Study of glycoluril and its derivatives by ¹H and ¹³C NMR spectroscopy

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UDC 544.42+519.242.7

S.Yu. Pansh V.S. Ma

1Na

2Nation

3L.N. Gumily (Corres

Study of glycoluril an

Bicyclic bisureas, especially 2,4 in chemistry of heterocyclic com erties of the molecule, which are the molecule. In this work, we an (86 compounds) in the NMR sp the electron density in the bicycl ysis of the 1H and 13C NMR sp figurations of molecular symme carbon atoms of the bicyclic fra 13C chemical shifts in the NMR guished by the shielding of car deshielding of CH-CH-carbons, amagnetic contributions owing t Keywords: glycoluril, NMR, ch diffraction.

In the chemistry of heterocyc greatest interest are 2,4,6,8-tetraaza The history of glycoluril chemistry searchers succeeded in synthesizing glycolurils, first of all, due to polyf the creation of valuable substances i [3; 86, 4], polymer stabilizers [5], substances and materials based on th

1a Figure 1. The structural form Glycoluril 1 is a polyfunctiona mines the properties of the molecu groups (–NH) and 2 acceptor group

*Corresponding author

hina^{1, 2*}, O.V. Ponomarenko³, A.A. Bakibaev¹ alkov¹, O.A. Kotelnikov¹, A.K. Tashenov³

ational Research Tomsk State University, Russia;

nal Research Tomsk Polytechnic University, Russia;

yov Eurasian National University, Nur-Sultan, Kazakhstan sponding author′s e-mail: janim_svetatusik@mail.ru)

nd its derivatives by

¹

H and

¹³

C NMR sp

4,6,8-tetraazabicyclo[3.3.0.]octan-3,7-dione (glycoluril), hav mpounds. The carbamide fragment in glycoluril structure det

e due to the presence of two reaction centers (NH-groups an nalyzed the proton and carbon chemical shifts of glycoluril ectra to reveal the effect of the donor-acceptor substituents lic framework from the position of symmetry and asymmetr pectra of glycolurils makes it possible to accurately determin etry, in the presence of which (σ1 and / or σ2) the enantioto amework are manifested by equivalent signals. Also, accord R spectra, glycolurils with electron-acceptor substituents can rbon atoms of C=O-groups, and with electron-donating su

due to the rearrangement of electron density and the occurr to anisotropy

hemical shifts, symmetry, enantiotopic atoms, shielding, d

Introduction

clic compounds, bicyclic ureas have a special p abicyclo[3.3.0.]octan-3,7-dione 1 (glycoluril) (Fig dates back to the second half of the 19^th century the progenitor 1 of this class of compounds. Sinc functionality of their structure, has developed rap in various fields of human activity such as disinf

independent explosives or their components [6–

hese compounds.

1b mula of glycoluril 1 (1a) and its spatial configuration in

al compound in which the carbamide fragment (F ule 1 being resulted from the presence of two re ps (C=O)) in the molecule. Glycoluril 1 has the p

1,

pectroscopy

ve a special place termines the prop- nd C=O-groups) in

and its derivatives on the changes in ry. A general anal-

ne the spatial con- opic hydrogen and ding to the 1H and n be clearly distin-

ubstituents by the rence of local par-

deshielding, X-ray

place, among which the g. 1) and its derivatives.

y, when a number of re- ce then, the chemistry of pidly. It was reflected in fectants [1, 2], medicines –8] and other important

n the crystal (1b)

Fig. 2) essentially deter- eaction centers (4 donor properties of a highly ac-

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tive N-nucleophile and a significan rather difficult to protonate, but it N-nitrosation, N-hydroxyalkylation

NH O

Figure 2. Resonance st The synthesis and study of the nitrogen-containing heterocyclic co clic condensed systems such as cuc which is glycoluril 1.

Due to the complex structure o the studied compounds, where the m nuclear magnetic resonance spectros

The molecule of glycoluril 1 co the bonds of which it is convenient these nuclei can provide enough inf formational features. Due to the low literature on the use of NMR on ¹⁷O of the ¹⁵N chemical shifts of glycolu and the establishment of the direct work, we analyzed the chemical shi 2-13, recorded on ¹H and ¹³C nuclei

Taking into account the specif depends on the presence of substitue used for analysis. N-acylderivatives overlapping signals of atoms.

When recording the NMR spe spectrum there are 2 CS in the regio and NH groups, and in the ¹³С spect 160.30 ppm respectively. These dat molecule 1, there are two planes of s CH–CH bridge, and the plane σ² inte

Figure 3. Sym However, when studying the c established [18] that, in addition to

ntly deactivated p-nucleophile. Despite its weak t is capable of N-alkylation, N-acylation, N-ha

reactions, etc. [9; 126–129].

NH O

HN

NH O

HN

NH O

tructures of the carbamide fragment of the glycoluril m chemical properties of bicyclic bisureas allows cr mpounds with other practically useful propertie urbit[n]urils [10–12] and bambus[n]urils [13, 14 of glycoluril derivatives, the problem arises of the most convenient method for solving structural pr

scopy (NMR).

ontains nitrogen, oxygen, carbon and hydrogen a to record the spectra on ¹H, ¹³C, ¹⁵N, ¹⁷O nuclei formation to determine the structure of a molecule

w content of natural isotopes ¹⁵N and ¹⁷O, there O nuclei for a number of glycolurils. To obtain inf uril 1 and its derivatives 2D heterocorrelation of t coupling constant ¹⁵N–¹H [16] are most often

fts (further in the text, CS) of the NMR of glycol (Table 1-10).

fic and limited solubility of glycoluril 1 and its ents, in practice, the universal solvents DMSO-d₆ s of glycoluril 12 is convenient to analyze in a ectra of glycoluril 1, it was found that in the pro ons of 5.24 ppm and 7.16 ppm, which correspond trum, the carbons of the CH-CH and C=O group ta certainly indicate the spatial symmetry of gly symmetry σ¹ and σ² (Fig. 3), where the plane σ¹ p ersects two carbonyl oxygen atoms (Fig. 3) [17].

