nitro ⇌ aci-nitro tautomerism and e/z isomeric preferences of nitroethenediamine derivatives: a...

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Nitroethenediamine exists in enamine, imine and aci-nitro tautomeric forms, of which aci-nitro

invokes in polymorphism and metabolism

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This journal is © The Royal Society of Chemistry [year] [journal], [year], [vol], 00–00 | 1

Nitro aci-nitro tautomerism and E/Z isomeric preferences of

Nitroethenediamine Derivatives: A quantum chemical study

Devendra K. Dhakeda and Prasad V. Bharatam *a

Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 5

Nitroethenediamine moiety is present in several important chemical species including therapeutic agents like ranitidine. In the scientific literature, ranitidine molecule is represented in three different tautomeric forms: enamine, imine and nitronic acid (aci-nitro) and the observed polymorphic differences in ranitidine are attributed to the structural differences. Quantum chemical calculations have been performed using HF, B3LYP, BHandHLYP, M06-2X and MP2 methods, on model nitroethenediamine to understand the isomeric preferences. Calculations indicated that in model nitroethenediamine (NED), enamine is the most preferred tautomeric state which exists 10

in two geometrical isomers (E/Z). These isomers are in dynamic equilibrium due to low barriers (~14 kcal/mol in solvent conditions) for rotation across C1-C2 double bond as a result of push-pull effect of nitroethenediamine moiety. The aci-nitro form of the nitroethenediamines is invoked in explaining the polymorphism, metabolism as well as activity of these species. The relative importance of the aci-nitro form has been explored in this article. The results indicate the aci-nitro form becomes easily accessible under acidic conditions, though this tautomer is about 13 kcal/mol less stable under gas phase conditions. The observed polymorphic differences have 15

been traced to easy E/Z conversions and the tautomerism in acidic conditions.

Introduction

Nitro group (R-NO2) is considered as a structural alert in drug discovery process and generally avoided during drug design. 20

However, alkenyl nitro group containing species (H2C=CH-NO2) found special application. In all these cases, nitronic acid tautomers are invoked to explain drug action, metabolism, safety profile and polymorphism issues. In this article, we study the nitro aci-nitro tautomerism in this class of drugs or leads. 25

Nitronic acids (R1R2C=N(-O)OH) are important but rare class of compounds which participate as intermediates in chemical process. Nitroethenediamine derivatives are known to show nitro

aci-nitro tautomerism, E/Z isomerism and enamine-imine tautomerism.1, 2 Important examples of nitroethenediamines 30

derivatives are ranitidine (1), nizatidine (2) (Fig. 1) and niperotidine (3) (H2-receptor antagonists), introduced for the treatment of acid reflux, heartburn, ulcer and treatment of Zollinger–Ellison syndrome.3-4 Various neonicotinoids containing nitroenamine moiety are used as insecticidal agents. Nitenpyram 35

(4) and nithizine (5) are the first generation neonicotinoides. These neonicotinoids are being used in crop protection, termite control and in veterinary medicine.5 Ranitidine, a widely used H2 receptor antagonist, shows nitro

aci-nitro tautomerism and this phenomenon is attributed to the 40

observed polymorphic states of this compound. Cholerton et al.,6 based on spectroscopic studies, discarded the nitronic acid portrayal of ranitidine in 1984. However, the equilibrium between nitro aci-nitro forms of ranitidine is continuously being invoked in all scientific studies of ranitidine.7 A few studies 45

indicated that nitronic acid tautomer is present in biological

conditions and interact with heam to inhibit oxidation of drug by cytochrome P450.8 Recently Gore et al.9 reported the presence of nitronic acid form of ranitidine and claimed that, this electron rich species is involved in the formation of charge transfer 50

complex with holes, generated from excited semiconductor quantum dots. Basit et al.,10, 11 based on UV and mass spectrometry analysis, indicated that ranitidine and nizatidine in colon are metabolized from nitronic acid tautomer via cleavage of an N-oxide bond. Zapol’skii et al.12 indicated the presence of 55

mesomeric nitronic acid in 2-nitromethylene-imidazolidine and nitromethylene-oxazolidine derivatives. Mirmehrabi et al.2 reported that the polymorphic form II of ranitidine hydrochloride (RNH) contains two tautomers –an enamine (A) and nitronic acid (B) (Fig. 2). C and D are other 60

