexylurea and two 1-aryl-3-cyclohexylurethane with and without alkyl tail in aryl fragments were synthesized and their variable-temperature 1H NMR spectra in chloroform, DMSO and DMF were recorded. The temperature dependences of chemical shift of NH protons for all compounds have been observed. The type of dependence has been explained by the aggregation of molecules and formation of ionic structures. The formation of intermolecular complexes leads to possible formation of symmetrical N1 … … H ……N3 intramolecular hydrogen bond in urea fragment. As a result,4hJH1H3 transhydrogen bond scalar coupling constants have been observed for the first time in low molecular weight compounds using a simple one-dimensional 1H NMR experiment. The formation of strong intramolecular H-bond leads to p-conjugation not only with spacer but with phenyl ring too. It support the Gilli conception that RAHB formation is a result of p-electron delocalization. The presence in urea fragment of such kind interaction leads to formation of ionic structure, which has been detected by NMR and UV spectroscopies. The formation of ionic structure can explain the catalytic activity of such compounds and the mechanism of transformation in organic and bioorganic reactions in which involved the urea compounds. © 2019 Elsevier Ltd. All rights reserved.
Keywords: NMR 1 H 13 C Prototropic behavior Cyclohexane Urea Urethane Temperature dependence
1. Introduction Organic catalysts based on H-bonding motifs are now very popular in organic and polymer synthesis [1,2]。 Considerable efforts in recent years have provided catalysts systems based on urea or thiourea that are highly active [3,4]。 The understanding of a mechanism of catalytic activity of these species is very important to address an extensive for a broad range of scientific and technological problems not only in chemistry, but also in medicine, biology, physics, and materials science [5]. One unusual observation is the fact that the catalytic activity of 1-aryl-3-cyclohexylurea with different substituents in phenyl ring is much higher than activity of diaryl analogues for the ring-opening polymerization of the lactones initiated urea/alkoxide or urea/amine catalytic systems [6]. Other motif for our investigation is comparison of urea and
* Corresponding author. Institute of Macromolecular Compounds of the Russian Academy of Sciences, Bolshoi pr. 31, 199004 Saint-Petersburg, Russian Federation. E-mail address: [email protected] (V.V. Zuev). https://doi.org/10.1016/j.tet.2019.130691 0040-4020/© 2019 Elsevier Ltd. All rights reserved.
urethane compounds because the well accepted statement believe that H-bonding in urea compounds is much stronger than in urethane analogues [7]. Therefore, can expect that the urethane also may been used as organocatalyst. This catalytic behavior can be connected with H-bond strengths into urea and urethane fragments. H-bond inside these fragments should be strong, and, therefore, be like to resonance-assisted Hbond, new type of strong H-bond where donor and acceptor are linked by a short p-conjugated fragment. We could go on to study this possibility because it is important for all H-bonds normally occurring in most chemical and biochemical systems. Here we aim to clarify how the 1-aryl-3-cyclohexylurea and 1aryl-3-cyclohexylurethane form H-bonds and makes proton exchange with surrounding solvent or the same molecules depending on the temperature and the solvent polarity and proton accepting properties. The urea and urethane are readily prepared from commercially available dicyclohexylmethane 4 40 -diisocyanate and amine or phenol with minimal workup.
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2. Experimental part 4-n-hexylphenol and 4-n-hexylaniline were purchased from Aldrich (USA). Dicyclohexylmethane-4,40 -diisocyanate (Vestanate H12MDI) was purchased from Evonic Industries AG (Germany). Deuterated solvents (D2O, chloroform-d, DMF-d7, and DMSO‑d6) were purchased from Reachim (Russia). Compounds 1 (Scheme 1) were easily obtained in one step by following a standard method [8] by reaction of aniline, phenol, 4-nhexylphenol or 4-n-hexylaniline with H12MDI. As result were obtained bis-p-phenylurea 4,40 - dicyclohexylmethane 1a, bis-pphenylurethane 4,40 - dicyclohexylmethane 1b, bis-p-40 hexylphenylurea 4, 40 - dicyclohexylmethane 1c, and bis-p-40 hexylphenylurethane 4, 40 - dicyclohexylmethane 1d. Absorption spectra were recorded on an AvaSpec-ULS2048L StarLine (Avantes) UVevis spectrophotometer using a 1 cm quartz cell. The NMR experiments were carried out on a Bruker Avance-400 spectrometer (400.13 MHz for1H) equipped with variable temperature 5-mm BBI probehead. All 1D (1H, 13C) and 2D NMR(COSY, TOCSY, NOESY, HSQC) experiments were performed with standard pulse sequences supplied by spectrometer software.