mmetry planes σ¹ and σ² in the molecule of glycoluril 1 crystal structure of glycoluril 1 by X-ray diffracti symmetry, the conformation of bicyclic framew

basicity, glycoluril 1 is alogenation, N-nitration,

molecule 1

reating of new classes of es. For example, polycy- 4], the building blocks of e precise identification of roblems is the method of atoms, for the analysis of i. NMR spectroscopy on e, its electronic and con-

is no information in the formation of the position f the ¹H–¹⁵N spectra [15]

used. Therefore, in this luril 1 and its derivatives derivatives 2-13, which

6 and D₂O are most often CDCl₃ solvent to avoid oton magnetic resonance d to signals of the CHCH s resonate at 64.60 ppm, ycoluril 1. Indeed, in the passes along the methine

1

ion (Fig. 1b), it was first work 1 due to the rigidity

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of the cis-joint of annelated imidazolidinone rings has a folded structure in the form of a «half-opened book». The dihedral angle between the imidazolidinone rings in molecule 1 is 124.1°. In addition, it was found that the nitrogen atoms in molecule 1 are located equidistant from each other. The hydrogen atoms of the CH-CH group are cis-oriented, and the imidazolidinone rings are characterized by an almost flat structure with a slight deviation of the C=O groups from the plane.

Thus, the goal of this work was to study CS of glycoluril 1 and its derivatives 2-13 to identify the effect of substituents on changes in electron density in the bicyclic framework, taking into account the symmetry and asymmetry of the 86 molecules considered.

Experimental

The substances 2e–g, 3c, d, 4b–c, 5d, e, g, 6c–f were synthesized in accordance with the methods of [9; 113]. NMR spectra for substances 2e–g, 3c, d, 4b–c, 5d, e, g, 6c–f were recorded on a Bruker AVANCE III HD spectrometer (Bruker Corporation, Germany) with an operating frequency of 400 and 100 MHz for

1H and ¹³C nuclei respectively, in a solution of DMSO-d₆ with a concentration of 0.001 mol of the substance in 0.5 ml of solvent. The internal standard is tetramethylsilane (TMS).

Results and Discussion

N-Monosubstituted glycolurils. First of all, it should be noted that with N-monosubstitution in the glycoluril framework, the symmetry of the molecule is violated (glycolurils 2a–g). In the analyzed molecules 2a–g, there are no symmetry planes σ¹ and σ², which, as we have found, is reflected in the change of CS in the ¹H and ¹³C NMR spectra (Table 1).

T a b l e 1 Сhemical shifts of N-monosubstituted glycolurils 2a–g

№ Substituent ¹Н NMR, ppm, (J/Hz) ¹³С NMR, ppm

R1 СН–СН NH СН–СН С=О

1^[19] Н 5.24 (s. 2H) 7.16 (s. 4H) 64.60 160.30

2а^[19] СH3 5.14 (d. 1Н, J = 8.0)

5.19 (d. 1Н, J = 8.0) 7.20 (s. 1H)

7.30 (s. 2H) 62.54

69.89 159.75 161.79 2b^[20] CH2CONHСН(CH3)C2H5 5.22 (d. 1H, J = 7.9)

5.29 (d. 1Н, J = 7.9) 7.29 (s. 2H)

7.44 (s. 1Н) 62.39

68.55 159.40 161.14 2c^[21] CH2CH2N(CH3)2 5.21 (d. 1Н, J = 8.2)

5.32 (d. 1Н, J = 8.2)

7.29 (s. 1Н) 7.40 (s. 2Н)

62.24 67.75

159.13 161.00 2d^[21] CH2CH2NHCOCH3 5.18 (d. 1Н, J = 8.1)

5.31 (d. 1Н, J = 8.1) 7.25, 7.30,

7.39 (3s. 3Н) 62.33,

67.74 159.36 161.15 2e СН2ОН 5.45 (d. 1Н, J = 8.0)

5.65 (d. 1Н, J = 8.0) 7.17, 7.29,

7.22 (3s. 3Н) 64.10

67.70 158.30 160.08 2f СОСН3 5.68 (d. 1Н, J = 8.0)

5.23 (d. 1Н, J = 8.0) 8.55, 7.57,

7.49 (3s. 3Н) 61.55

63.24 151.40, 154.80 2g NO 5.34 (d. 1Н, J = 7.6)

5.66 (d. 1Н, J = 7.6) 7.94, 7.97,

9.38 (3s. 3Н) 62.11

63.48 152.30 160.68 Chemical shift range (Δ) 5.14–5.68 7.17–9.38 61.55–69.89 151.40–161.79

An analysis of the NMR data for compounds 2a–g shows that in the absence of planes of symmetry σ¹ and σ², the protons and carbons of methine (CH–CH) groups appear to be non-equivalent peaks. In the PMR spectra, CH-protons resonate in pairs in the form of doublet signals in the region from 5.1 ppm to 5.7 ppm, and in the ¹³C NMR spectra, shielding of signals of one CH up to 2 ppm (2f) and CH carbon deshielding from the substitution side up to 4.4 ppm (2a) relative to the CS of similar glycoluril atoms 1 are observed.

The deshielding of CH atoms in substances 2a–e is probably due to the positive inductive effect of electron- donating substituents on nitrogen atoms [22; 712], which makes its unshared electron pair more available for sharing with a five-membered ring. Such an effect of electron-donating groups makes C–C carbons on the substitution side partially sp²-hybridized atoms due to an increase in electron density, which shifts the CS of carbon CH to the fields of «molecular currents» or π-conjugated systems.

The CS of NH groups in compounds 2a–g become unequal and resonate in the form of two or three singlets in the regions from 7.2 ppm to 9.4 ppm. In compounds 2a–e with electron-donating substituents at nitrogen atoms, a shift in the CS of NH groups in the range of ±0.5 ppm relatively to 1 is observed. These

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changes indicate a weak effect of the substituents on the inhibition of amide conjugation in the urea fragment of the molecules 2a–g (Fig. 2). While in the case of substances 2f, g with acceptor substituents, the CS of the NH group shifts to the low-field region by 2.2 ppm relatively to glycoluril 1, due to the inductive effect of the substituent on the unshared pair of electrons of the neighboring unsubstituted amino group, which is isolated and not shared with the imidazolidine ring.