putative structures of nitronic acid. Structure D is commonly used in the scientific literature for the representation of nitronic acid portrayal of ranitidine and nizatidine. Ishida et al.13 proposed enamine tautomer as a correct molecular structure of nitroethenediamine moiety of RNH, on the basis of crystal data, 65

without mentioning its polymorphic form. In contrast, Agatonovic-Kustrin et al.14 reported imine (E) as a correct structure for form II, on the basis of IR spectroscopy (IR peak at 2400 cm-1) and assigned enamine for form I by inference. Moreover, they reported that enamine and imine are the stable 70

tautomers which are responsible for polymorphic behavior of RNH. Mirmehrabi et al.15, 16 observed that polar solvents favor production of form II, while nonpolar solvents resulted in the formation of form I.

75

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2 | Journal Name, [year], [vol], 00–00 This journal is © The Royal Society of Chemistry [year]

N

OS N

H

NO2

NH

N

N

SS N

H

NO2

NH

Ranitidine Nizatidine1 2

Niperotidine

3

N NH

NO2

N

Cl

Nitenpyram

HN S

NO2

Nithiazine4 5

N

N

SS N

H

NO2

NH

O

O

Fig. 1 Several medicinally important nitroethenediamine

derivatives.

Enamine tautomer of nitroethenediamine moiety can have two geometrical isomers (E and Z) across the C-C double bond in which nitro and alkylamino groups are trans and cis to each other, respectively. The Z isomer is reported in form I of RNH,17 5

two polymorphs of ranitidine base18 and one polymorph of nizatidine.19 Kojic´-Prodic et al.20 reported E configuration in oxalate salt of ranitidine. Ishida et al.13 found an equal population of E and Z geometrical isomers in form II of RNH. Cholerton et al.6 reported an equimolar mixture of E/Z configurational isomers 10

of enamine in solution. A nitrolic form F is also considered during E/Z isomerization and reported to have important role in the interconversion of configurational isomers (E/Z) of enamine tautomer A.21 Nitro aci-nitro tautomerism was extensively studied using 15

theoretical methods on simple nitro compound like nitroenamines, nitroalkanes, etc.22-26; no studies are reported on this tautomerism in nitroethenediamines. Marcos and co-workers studied geometries, rotational barriers and isomer populations of 2-nitroenamine, as well as effect of solvent on equilibria, using 20

the MNDO/H and AM1 methods in order to explore push-pull effects.27 Same group in a different report tried to correlate vibrational spectra of nitroenamines with the calculated values by ab initio MO and semi-empirical methods.28 Quantum chemical study on nitroethylenes indicated that nitro aci-nitro 25

tautomerism in 2-nitrovinylamine is relatively easier by 13.2 kcal/mol in comparison to that in 1-nitro-propene (37.8 kcal/mol).22 Dumanovic et al.29 reported the heat of formation and spectral transitions of N,N`-dimethyl-2-nitro-1,1-

ethenediamine and it anions (deprotonated or hydroxylated 30

species) as well as cations (C or N or O protonated species) in gas and water using semiemprical methods. These calculations indicated low heats of formation for the C-protonated and O-protonated species. In addition, they determined pK and pKa constants for ranitidine and nizatidine besides N,N`-dimethyl-2-35

nitro-1,1-ethenediamine. The above cited theoretical studies did not address the isomeric/tautomeric states of nitroethenediamine explicitly. Till now there is no report which describes the molecular level understanding of tautomeric, configurational preferences and 40

electronic structure studies of nitroethenediamine. Several research groups reported the importance of tautomerism in explaining drug-receptor interaction, drug metabolism, toxicity, etc. Our research group has been working on the detailed electronic structure studies, conformational and tautomeric 45

preferences on aminoguanidines, biguanides, biurets, thiobiurets, guanylthioureas and sulfonylureas.30-35 In this article, we report the structural preferences of (enamine/imine/nitronic acid) a model N-ethyl-N`-methyl-2-nitro-1,1-ethediamine (NED). The results in this article are presented in four sections (i) isomeric 50

preferences; (ii) effect of microsolvation on tautomeric preferences; (iii) protonation behavior and (iv) E/Z isomerization.