signals in the 1H NMR spectrum of 4,40 -Diisocyanatodicyclohexylmethane used in this study. Polyurethanes based on commercial H12MDI are known for their excellent optical clarity, light and hydrolytic stability, and good physical and mechanical properties [10]. The commercial H12MDI is comprised of a mixture of cis-cis, cistrans and trans-trans stereoisomers (see Scheme 2). The content of
3. Results and discussion The compounds for the study were chosen to span a range of factors which affect prototropic behavior of ureas and related compounds. Firstly, were synthesized the urea and corresponding urethane to compare the prototropic behavior compounds forming the two-centered and mono-centered hydrogen bonds. Second structural motif was selected to use the aromatic ring. As part of this modification, we also elaborated one of the aromatic rings with oxy-n-hexyl groups at the para positions. Phenyl groups have been shown to enhance the hydrogen-bonding potential of the urea group [9]. Hexyl groups introduce the hydrophobic motif in the compounds under study and can promote their aggregation in different solvents. The first step of our NMR investigation was the assignment of
Scheme 1.
Scheme 2.
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stereoisomers varies in commercial products from different producers. The 1H NMR spectrum of H12MDI complicated by the presence of axial and equatorial protons in the cyclohexane ring. As results, to the best of our knowledge, full assignment of signal in the 1 H NMR spectrum of commercial H12MDI was never published before. The assignment of signals in 13C NMR spectrum is relatively simple because it is based on isolation of pure isomers by separate crystallization and liquid chromatography, and was described previously [11]. It allows us to evaluate the assignment of signals in the 13C NMR spectrum of used H12MDI (Fig. 1). A complete assignment of their 1H NMR spectrum is prevented by the fact that a commercial H12MDI is a mixture of three geometrical isomers (trans-trans, cis-cis, and cis-trans) and isomers content varies for different producers. Even with high-field spectrometer, some regions of lH NMR spectra of these molecule remain unresolved. Main problems are connected with inequivalence of equatorial and axial protons which makes the 1H NMR spectrum very complex. It is well known that, because of perturbation caused by the anisotropy of CeC bonds, the equatorial proton in a cyclohexane is generally deshielded by 0.1e0.7 ppm with respect to the corresponding axial proton [12]. Two-dimensional (2D) NMR methods have been shown to be of great help in solving the problems described above. Starting from the assignment of signals in the 13C NMR spectrum of H12MDI we use 2D 1He13C HSQC NMR to determine the signals of isomers in their 1H NMR spectrum using peak correlation plots (See Supplementary). Also, we applied the COSY-type spectra which use the J-coupling interaction to report on which proton resonances are located on the same or adjacent carbon nuclei (See Supplementary). In addition, we use the NOESY spectrum to provide information about proton resonances from protons, which are close together in space, as well as the 1He1H TOCSY spectrum which is useful for dividing the proton signals into groups or coupling networks, especially for overlapped multiplets (having very similar chemical shifts) (See Supplementary). It allows us to give a full interpretation of 1H NMR spectrum of H12MDI (Fig. 1) and to calculate the ratio of geometrical isomers. H12MDI from Evonic contains 36% trans-trans, 43% cis-cis and 21% cis-trans.