The CS of carbons of C=O groups are shielded in substituted imidazolinone rings in average up to 2.0 ppm (2a–e), and for compounds 2f, g with electron-acceptor substituents (–NO, –СОCН₃) the carbonyl signals shift to the high-field region by 8.9 ppm. The observed effect of strong shielding of the C=O group in compounds 2f, g is explained by the circulation of electron-acceptor substituents’ electrons due to the presence of π-bonds, which leads to the appearance of a field additionally strengthening the external [23; 183] or «anisotropy cone» [24]. This effect is similar for 2,6-N-disubstituted compounds 5e–h and is shown in Figure 4.

2,8-N-disubstituted glycolurils. The absence of plane of symmetry σ² in 2,8-N-disubstituted glycoluril 3a-d molecules can also be detected in the ¹H and ¹³C NMR spectra (Table 2).

T a b l e 2 Сhemical shifts of 2, 8-N-disubstituted glycoluril 3a-d

1^[19] Н 5.24 (s. 2Н) 7.16 (s. 4H) 64.60 160.30

3а^[19] СH3 5.15 (d. 1Н, J = 8.4)

5.18 (d. 1Н, J = 8.4) 7.39 (s. 2Н) 60.63

75.63 160.19 3b^[25] СН2Ph 4.98 (d. 1Н, J = 8.5)

5.39 (d. 1Н, J = 8.5) 7.64 (s. 2Н) 60.40

70.70 159.70 3с СН2ОН 5.41 (d. 1Н, J = 8.0)

5.58 (d. 1Н, J = 8.0) 7.39 (s. 2H) 64.10

67.70 160.90 3d СОСН3 5.25 (d. 1Н, J = 7.2)

6.44 (d. 1Н, J = 7.2) 8.74 (s. 2Н) 59.50

63.31 154.73

Chemical shift range (Δ) 4.98–6.44 7.39–8.69 59.50–75.63 154.73–160.19 The CS of 2,8-N-disubstituted glycolurils 3a–d indicates the equivalence of the C=O signals in the ¹³C

spectra and the NH groups in the ¹H NMR spectra due to the presence of the plane of symmetry σ¹of the molecules that passes through the C–C bond. The lack of symmetry along the σ² plane is demonstrated by the none- quivalence of carbons and protons of methine groups (CH–CH) in such a way that the carbons resonate with pair signals in the regions of 59.5–75.6 ppm, and the protons appear doublets in the range of 4.9–6.4 ppm.

The CS of the NH groups in the compounds 3a–d appear as singlet peaks, and, in the case of glycolurils 3a–c, with a shift to a low-field of up to 0.5 ppm, and for 2,8-N-diacetylglycoluril 3d to 1.6 ppm relatively to 1. The shielding of carbonyl carbon atoms for compounds 3a–c is on average 1 ppm. For compound 3d a shift of CS of the C=O groups to the high-field by 5.6 ppm relatively to the parent 1 is observed. The general character of the shift of the C=O groups signal for 3a–d is similar to substances 2a–h, but 2a–h have in their structure only one substituted imidazolinone ring, and compounds 3a–d combine the properties of two similarly substituted rings. In the structures of glycolurils 3a–d, there is a synergistic effect of pairs of substituents on the electronic density of glycoluril framework, distribution of which is reflected in NMR spectra by stronger shielding and deshielding of the corresponding atoms relatively glycoluril 1. So in ¹³С NMR spectra of glycolurils 3a–d there is the shielding of signals of one CH in 3d (up to 5.1 ppm) and a significantly higher deshielding of CH carbon in 3a–c from the substitution side (up to 11 ppm) relatively to CS of similar glycoluril atoms 1. In the latter case, the found effect is due to the positive inductive effect of electron- donating groups to nitrogen atoms [22; 712], which determines the «pushing out» of unshared pairs of nitrogen electrons to C–C carbons from the substitution side, making them partially sp²-hybridized. This interpre- tation can explain the shift of CS of CH-carbons to fields of «molecular currents» or π-conjugated systems.

2,4-N-Disubstituted glycolurils. In the molecules of 2,4-N-disubstituted glycolurils 4a–e, in the case of equivalent substituents, there is a symmetry corresponding to the σ² plane. This fact is confirmed by the CS in the NMR spectra (Table 3), where the signals of protons of equivalent NH groups give singlet peaks in the region of 7.5–8.9 ppm, the CS of carbons (62.6–76.7 ppm) and protons (5.1–5.7 ppm) of the CH–CH groups appear in the form of single signals. The absence of symmetry along the σ¹ plane is indicated by nonequivalent CS of C=O-groups.

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T a b l e 3 Сhemical shifts of 2, 4-N-disubstituted glycolurils 4a–e

R1 R2 СН–СН NH СН–СН С=О

1^[19] Н Н 5.24 7.16 (s. 4H) 64.60 160.30

4а^[19] СH3 СH3 5.12 (s. 2Н) 7.54 (s. 2H) 76.67 158.22

160.20 4b СН2ОН СН2ОН 5.55 (s. 2Н) 7.47 (s. 2H) 66.86 158.01 161.47 4с СОСН3 СОСН3 5.65 (s. 2Н) 8.87 (s. 1H) 62.62 154.68 161.10 4d^[21] CH3 CH2CH2NHCOСH3 5.10 (d. 1H, J = 8.1)

5.27 (d. 1H, J = 8.1) 7.49 (s. 1H)

7.56 (s. 1H) 66.16

67.93 158.36 161.61 4e^[21] Ph CH2CH2NHCOСH3 5.41 (d. 1H, J = 8.3)

5.82 (d. 1H, J = 8.3) 7.71 (s. 1H)

7.87 (s. 1H) 65.11

66.24 155.17 161.11

Chemical shift range (Δ) 5.10–5.82 7.47–8.87 62.62–

76.67 154.68–

161.61 The structures of compounds 4a–e combine the properties of unsubstituted and disubstituted by nitrogen atoms imidazolinone rings, where the CS of C=O groups for 4a, b, d in the substituted fragment are shielded by an average of 2.0 ppm, and in the case of compounds 4c, e with substituents of acceptor type — up to 5.5 ppm relatively to glycoluril 1. In the unsubstituted cycle of compounds 4a–e, on the contrary, carbonyl carbon atoms are deshielded up to 1.3 ppm compared to 1.