Methodology

Ab initio Molecular Orbital (MO)36, 37 and Density Functional (DFT)38, 39 calculations have been carried out using the 55

GAUSSIAN0940 software package. Complete optimizations of various conformers, tautomers (N-1 to N-16) have been performed using HF (Hartree-Fock), B3LYP (Becke3, Lee, Yang, Parr),41-43 and MP2(Full) (Moeller-Plesset perturbation)44 methods with the 6-31+G(d,p) basis set in gas phase. Further 60

optimizations were performed at B3LYP and MP2(Full)/6-311+G(d,p) levels of theory to see the effect of basis set on geometries and energetic. In addition, optimization of some of the tautomers is performed using Becke-Half-and-Half-LYP (BHandHLYP)41, 45 functional with 6-311+G(d,p) basis set. 65

Some of the optimizations have been carried out using parameterized hybrid meta-GGA functional M06-2X46 that contains description of dispersion energy. Water clusters of N-1, N-10 and N-13 (in the presence of 1-4 water molecules) were optimized in the gas phase at B3LYP and M06-2X levels of 70

theory with 6-31+G(d,p) basis set. The proton affinities have been calculated to confirm the relative basic sites of molecules. The polarizable continuum models CPCM47 IEFPCM48 and SMD49 have been used for solvent calculations at B3LYP/6-311+G(d,p) level of theory. Frequencies have been computed 75

analytically to characterize each stationary point as a minimum or a transition state and to estimate the zero point vibrational energies (ZPE) for all optimized structures. The estimated ZPE values (at 298.15 K) have been scaled by a factor of 0.9153, 0.9806, and 0.9661 for the HF, B3LYP, and MP2(full) levels, 80

respectively.50, 51 Some of the calculations were performed with the ORCA program52 version 2.9.1 (Local pair natural orbital based correlation methods:- LPNO-CCSD53 or LPNO-CEPA/154 using def2-TZVPP basis set55). Both of methods were used with the default setup given in ORCA. In addition, some of the solvent 85

phase calculations have been carried out using conductor-like screening model (COSMO) of ORCA, in water medium. The NBO (Natural Bond Orbital) 56, 57 analysis was employed to quantitatively estimate the second-order interactions.

90

C

CN

H

ONH

NH

R

CH3

O

C

CN

H

ONH

NH

R

CH3

O

H2C

CN

RN

Enamine

Nitronic acid Imine

1, 3 H-shift1, 5 H-shift

C

CN

H

ONH

NR

CH3

O

C

CN

H

ONH

NR

CH3

OH

H

A

B C D E

C

CN

ON

NH

R

CH3

OH

FNitrolic form

1

2 3

4

5

67

NO

O

C

CN

H

HN

NH

R

CH3

E Z

O

O

E/Z isomerization

H

CH3

..

Fig. 2. Possible tautomers of ranitidine.


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This journal is © The Royal Society of Chemistry [year] Journal Name, [year], [vol], 00–00 | 3

Results and discussion

Electronic Structure Analysis of Geometric and Tautomeric Isomers

N-ethyl-N-methyl-2-nitro-1,1-ethediamine (NED), has been taken as a model system for 2-nitro-1,1-ethenediamine derivatives, all 5

possible geometrical isomers and tautomers, on the potential energy surface were explored using quantum chemical methods. Fig. 3 shows the 3D structures of N-1 to N-16 and Table 1 shows their relative energies both in gas and solvent phase. N-1 to N-8 are the enamine tautomers. On the potential energy surface, 10

enamine isomer (E) N-1 has been found to be the most stable in the gas phase as per B3LYP,M06-2X and BHandHLYP calculations (Table 1). N-1 is characterized by a N6-H…O5 intramolecular H-bond. N-2 is a geometrical isomer (Z) of N-1, which is also characterized by the presence of an intramolecular 15