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By using the same approach we made the assignment of signals in the 1H and 13C NMR spectra of compounds 1a-d (See Supplementary). The ratio of geometrical isomers in compounds 1ad differs from corresponding value for H12MDI due to purification procedure because each isomer have different solubility. However, fractions of geometric isomers in compounds 1a-d are very similar to those in H12MDI, for example, 1b contains 36% trans-trans, 52% cis-cis and 12% cis-trans. We recorded the variable-temperature 1H NMR spectra of compounds 1a-d in polar solvents which are capable (DMSO‑d6 and DMF-d7) or not (CDCl3) to form the intermolecular hydrogen bonds. The variable-temperature 1H NMR spectra of compound 1b in CDCl3 in the temperature range from 30 to 25 C for NH of urethane group are given in Fig. 2. As one can see, the signals from all three geometrical isomers are present in the spectra. The temperature dependences of NH proton resonances are given on Fig. 2. This dependence for all isomers is usual for protons participating in the formation of hydrogen bonds: chemical shift increases with decreasing temperature; the signal of NH proton moves downfield as the temperature decreases. As a matter of fact, a linear relationship between 1H NMR chemical shift and temperature has been observed. The slopes of dependences are the same for cc and tt isomers (0.00223 for cc and 0.00242 for tt) and increases in two time for ct isomers (0.00441). At this point we note that a similar inverse dependence of the chemical shift as a function of the temperature was previously found experimentally by Kato et al. [13] for the proton forming the hydrogen bond in the hexabenzyloxymethyl- XDK [m-xylidenediamine-bis(Kemp’s triacid)imide] monoanion in apolar organic media, a symmetric hydrogen bond (in the sense that the proton-donor and the protonacceptor groups are identical) that turns out to be a low-barrier hydrogen bond. However, the temperature dependence of signal shape is different for each isomers. For cis-cis isomer the shape of signal did not depend on the temperature both for protons 1H of cyclohexane and NH of urethane group. For trans-trans isomer the normal dependence on the temperature of signal shape is observed both for protons 1H of cyclohexane and NH of urethane group. With
Fig. 1. 1H NMR spectrum of commercial H12MDI.
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Fig. 2. The variable-temperature 1H NMR spectra of compound 1b (region of NH resonance) in CDCl3 (a; slope -0.00223) for cc and 0.00242 for tt; (0.00441 for ct), DMSO‑d6(b; slope 0.00640), and DMF-d7(c; slope 0.00838) and correspondence dependence NH resonance on temperature.
temperature decreasing the signals are becoming sharper and 1HeNH coupling splitting are observed. For trans-cis isomer the opposite temperature dependence was observed. Such anomalous behavior can be explained only by the formation of intermolecular hydrogen bond as result of formation of dimer or more complex aggregation of molecules 1b. Indeed, the urethane or urea groups sometimes have been introduced into organic molecules to stimulate their aggregation. In the case of formation of intramolecular hydrogen bond in the OOCNH fragments their properties should not depend from isomeric form of molecules as a whole. To proof this suggestion we recorded the variable-temperature 1 H NMR spectra of 1b in DMSO‑d6, in the solvent which can form intermolecular hydrogen bonds with urethane groups and prevent aggregation of 1b molecules. According to Linas and Klein [14], comparing the chemical shift of this NH resonance in DMSO‑d6 to the position of the resonance in CDCl3 can give an insight into how
“solvent accessible” the NH group is. If the NH is strongly intramolecular hydrogen bonded, it will have minimal interaction with solvent and thus a downfield shift should not be observed on moving to a more strongly coordinating system. The spectra are given on Fig. 2b. We observed the downfield shift of 1H NMR signal of NH groups (from about 5.5 ppm to 7.8 ppm). However, the temperature dependence is also normal, i.e., with increasing the temperature the signal shifts upfield. The signals of isomers are unresolved. With increase of temperature the peak broadening is observed regarding to increasing of proton exchange in these complexes. The temperature dependence of chemical shift are cooler addiction (slope is 0.00640). Similar experiment was performed in DMF-d7 solution (Fig. 2c). The result are very similar to that in DMSO solution and slope is 0.00838. Hence, the temperature dependence of chemical shift is cooler addiction. However, a precise investigation of 1H NMR
Fig. 3. The variable-temperature 1H NMR spectra in DMF-d7(region of azomethine proton resonance) of compound 1b (a; slope 0.00212), 1a (b; 0.00207), 1d (c; 0.00198), 1c (d; 0.00200) and correspondence dependence azomethine proton resonance on temperature.
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spectra in DMF shows one peculiarities. In these spectra we observed minor signals at about 8.3 ppm (Fig. 3a). Their temperature dependence have slope of 0.00212. To explain the inverse dependence of the chemical shift on the temperature found for the phenolic proton of 4-(dimethylamino)2¢-hydroxychalcone Wachter-Jurcsak and Detmer [15] hypothesized that the ground electronic state of this molecule has a significant contribution from the zwitterionic resonance. We suggest that in our case in dimers formation of ionic structure is also possible.