For compounds 4a and 4c, the symbatic effect of two substituents is observed. Acetyl substituents (4c) lower the electron density of the adjacent annelated ring, this is reflected in the shift of the CS of NH groups by 1.7 ppm in a low-field relatively to 1. Methyl substituents in 4a increase the electron density in the disubstituted cycle, which affects the deshielding of signals of CH–CH groups by 12 ppm relatively to 1.

In compounds 4a, b, d, aminogroups are deshielded by an average of 0.5 ppm, which corresponds to the range of compounds 2, 3 considered above with electron-donating substituents at nitrogen atoms.

The presence of various functional groups at 2,4-N-positions in compounds 4d and 4e leads to asymmetry of the molecule and, accordingly, to a change in the number of signals in the NMR spectra for NH, C=O, and CH-CH groups. For the substance 4e, the CS of unsubstituted NH groups also reflect a moderate acceptor effect of the phenyl substituent, which deshields NH by 0.7 ppm relatively to 1.

2,6-N-disubstituted glycolurils; and 2,4,6,8-N-tetrasubstituted glycolurils. Similarly to the glycoluril molecule 1, 2,6-N-di- 5a–h (Table 4) and 2,4,6,8-N-tetra-substituted compounds 6a–i (Table 5) have two planes of symmetry (σ¹ and σ²). In ¹H NMR spectra of substances 5a–h and 6a–i, we observe the equivalent singlets of protons of CH–CH groups of a bicyclic framework and in ¹³C NMR spectra the equivalent CS of CH–CH and C=O groups, as well as singlet peaks of two unsubstituted NH-groups in 5a–h.

T a b l e 4 Сhemical shifts of symmetric 2, 6-N-disubstituted glycoluril 5a–h

R1 СН-СН NH СН-СН С=О

1^[19] Н 5.24 (s. 2Н) 7.16 (s. 4H) 64.60 160.30

5а^[19] СH3 5.10 (s. 2Н) 7.57 (s. 2Н) 67.39 159.66 5b^[26] CH2C6H5 5.04 (s. 2H) 7.81 (s. 2Н) 64.88 158.86

5с^[27] CH2CH2NHCOCH3 5.25 (s. 2H) 7.49 (s. 2H) 65.40 159.20

5d СН2ОН 5.53 (s, 2Н) 7.61 (s. 2H) 66.34 160.56 5e СОСН3 5.66 (s. 2H) 8.85 (s. 2H) 61.80 154.34 5f^[28] СОСН2Cl 5.34 (s. 2H) 8.83 (s. 2H) 63.32 154.03 5g NO 5.64 (s. 2H) 9.96 (s. 2H) 60.19 152.00 5h^[29] NO2 6.03 (s. 2H) 9.83 (s. 2H) 63.80. 149.00

Chemical shift range (Δ) 5.10–6.03 7.49–9.96 60.19–67.39 149.00–160.56

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T a b l e 5 Сhemical shifts of symmetric 2, 4, 6, 8-N-tetrasubstituted glycolurils 6a–i

№ Substituent ¹Н NMR, ppm, (J/Hz)¹³С NMR, ppm

R1 R2 СНСН СНСН С=О

1^[19] Н Н 5.24 (s. 2Н) 64.60 160.30 6а^[19] СH3 СH3 5.06 (s. 2Н) 71.92 159.05 6b^[26] CH2C6H5 CH2C6H5 4.84 (s. 2Н) 67.71 159.54 6с СН2ОН СН2ОН 5.59 (s. 2Н) 70.65 158.62 6d СН2OCH3 СН2OCH3 5.52 (s. 2Н) 74.86 158.45 6e Cl Cl 5.48 (s. 2Н) 72.72 160.51 6f СОСН3 СОСН3 6.33 (s. 2Н) 62.69 151.58 6g^[31] NO2 NO2 7.77 (s. 2H) 65.90 142.40 6h^[20] CH3 СН2NHSO2Ph 4.70 (s. 2Н) 66.75 156.80

6i^[20] C2H5 СН2NHSO2Ts 4.65 (s. 2Н) 65.38 156.85

Chemical shift range (Δ) 4.65–7.77 62.69–74.86 142.40–163.81

Structures 5a–h are two annelated monosubstituted imidazolinone rings with anti-arrangement of substituents relatively to each other.

The type of the action of the substituents on the shift of the signals of NH groups to a low-field for substances 5a–h is similar to compounds 2, 3 considered above. In the substances 5a–d, electron-donating substituents of nitrogen atoms deshield the nuclei of NH groups by 0.6 ppm, and acceptor substituents (5e–h) deshield the CS of NH groups at 2.8 ppm relatively to 1.

The CS of C=O-group carbons undergo shielding on average up to 1.5 ppm (5a–d), and for compounds 5e–h with electron-acceptor substituents on nitrogen atoms, a synergy of electronic effects with shielding of carbonyl signals by 11 ppm is observed, which is due to the formation of π-electron shielding regions (Fig. 4, 5e).

13С NMR

5а 1 5е

СНСН δ 67.39 ppm δ 64.6 ppm δ 61.80 ppm С=О δ 159.66 ppm δ 160.30 ppm δ 154.34 ppm Figure 4. Diagram of the distribution of electron density in the imidazolinone fragment of glycolurils 1, 5a, 5e

It was found, that the CS of CH–CH protons in compound 5h is most deshielded compared to 5a–g and is shifted to the low-field region by 0.8 ppm relatively to 1. This effect can be explained by the spatial intramolecular interaction of nitrogroups with methine protons, which was discovered by studying the substance 5h by X-ray diffraction analysis (Fig. 5, 5h) [30], where it is reported that one of the oxygen atoms of the two nitrogroups is maximally reversed towards the cis-protons of the methine bridge.

The structures of compounds 6a–i combine the properties of two N-disubstituted imidazolidinone rings, where for substances 6f, g, the symbatic effect of 4 acceptor substituents is reflected in the spectral data. In this case, shielding of C=O groups to 17.9 ppm relative to 1 is observed. Electron-donating substituents in glycolurils 6a–e, h, i increase the electron density in disubstituted imidazolinone rings, which is shown in

13C NMR spectra by deshielding of CH-CH carbons to 10.2 ppm relatively to 1.