H-bond N7-H…O5. This Z isomer (N-2) is found in form I, II of ranitidine base, polymorph of nizatidine and form II of RNH, whereas, E isomer is present in oxalate salt of ranitidine base. The relative energy data (Table 1) shows that the geometrical isomers N-1 and N-2 are almost isoenergetic. On the PE surface 20

of NED, two more low energy enamine isomers (N-3 and N-4; E/Z isomeric pair) could be identified, which lies below 4 kcal/mol compared to N-1. The enamine tautomers are almost planar due to the presence of conjugation from amino to nitro

group. This energy analysis indicates that NEDs may prefer any 25

of the isomeric states (N-1 to N-4) under equilibrium conditions. N-5 to N-8 are other enamine isomers whose energies lie about 9 kcal/mol higher in comparison to N-1 and thus these isomers may not be observable in equilibrium conditions. N-9 to N-12 are the imine tautomers of N-1 and N-2, which 30

arise as a result of 1,3 shift of proton from any of the amino groups to C2 carbon. This shift of proton leads to a loss of conjugation between nitro and amino groups, therefore nitro group is no longer coplanar with the rest of the molecule. N-9 and N-10 are characterized by the presence of weak intramolecular H-35

bond therefore; these are preferred slightly over N-11 and N-12 isomers. These tautomers are near about 6 and 8 kcal/mol less stable than N-1 at the M06-2X and B3LYP levels, respectively. However, at the MP2 level N-10 turns out to be the most stable tautomer. As per MP2 calculations, imine isomers are the most 40

preferred, this is in contrast to the trends observed at HF, B3LYP, M06-2X and BHandHLYP methods. In order to see astonishing disagreement between MP2 and DFT for the relative stabilities of enamine/imine isomers, calculations at LPNO-CCSD and LPNO-CEPA/1 methods are carried out.58, 59 The results indicate that the 45

imine tautomers are only about 1-2 kcal/mol less stable than the

Table 1 Relative energies (in kcal/mol) of various geometrical isomers and tautomers of model nitroethylenediamines.a

Entry

Gas phase (Eg) Solvent phase (Es)e

Tautomer CPCM IEFPCM SMD COSMO B3LYP

b M06-2X b

B3LYP

c BHand HLYP

c

MP2 (Full)

c

LPNO-CCSDd

LPNO-CEPA/1d

B3LYPc LPNO-CCSDd

N-1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

Enam

ine

N-2 0.18 0.12 0.13 0.02 -0.01 0.00 0.02 0.18 0.18 0.31 0.09

N-3 3.56 3.47 3.57 4.10 2.08 2.38 2.16 4.54 4.55 4.11 4.73

N-4 3.74 3.45 3.74 4.24 2.00 2.45 2.22 4.61 4.62 4.33 5.01

N-5 8.86 7.54 8.59 8.80 5.61 7.65 7.42 8.14 8.15 7.40 9.26

N-6 8.89 7.68 8.62 8.83 5.95 7.74 7.50 8.31 8.33 7.25 9.37

N-7 9.52 8.30 9.28 9.55 7.13 8.69 8.38 7.73 7.76 6.66 10.17

N-8 9.36 8.08 9.14 9.39 6.56 8.63 8.34 7.71 7.74 6.24 9.72

N-9 7.49 6.28 7.19 7.60 -1.44 1.80 1.08 14.69 14.59 15.60 10.74

Imine

N-10 7.34 6.10 6.98 7.30 -1.30 1.63 0.94 14.35 14.35 15.42 10.63

N-11 8.63 6.10 8.22 8.05 -0.92 1.82 1.20 14.01 14.01 13.94 9.74

N-12 8.46 6.06 8.06 7.94 -0.88 2.02 1.41 13.89 13.90 14.23 9.56

N-13 13.58 12.76 13.44 14.72 10.75 12.14 10.86 21.54 21.53 22.58 22.12 Nitronic

acid

N-14 17.96 17.29 17.81 19.47 15.04 16.53 15.12 25.20 25.20 25.56 26.35

N-15 -- -- -- 10.43 5.61 9.51

8.84 -- -- 0.00 18.37

N-16 38.23 36.54 38.12 39.31 38.91 37.65 35.81 39.62 39.07 37.96 39.51 Nitrolic form

a All energies are corrected for zero-point vibrational energy. b Basis set 6-31+G(d,p). c Basis set 6-311+G(d,p). d Basis set def2-TZVPP. eImplicit solvent analysis, using CPCM, IEFCPCM, SDM and COSMO methods, in water solvent.


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global minimum, in contrast to the prediction using DFT methods (i.e. 6-9 kcal/mol less stable) and the MP2 methods (~ 1 kcal/mol more stable). The results from these local natural orbital approaches are more closely comparable to that of G2MP2 and 5

CBS-QB3 methods (Supporting information Table S1).