At low temperatures molecular motions of solvent would decrease in such a way that the polarization of the solvent would grow, thus amplifying the fraction of that ionic form. For the signals of azomethine protons also observed the dependence of the chemical shift on the temperature. The downfield signal connected with trans-trans isomer is more intensive then signals of other geometrical isomers. Probably, this isomer have a conformation, which favors the aggregation. The compounds 1a is practically not soluble in chloroform. Therefore, we recorded its variable-temperature 1H NMR spectra only in DMSO and DMF.
In these solvents both NH protons of urea group give common signal for cis-cis and trans-trans geometrical isomers and separate signal for cis-trans isomer. In DMSO‑d6 the normal temperature dependence of chemical shift was observed for both NH protons for all geometrical isomers (Fig. 4). The slopes of these dependences are the same for both urea protons and all geometrical isomers (0.00212; 0.00207; 0.00198;-0.00200). However, the slopes are similar to those for slopes of temperature dependence of chemical shifts of urethane 1b in chloroform. The of variable-temperature 1H NMR spectra of compound 1a in DMF-d7 and DMSO‑d6 gives similar results with 1b (Fig. 4). We observed the normal temperature dependence of chemical shifts of both protons of urea unit. The cis-cis and trans-trans isomers give the common signal. The slopes of these dependences a less steep than for urethane 1b but in DMF-d7 this differences are minimal (the slopes are 0.00755; 0.00537; 0.00511; 0.00676). To proof the suggestion about the aggregation of compounds 1a-b we synthesized the compounds 1 c-d with aliphatic tail. These compounds should be more prone to aggregation in polar solvents. The compounds 1d have similar isomer content as 1b. Their variable-temperature 1H NMR spectra are also very similar (Fig. 5).
Fig. 4. The variable-temperature 1H NMR spectra of compound 1a (region of NH resonance) in DMSO‑d6(a; slope 0.00263, 0.00303, 0.00330, 0.00254), and DMFd7(b; 0.00755, 0.00537, 0.00511, 0.00676) and correspondence dependence NH resonances on temperature.
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Fig. 5. The variable-temperature 1H NMR spectra of compound 1d (region of NH resonance) in CDCl3 (a; slope 0.00255 (tt), 0.00174 (cc), 0.00227 (ct)), DMSO‑d6(b; 0.00648), and DMF-d7(c; 0.00756) and corresponding dependences of NH resonance on temperature.
However, one can be hypothesized that the compound 1d is more prone to aggregation. This is supported by its variabletemperature spectra in CDCl3 (Fig. 5a). The broad signals of NH proton are observed for all three isomers (Fig. 5) at 30 C (not only for trans-trans as for 1b). Hence, this supports their higher tendency towards aggregation. It is more clear from analysis of variable-temperature 1H NMR spectra in DMF-d7. The behavior of proton of NH group in region 7.3e7.8 ppm is very similar to its behavior in compounds 1b (although the slope of temperature dependence is less pronounced (0.00756)). This is seen even better from the spectra in the region 8.0e8.35 ppm (Fig. 3c). Similar to compound 1b the signals observed in the spectra characteristic of the ionic structure. However, their relative fraction measured with respect to the side-band of solvent is much higher (more than
in 3 times). Hence, the introduction of aliphatic tails contributes to aggregation that leads to formation of ionic structure. More interesting is the temperature behavior of compound 1c in DMF (Fig. 6). At low temperature (40 C) the NH(2) proton gives common signal for all geometric isomers. With increasing temperature its start to separate from common signal, and difference in their chemical shifts increases with temperature. The signals of NH(1) protons of cis-trans and (cis-cis and trans-trans) isomers are separated at all temperatures. However, the signal of NH(1) proton of cis-trans ispmer is broad at high temperature (70 C) and convert to doublet with temperature decrease. This behavior can be explained as before by aggregation of compound 1a. In this situation the formation of ionic structure can also be expected. Likewise to compound 1d, we found in these spectra the signal
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Fig. 6. The variable-temperature 1H NMR spectra of compound 1c (region of NH resonance) DMSO‑d6(a; slope 0.00755, 0.00537, 0.00511, 0.00675), and DMFd7(b; 0.00254, 0.00303, 0.00328, 0.00283) and correspondence dependence NH resonance on temperature.