In the PMR spectra of compounds 6f, g, the singlets of protons CH-CH are most deshielded compared to the CS of the corresponding atoms of compounds 6a–e, h, i and are shifted to a low-field by more than 1.1 ppm (6f) and 2.5 ppm (6g) relative to 1. Intramolecular interactions between substituents (-COCH₃, -NO₂) and cis-protons of the CH–CH groups may be present in these compounds. In the case of tetraacetylsubstituted glycoluril 6f, these interactions were recorded by X-ray diffraction [32] (Fig. 5, 6f),

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where it was shown that the oxygen atoms of the two most twisted acetylgroups are maximally turned toward the protons of the methine bridge.

5h 6f

Figure 5. Intermolecular interactions between the oxygen atoms of the substituents and the protons of the methine bridge in 2,6-N-dinitroglycoluril 5h

according to X-ray diffraction data

Figure 6. Intermolecular interactions between the oxygen atoms of the substituents and the protons

of the methine bridge in 2, 4, 6, 8-N-tetraacetyl glycoluril 6f according to X-ray diffraction data 2,4-N-Dimethylderivatives of glycoluril. Comparing CS of 1 and substances 2a, 3a, 4a, 5a, 6a, it should be noted that the presence of CH₃ groups at nitrogen atoms causes deshielding of CH-carbon signals by an average of 10 ppm. Based on these data, CS in the series of asymmetric 2,4-N-dimethylderivatives of glycolurils 7a–f are further considered (Table 6).

T a b l e 6 Сhemical shifts of asymmetric 2,4-N-dimethylderivatives of glycolurils 7a–f

№ Substituting group ¹Н NMR, ppm, (J/Hz) ¹³С NMR, ppm

1^[19] - 5.24 (s. 2Н) 7.16 (s. 4H) 64.60 160.30 4a^[19] Н 5.12 (s. 2Н) 7.54 (s. 2H) 76.67 158.22 7a^[19] СH3 5.08 (d. 1Н, J = 8.3)

5.22 (d. 1Н, J = 8.3) 7.62 (s. 2H) 65.30 72.92

158.07 159.54 7b^[20] СН2СООН 5.15 (d. 1Н, J = 8.3)

5.22 (d. 1Н, J = 8.3) 7.90 (s. 1H) 65.93

71.85 158.08 160.05 7c^[21] С(CН3)2СООН 5.18 (d. 1Н, J = 8.1)

5.41 (d. 1Н, J = 8.1) 7.77 (s. 1H) 66.51

70.54 158.45 160.09 7d^[21] CH2CH2NН(CH3)2Cl 5.16 (d. 1Н, J = 9.5)

5.34 (d. 1Н, J = 9.5) 7.91 (s. 1H) 65.81

70.92 158.43 159.45 7e^[21] CH2CH2NHCOCH3 5.06 (d. 1Н, J = 8.3)

5.22 (d. 1Н, J = 8.3) 7.65 (s. 1H) 65.65 71.31

158.25 159.51 7f^[27] N=CHPh 5.33 (d. 1Н, J = 8.4)

5.62 (d. 1Н, J = 8.4) 8.43 (s. 1Н) 63.10

72.10 156.70 157.60

Chemical shift range (Δ) 5.06–5.61 7.54–8.42 63.10–

76.67 156.00–

160.09 When analyzing the CS of 2,4-N-dimethylglycolurils 7a–f, the asymmetry of the structures is clearly distinguished. The carbon atoms of the carbonyl groups of compounds 7a–e shift toward a high-field in the range from 0.2 ppm up to 2.2 ppm relative to the CS C=O of glycoluril 1. For compound 7f shielding of the carbonyl group to 4.3 ppm, and the shift of the CS of NH groups to a low-field by 1.3 ppm relative to 1 are observed, which is probably due to the positive mesomeric and negative inductive effect of the N=CHPh substituent.

In the spectra of compounds 7a–f, the highest deshielding of CH-carbons up to 8.3 m from the N-2,8- disubstitution of the molecule was recorded, and the CS of the neighboring CH carbons are manifested in NMR spectra with a shift of ±1.5 ppm relative to 1.

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Tricycles and tetracycles. It was interesting to trace the influence of the hard formation of substituents in polycyclic structures 8a–c and 9a–c on the CS of the reference atoms of NH, CH–CH, C=O groups of the glycoluril framework (Table 7).

T a b l e 7 Сhemical shifts of asymmetric tricyclic 8a–c

and symmetric tetracyclic structures 9a–c, derivatives of glycoluril 1

№ Substituting group ¹Н NMR, ppm, (J/Hz) ¹³С NMR, ppm

R1 R2 СН-СН NH СН-СН С=О

1^[19] 5.24 (s. 2H) 7.16 (s. 4H) 64.60 160.30

8a^{[20, 33]} t-Bu C2H5 5.25 (d. 1Н, J = 8.0)

5.52 (d. 1Н, J = 8.0) 8.03 (s. 1H) 63.40

64.20 157.20 159.40

8b^{[20, 33]} t-Bu Pr 5.20 (d. 1Н, J = 8.0)

5.52 (d. 1Н, J = 8.0) 8.00 (s. 1H) 63.40

64.30 157.30 159.50

8c^{[20, 33]} t-Bu s-Bu 5.25 (d. 1Н, J = 8.0)

5.51 (d. 1Н, J = 8.0) 7.92 (s. 1H) 63.39

64.35 157.02 159.28

9a^[20] c-C6H11 c-C6H11 5.50 (s. 2H) – 64.27 159.27 9b^[20] (CH2)2COOH (CH2)2COOH 5.56 (s. 2H) – 64.42 159.37 9c^[20] CON(CH3)2 CON(CH3)2 5.59 (s. 2H) – 53.18 160.02

Chemical shift range (Δ) 5.20–5.59 7.92–8.03 53.18–64.42 157.02–160.02 Analysis of the CS of tricyclic pentaazabicyclo[5.3.1.0]undecane-1,5-diones 8a–c and tetracyclic

hexahydrohexaazacyclopeite[def]fluoren-4,8-diones 9a–c made it possible to establish that these substances do not have significant differences in NMR signals for glycoluril scaffolds indicating the presence of polycyclicity and a rigid frame. It was found that the CS of CH-CH carbons in the 9c polycycle are shielded by 11 ppm, relative to 1, which is probably due to the additional shielding field, created by the π-group of NCON(CH₃)₂.