at about 8.4e8.5 ppm (Fig. 3d). Hence, this finding support the formation of ionic structure containing azomethine unit. If this hypothesis is correct, such observation should be more pronounced for compound 1c. We recorded its variabletemperature 1H NMR spectra in DMSO and DMF. During the testing of compound 1c we observed some unusual behavior. Common signal of NH(2) proton of cis-cis and trans-trans isomers in DMSO‑d6 solution splits with coupling constant about 2 Hz which decreases with temperature increase. As shown in COSY experiment coupling is possible only with aromatic protons. Hence, the aggregation of 1c molecules in the case of cis-cis and transtrans isomers leads to restrictions of the range of motions of aromatic rings that allows direct coupling of aromatic and urea protons. The slope of temperature dependence of chemical shifts of urea protons are practically the same as for all other compounds under study. Therefore, it indicates the similar nature of hydrogenbonded molecular complexes. Much more interesting are the variable-temperature 1H NMR spectra recorded in DMF-d7 (Fig. 3d). Firstly, the resonances connected with formation of ionic structure are much more intensive at all temperatures (about in one order of magnitude). Hence, the aggregation and, therefore, the formation of ionic structure are more pronounced. However, the NMR spectra show the complex behavior of NH protons. At 30 C the NH(2) protons produce the common signal for all isomers. NH(1) protons give separate signals for cis-cis/trans-trans and cis-trans isomers. Unexpectedly, the signal for cis-cis/trans-trans isomers is doublet. With temperature increase the coupling constant decreases up to transformation of resonance to singlet at 50 C (Fig. 6b). The slopes of temperature
dependences of NH(1) resonances for geometric isomers are different, and they with temperatures change places. NH(2) resonance for cis-trans isomer is doublet coupled with H1 proton of cyclohexane and its coupling constant did not depends on temperature (Fig. 6b). The NH(2) resonance for cis-cis/trans-trans isomers have complex shape. It can be deconvoluted into two doublets (Fig. 7) one of which has the same scalar constant with NH(2) resonance as cis-trans isomer (coupling with H1 proton of cyclohexane) and another one has the same coupling constant of NH(1) protons as cis-cis/trans-trans isomers and also has the same dependence on temperature (Fig. 7). Hence, NH(1) and NH(2) protons of cis-cis/trans-trans isomers are scalar coupled. Therefore, we observed indirect spinespin coupling constants across intramolecular hydrogen bond (4hJH1H3). The number of such observations is very limited [16], and observation of 4hJH1H3 scalar coupling constants, to the best of our knowledge, is for the first time. The value of this constant increases from 2 Hz at 40 C to 10 Hz at 40 C. Hence, the strength of hydrogen bond also increases in this direction. It is known that the dielectric constant of solvents increases considerably when the temperature is lowered and this, in turn, affects the stability of charge-separated species such as 2. Therefore, that also stabilizes the formed aggregates. These observations suggest that this hydrogen bond has geometric features that deviate from those typically observed in small molecules and brings it close to those observed in proteins. These results suggest that hydrogen bonds within the aggregates are conformationally coupled with cyclohexane unit. The formation of aggregates is strongly supported by additional observations described below, although we note that the central
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complex or ion-free radical structure. The latter suggestion may be supported by the following observation. All our attempt to received 1 H NMR spectrum of compounds 1c of the urea fragment region in chloroform failed. The observed spectra (Fig. 9) confirm the presence of paramagnetic species near urea unit near urea unit. Thus, we propose that catalytic activity of urea unit substituted phenyl and cyclohexyl fragments is due to the structural rearrangements upon aggregation in solution and active role of hydrogen bonds in these processes. Indeed, the structural rearrangements we observed in response to mutations within the hydrogen bond network support this view. The aggregation of molecules under study is sensitive to isomer geometry. The importance of H-bonds in chemistry and biology leads to growth a study in explaining their nature. Unlike normal chemical bonds, H-bonds characteristically feature binding energies and contact distances that do not simply depend on the donor and acceptor nature. For strong H-bonds. Gilli et al. [17] introduced a concept of resonance-assisted hydrogen bonding (RAHB). RAHB occurring when the donor and the acceptor are connected by a short p-conjugated fragment. According to this concept of RAHB, a mechanism of synergetic interplay is assumed between the resonance of p-electrons in the spacer and the H-bond formation. It
Fig. 7. Dependence scalar coupling constants J compound 1c on temperature.