The obtained values of CS make it possible to conclude that there is no symmetry in 8a–c molecules and its presence in 9a–c substances.

1,5-C-Substituted glycolurils. In comparison with N-substituted tetracycles 9a–c, in the NMR spectra of 1,5-C-substituted glycolurils 10a–h and their diester polycyclic derivatives 11a–d, the influence of ether fragments on the CS of atoms of the glycoluril framework is noticeable (Table 8).

From the obtained data of ¹³C NMR spectra of substances 10a–h, 11a–d, it is seen that the diester fragments shield the signals of the carbon of C–C and C=O groups by an average of 2 ppm.

In compounds 10a–d, 11a, b, d, the CS of C₁–C₅ carbons, due to their «Quaternary», are shifted to the low-field up to 10 ppm on average and in the case of phenyl substituents at C₁-C₅ atoms in substances 10e–g, 11c up to 15 ppm.

The drift of the CS of NH-groups of substances 10a–h directly depends on the nature of the substituent at the C–C bond. Thus, electron-donating substituents in substances 10a–d cause a displacement of the CS on average ± 0.5 ppm relative to 1, and the inductive effect of electron-withdrawing substituents in substances 10e–h deshields the nuclei of NH group protons by 0.6–1.6 ppm relative to 1.

It is noteworthy, that acceptors at the 1, 5-C-substitution (10e–h) do not affect the shielding of C=O in

13C NMR spectra as compared to the N-substitution (2f, g, 3d, 4c, e, 5e–h, 6f, g, 7f), which probably indicates the absence in this case of the formation of π-electronic «anisatropy cones» with an additional shielding field.

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T a b l e 8 Сhemical shifts of symmetric 1,5-C-substituted glycolurils 10a–h and their diester

polycyclic derivatives 11a–d

1 2N

4 3

N

5

N⁶ ₇ ⁸N

O O

R₂

R₁ O

1 O

2NH

4 3

HN

5

HN⁶₇8NH

O O

R₂ R₁

10 11

Substituting group ¹Н NMR, ppm, (J/Hz) ¹³С NMR, ppm

№ R1 R2 СН-СН NH СН-СН С=О

1^[19] 5.24 7.16 (s. 4H) 64.60 160.30

10a^{[34, 35]} CH3 CH3 7.10 (s. 4Н) 75.20 159.30

10b^[34] H CH3 4.8 (s. 1Н) 7.10 (s. 2Н)

7.20 (s. 2Н) 69.80

73.10 160.30 10c^[34] CH3 C2H5 7.10 (s. 2Н)

7.20 (s. 2Н) 77.80 159.70 10d^[34] -CH2CH2CH2CH2- 7.00 (s. 4Н) 73.60 160.30

10e^{[34, 35]} C6H5 C6H5 7.80 (s. 4Н) 81.70 160.60

10f^[35] 3-ClC6H4 3-ClC6H4 7.98 (s. 4Н) 81.30 160.40 10g^[35] 4-ClC6H4 4-ClC6H4 7.88 (s. 4Н) 81.20 160.30 10h^[36] CF3 CF3 8.83 (s. 4Н) 77.11 158.27

11a^{[34, 37]} CH3 CH3 – 73.40 157.40

11b^[34] CH3 C2H5 – 73.40

75.60 157.60

11c^{[34, 37]} C6H5 C6H5 – 79.00 158.00

11d^[38] –CH2CH2CH2CH2– – 72.20 158.00 Chemical shift range (Δ) 7.00–8.83 69.80–81.70 157.40–160.60 C,N-Substituted glycolurils. In considering particular cases — compounds 12a–k (Table 9) and 13a–r

(Table 10) with a mixed type of N- and C-substitution the ¹³C NMR spectra are the most informative for the analysis of electronic properties and conformational changes in the glycoluril framework. In the presence of an unsubstituted NH group, its signals in the PMR spectra are observed in the region of 5.91–6.19 ppm for 12a–k and 7.95–8.66 for 13a–r.

T a b l e 9 Сhemical shifts of 1,5-C-dimethyl-2,6-N-dimethylglycolurils 12a-k

№ Substituting group ¹Н NMR, ppm,

(J/Hz) ¹³С NMR, ppm

R1 R2 NH СН-СН С=О

1 2 3 4 5 6 7

Solvent CDCl3

1^[19] - - 7.16 (s. 4Н) 64.60 160.30 12a^[39] H H 5.91 (s. 1Н) 74.70

83.10 161.00 12b^[39] СН3CO H 6.00 (s. 1Н) 76.40

78.50 153.00 157.20 13c^[40] СН3(СН2)8COСН2CO H 6.05 (s. 1Н) 76.60 76.71 152.73 157.14 12d^[39] СН3СН=СНCO H 6.13 (s. 1Н) 76.20

78.20 152.60 157.10 12e^[39] СН3СOСН2CO H 5.95 (s. 1Н) 76.60

78.70

152.80 157.10 12f^[39] (СН3)CСOСН2CO H 6.04 (s. 1Н) 78.60

86.60 152.60 157.20

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C o n t i n u a t i o n o f T a b l e 9 1 2 3 4 5 6 7