NH1CH1
and
4h
JH1H3 (slope 0.10995) of
conclusions of our study do not depend on this assignment. For this purpose we used UV spectroscopy (Fig. 8). UV absorbance spectra of 1c in DMSO and DMF confirmed that this compound does indeed bind ionized azomethine structures (absorbance around 440 nm). This observation is supported by solvatochromic effect (See Supplementary). The color of DMSO solution is yellow and DMF solution is rose. However, the chloroform solution of 1c has violet color. In UV absorbance spectrum of this solution is absence of absorbance band around 440 nm is absent, and a new one appears around 700 nm. This absorbance can be due to formation of charge-transfer
Fig. 9. 1H NMR spectra of compound 1c in CDCl3 at room temperature.
Fig. 8. UV/vis absorption spectra of compound 1c.
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Fig. 10. COSY spectrum of 1с in DMF-d7.
should to be mentioned that the original concept of RAHB was l criticized by some authors working with NMR method [18e20]. According to this criticism the stronger H-bonds in RAHB models result from steric effects and not from the p-electron delocalization, as it was proposed by Gilli. These statements were based on study of magnetic properties of coupling constants (2hJOeO and 2h JNeN) and proton chemical shifts of the hydrogen-bonded protons. However, numerous papers described the direct relation between the p-electron structure and the parameters of RAHB [21e26]. Our study give a possibility to contribute in this discussion. The formation of ionic fragment 2 assist to strong intramolecular Hbond. This fragment is p-conjugate. Our studies attested to the covalent nature of these strong H-bond because spinespin coupling constants across intramolecular hydrogen bond (4hJH1H3) possible only at covalent bonding. The covalent contribution in Hbond increases with decreasing temperature as relived by increasing of 4hJH1H3 (Fig. 7). We applied the COSY-type spectra which use the J-coupling interaction to compound 1c in DMF-d7 solution. These spectra shown that NH protons interact also with protons of phenyl ring (Fig. 10). Hence, the formation of strong intramolecular H-bond leads to p-conjugation not only with spacer but with phenyl ring too. It support the Gilli conception that RAHB formation is a result of pelectron delocalization.
formation of intermolecular complexes makes possible formation of symmetrical N1 … …H ……N3 intramolecular hydrogen bond in urea fragment. As a result, 4hJH1H3 trans-hydrogen bond scalar coupling constants have been observed for the first time in low molecular compounds using a simple one-dimensional 1H NMR experiment. It is known, that the magnitude of the coupling constants depends mainly on H-bond length and strength, but can also vary with changes in intermolecular complex geometry. The dependence of the 4hJH1H3 hydrogen bond scalar coupling constant on temperature was recorded. Such behavior has been explained by the aggregation of molecules and formation of ionic structures. We propose that catalytic activity of urea unit substituted phenyl and cyclohexyl fragments is due to the structural rearrangements upon aggregation in solution and active play of hydrogen bonds in these processes. The formation of strong intramolecular H-bond leads to p-conjugation not only with spacer but with phenyl ring too. It support the Gilli conception that RAHB formation is a result of pelectron delocalization. The presence in urea fragment of such kind interaction leads to formation of ionic structure, which has been detected by NMR and UV spectroscopies. The formation of ionic structure can explain the catalytic activity of such compounds and the mechanism of transformation in organic and bioorganic reactions in which involved the urea compounds. The evidence of spontaneous formation of ionic structure in substituted ureas in polar solvents is important for understanding biochemical transformation of biomolecules.
4. Conclusions Declaration of competing interest In this paper we have studied the prototropic behavior of phenyl and cyclohexyl disubstituted urea and urethanes using the variable-temperature 1H NMR spectra in polar solvents such as chloroform, DMSO and DMF. For all cases under study the usual temperature dependence of chemical shift of proton participating in formation hydrogen bond have been observed, e.g. with temperature decreasing their resonances shifted downfield. The
Authors have not any conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tet.2019.130691.
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