Solvent CDCl3

12g^[39] СН3С(OH)СН2CO H 6.19 (s. 1Н) 76.70

78.70 152.09 157.10 12h^[39] СН3СOCH(СН3)CO H 5.94 (s. 1Н) 76.90

78.90 153.00 157.20 12i^[39] СН3CO СН3CO - 77.30

80.40 153.10 12j^[39] (СН3)3СCO СН3CO - 78.40

80.50

152.80 153.60 12k^[39] СН2=СНCO СН3CO - 77.90

80.50 153.00

Chemical shift range (Δ) 5.91–6.19 74.70–86.60 152.09–161.00

T a b l e 1 0 Сhemical shifts of 1, 5-C-diphenylglycoluril 13a–r

№ Substituting group ¹Н NMR,

ppm, (J/Hz) ¹³С NMR, ppm

R1 R2 R3 NH СН-СН С=О

13a^[41] СН3 СН3 Н 8.31 (s. 2Н) 83.70 159.00

160.10 13b^[21,

42] СН3 СН3 (СН2)2ОН 8.54 (s. 1Н) 82.64 87.74

158.62 1 59.86 13c^[21,

42] СН3 СН3 СН2СООН 8.61 (s. 1Н) 82.85

87.05 158.58 159.46 13d^[21,

43] СН3 СН3 СН2СООСН3 8.66 (s. 1Н) 83.00

87.98 158.64 158.94

13е^[21] СН3 СН3 (CH2)2NH(CO)CH3 7.95 (s. 1Н) 82.48

87.64 158.42 159.52

13f^[27] СН3 СН3 (CH2)2N(CH3)2 8.49 (s. 1Н) 83.00

87.90

158.40 161.00 13g^[21] H CH2COOCH3 CH2COOCH3 8.28 (s. 2Н) 83.70 158.69 13h^[21] CH2COOCH3 H CH2COOCH3 8.29 (s. 2Н) 79.95

88.28 159.00 13i^[21] (СН2)2ОН H (СН2)2ОН 8.16 (s. 2Н) 79.44

89.79 160.28 13j^[21] (СН2)2ОН H CH3 8.11 (s. 2Н)) 79.11

89.05 159.59 160.09 13k^[21] (СН2)2ОН H CH2COOPr-i 8.12 (s. 1Н)

8.26 (s. 1Н)

79.85 89.02

159.12 159.92 13l^[21] CH3 H n-Bu 7.98 (c. 1Н)

8.11 (s. 1Н) 79.02

89.04 159.65 13m^[21] CH3 H COOPr-i 8.10 (s. 1Н) 79.37

88.44 159.10 159.36 13n^[21] CH3 H (CH2)2NH⁺(CH3)2Cl 8.23 (s. 1Н)

8.40(s. 1Н) 79.33

89.17 159.52 1 59.84 13o^[21] CH3 H (CH2)3COOPr-i 8.04 (s. 1Н)

8.14 (s. 1Н)

79.03

89.07 159.63 13p^[21] CH3 H (CH2)3CHCOOHNH2 8.08 (s. 1Н)

8.12 (s. 1Н) 79.00

89.19 158.78 159.68 13q^[21] CH3 H COOPr-i 8.26 (s. 1Н) 79.37

88.44 159.10 159.36 13r^[27] (CH2)3COOCH3 H (CH2)3COOCH3 8.21 (s. 1Н) 83.90 159.00

Chemical shift range (Δ) 7.95–8.66 79.00–

89.79 158.40–

161.00

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It should be noted that in the analysis of the CS of 1,2,5,6-tetramethylglycolurils 12a–k, the solvent plays an important role, because the spectra of these compounds were recorded in the CDCl₃ solvent and the proton signals of unsubstituted NH-groups are shifted to the region of high-field (5.9–6.2 ppm) relative to 1, due to the absence of interactions with the solvent. In this case, the effect of the solvent on the CS of carbon atoms is negligible.

In 1,2,5,6-tetramethylglycolurils 12a–k, the CH-carbon signals are deshielded due to their «Quater- nary», on average, by 10 ppm, and in N-alkylglycoluril 12a from the N-dimethyl substitution side, up to 22 ppm, relative to the CS of glycoluril 1. In this case, the positive mesomeric effect of methyl groups [22; 712]

«pushes out» an unshared pair of electrons from nitrogen atoms to generalize with the ring, partially hybrid- izing neighboring C–C atoms to the sp² state.

The CS of the C=O groups of compounds 12b–k (field interval from 152.1 ppm to 157.2 ppm) demon- strate the presence of acceptor acylsubstituents as π-electron groups that create «anisatropy cones» (Fig. 4), due to which shielding occurs of carbonyl carbon relative to 1 and 12a.

After analyzing the NMR data for compounds 13a–r (Table 10), it is possible to clearly determine the presence of symmetry in the molecules and its type (σ¹ or σ²).

The CS of NH-protons of 1,5-С-diphenylglycolurils 13a–r appear singlet peaks and are shifted to a low-field by 0.8–1.5 ppm relative to 1, which may be due to the electron-withdrawing effect of phenyl substituents. The effect of the latter is also clearly observed in unsubstituted at nitrogen atoms diphenylglycoluril 10e (Table 8, (7.80 ppm)).

Carbons of the methine group in substances 13a–r are deshielded at 14.4–24.6 ppm relative to 1, where the largest shift of the CS of C5-carbon to the low-field region is observed from the 4, 6-N-substitution side.

Conclusions

The analysis of CS in the NMR spectra of glycoluril 1 and its derivatives 2–13 (86 compounds in total) makes it possible to accurately identify the spatial symmetry configurations of glycolurils, in the presence of which (σ¹ and/or σ²) one half of the molecule is a mirror image of the other, where the enantiotopic hydrogen and carbon atoms of the bicyclic framework are manifested by equivalent signals.

In the NMR spectra of asymmetric derivatives of glycolurils, in particular N-monosubstituted 2, N- trisubstituted 7, tricyclic derivatives 8 and glycolurils with a mixed type of N-,C,C-substitution 12, 13, it is seen that the molecules lose the symmetry planes σ¹ or σ² and the equivalent CS of protons and carbons of glycoluril bicycles manifest as nonequivalent peaks

Molecules 3 having one plane of symmetry σ¹ give equivalent signals of carbonyl carbons and singlet signals of two unsubstituted NH-groups, but protons and carbons of the CH–CH fragment in such symmetric molecules resonate in pairs. Glycolurils with the symmetry plane σ² (4), on the contrary, are identified only by nonequivalent CS of C=O-groups.

The CS of ¹H and ¹³C of the glycoluril framework of the symmetric molecules N-anti-5, N-tetra-6, and C-substituted compounds 10, 11 are present in the NMR spectra in the form of equivalent singlet signals, which indicates the presence of symmetry planes σ¹ and σ² in the molecules.

In the presence of alkylsubstituents at the nitrogen atoms in the structures of the studied glycolurils 2–

13, the shielding of С=О by 1-3 ppm relative to the signal C=O glycoluril 1 is observed, which can be determined by the effects of steric inhibition of conjugation in the amide fragment with a corresponding decrease in the order of the amide bond [44]. However, in the study of N-alkylglycolurils by the X-ray diffraction method [45], it was determined that nitrogen atoms with their unshared electron pairs participate in conjugation with C=O groups and have a flattened geometry; therefore, N-C(Alk) bonds are almost coplanar to the rings. In the presence of a decrease in the order of the amide bond, the coplanarity of this fragment should probably be violated, as in the case of glycolurils with acceptor substituents [30, 46].

It was shown that for mono- (2) and disubstituted glycolurils (3, 4, 5) at nitrogen atoms, the positions of the signals of unsubstituted NH groups in the NMR spectra are in the range from 7.0 ppm up to 9.9 ppm.

In the presence of electron-donating substituents in the structures of substances 2a–e, 3a–c, 4a, b, d, 5e–h, 7a–e, the shift of the CS of the NH-groups occurs in the range of ± 0.6 ppm. relative to 1, which indi- cates a weak effect of substituents for inhibition of amide conjugation. And in the presence of acceptor substituents in substances 2f, g, 3d, 4c, 5e–h, 7f, the CS of the NH-group shifts in the low-field region. Moreo- ver, the stronger the inductive effect of the acceptor, the farther the position of the signal in the PMR spectrum (up to 9.9 ppm, (5g, h), glycoluril 1 (7.14 ppm)). This fact is explained by a violation of the electron density of the amide fragment (Fig. 2), where the substituents reduce the bond multiplicity and the unshared

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pair of electrons of the neighboring unsubstituted NH group is isolated from the plane of the imidazolinone ring. Such regularities are also observed for 1, 5-C-substituted glycolurils 10, 12, 13, where electron- donating substituents in substances 10a–d cause a shift of the CS of NH-groups on average ±0.5 ppm, relative to 1. The negative inductive effect of electron-withdrawing substituents in substances 10e–h, 13a–r re- distributes the electron density from imidazolinone rings, thereby the nuclei of NH-groups are deshielded by 0.6–1.6 ppm, relative to 1.

In the ¹³C NMR spectra of compounds 2f, g, 3d, 4c, 5e–h, 7f, 12b–k, in which substituents with an electron-withdrawing property are present, shielding of the C=O signal to 18 ppm is observed, moreover, the stronger its acceptor character, the signal C=O shifts more to the region of a high-field. There are a number of factors [47; 163] that can affect the shielding constant of the carbonyl fragment in glycolurils 2–13 of which the most significant are the hybridization and resonance effects of substituents with magnetic anisotropy of neighboring groups. In the presence of an electron-withdrawing substituent at nitrogen atoms in the glycoluril framework, more efficient hybridization of carbonyl carbon atoms to the sp² state and in the С–N fragment to the sp³ state occurs [48]. An additional effect is exerted by the circulation of electrons of electron-withdrawing substituents with the presence of π-bonds [23; 183], which leads to the appearance of additional fields or «anisotropy cones» (Fig. 4). This circumstance mainly depends on the geometry of the molecule [24].

It should be added that the shielding of carbonyl carbon in the ¹³C NMR spectra correlates with the C=O bond length established by X-ray diffraction studies [18, 30, 32]. In compounds 5h and 6f, the nuclei of carbonyl carbon atoms show the CS at 149.00 ppm and 151.58 ppm respectively, and the length of C=O bond is on average 1.19 À, whereas the CS of the carbonyl carbon atoms of glycoluril 1 is 160.30 ppm, and the length of the C=O bond is 1.21 À. Thus, the results of NMR and X-ray diffraction studies of compounds 5h and 6f are consistent with each other and complement each other.

In compounds with electron-donating substituents at nitrogen atoms (in substances 2f, g, 3d, 4c, 5e–h, 7f, 12b–k), deshielding of C–C-carbon signals on average by 10–22 ppm is observed, which also can be ex- plained by the general redistribution of electron density in imidazolinone cycles. Thus, the enhanced electron supply by electron-donating groups to nitrogen atoms [22; 712] affects the possibility of pairing its unshared pair of electrons with a five-membered cycle. Therefore, C-C-carbons can partially acquire the properties of sp²-hybridized atoms due to an increase in the electron density, which shifts the CS carbon in the field of

«molecular currents» or π-conjugated systems. In this case, a local paramagnetic contribution arises due to the anisotropy of the electron density distribution on C–C carbons for which the CS is measured.

Around the C–C nuclei, an electron circulation occurs, which creates either a secondary magnetic field in the same direction as the superimposed field, or a diamagnetic field that is weaker due to circulation re- strictions, which makes a significant contribution to the CS of the CH–CH groups. A similar effect in the case of other nuclei (N, F, O) is observed, in which the ground and excited states are closer in energy [50].

However, anisotropic electron circulation for СН-СН proton atoms in 2f, g, 3d, 4c, 5e–h, 7f, 12b–k, substances is not observed, because the excitation energies of empty orbitals of a hydrogen atom with higher energies are very high. The excited state is far removed from the ground one, and this effect can only make an insignificant contribution to most the CS of protons [49; 163].

In a general analysis of the ¹H and ¹³C NMR spectra of glycolurils 1–13, it is clearly seen that for any type of N-,C-substitution, shielding of the carbonyl atom C=O in the imidazolidinone ring is observed.

Thus, in this work, an analysis of the nuclear magnetic resonance for glycoluril derivatives was carried out, where the NMR signals were characterized from the position of molecular symmetry and the nature of the substituents.

The generalization performed makes it possible to distinguish between symmetric and asymmetric molecules, to distinguish impurity signals, which can often accompany the synthesis of bicyclic bisureas. Ac- cording to NMR spectra, glycolurils with electron-withdrawing N-substituents by shielding the signals of the carbon atom of C=O groups and electron-donating N-substituents by deshielding of CH–CH-carbons can be clearly distinguished.

References

1 Patent 102004059041 Germany. Verwendung von Formaldehyd und Formaldehyd freisetzenden Verbindungen in einer Zusammensetzung zur Bekämpfung von Mykobakterien / Beilfuss W., Gradtke R., Krull I., Steinhauer, K. Publication date 08.06.2006.