N-13 to N-15 are nitronic acid tautomers stabilized through intramolecular H-bond. These may be obtained by 1,5-H shift in N-1. 1,5-H shift in N-1 originating from N7 atom is quite possible, the corresponding isomers (N-13 and N-14) adopt stable 10

structure with trans diene character. They are also characterized by intramolecular H-bond as in N-1. N-13 is near about 14 and 11 kcal/mol less stable than N-1 at B3LYP and MP2 methods, respectively. This tautomer is found in form II of RNH. 1,5-H shift from N6 atom of N-1 is expected to give N-15. This 15

tautomer converts back to N-1 during complete optimization at B3LYP or MP2(Full)/6-31+G(d,p) and B3LYP/6-311+G(d,p) levels. N-15 is found on the potential energy surface at BHandHLYP/6-311+G(d,p) and MP2(Full)//6-311+G(d,p) levels. Probability of finding this tautomer on PES is very low using 20

theoretical methods although it is commonly used for the representation of nitronic acid tautomer of NED moiety. In aqueous media, the nitronic acid isomer (N-13) is less stable with larger relative energy values of about 22 kcal/mol in all models (Table 1). N-16 is nitrolic tautomer stabilized through 25

intramolecular H-bond as in N-1. This may be obtained by 1,3-H shift from C2 atom of N-1 to O4 of nitro group (or 1,3-H shift from C2 atom of N-13 to N7 atom). On the relative scale it turns out to be the least stable isomer (by 38.23 kcal/mol). The presence of nitrolic tautomer is indicated in polarographic studies 30

at mercury electrode21 although it is less stable. After H-shift nitrolic tautomer is expected to adopt linear geometry along with sp hybridization at C2 center.21 But in the B3LYP optimized

geometry (at other levels also), N-16 is bent in which C2 center is sp2 hybridized. NBO analysis indicated the presence of one lone 35

pair of electron on C2, in sp2 orbital due to carbene like character of nitrolic tautomer. Effect of Microsolvation on Tautomeric Preferences

Direct interaction of water molecules affect the reactivity and structure of drugs, biomolecules, neurotransmitters, etc. by H-40

bonding or electrostatic interaction. Since all these systems show their molecular action under aqueous media, it is worth exploring their structural preferences in water media using microsolvation studies. NED have several polar functional groups as nitro, aci-nitro and amino which can participate in H-bonding with water 45

molecules. Therefore, in order to understand the effect of aqueous medium through H-bonds, the influence of explicit water molecules near the nitro and amino groups of NED has been studied. The influence of explicit water at the amino center has been found to be marginal and hence the following discussion is 50

limited to interaction of water molecules at nitro and aci-nitro groups.

Table 2 Relative energies of N-10-nw and N-13-nw water clusters in the presence of 1-4 water molecules.a,b Gas phase Solvent Phased

n B3LYPc M06-2Xc M06-2Xc

N-10-

nw

N-13-

nw

N-10-

nw

N-13-

nw

N-10-

nw

N-13-

nw

0 7.34 13.58 6.10 12.76 12.93 20.11

1 8.05 10.89 6.03 10.40 12.42 16.15

2 10.06 11.32 8.82 10.66 13.46 15.50

3 11.13 7.95 9.49 8.77 12.71 14.59

4 10.98 10.67 8.96 8.34 14.81 14.85

a All energies are corrected for zero-point vibrational energy. b Energies are relative to water cluster N-1-nw. c Basis set 6-31+G(d,p) is used for optimizations. In N-1-nw, n stands for number of water molecules and W for water. dImplicit solvent analysis using CPCM model.

55

The relative stability of enamine (N-1), imine (N-10) and

N-2N-1 N-3

N-7 N-8N-6

N-4

N-5

N-9 N-10 N-11 N-12

N-13 N-14 N-15 N-16

1.791.83 1.84

2.282.23

2.00

2.00

1.731.47

1.80

Fig. 3 B3LYP/6-31+G(d,p) optimized geometries of NED tautomers and isomers. (Geometry of N-15 is at BHandHLYP/6-311+G(d,p), H-bond distance is shown by dashed line in Å)

N-1-1w

N-10-1w

N-13-1w

N-10-2w

N-13-2w

N-1-3w

N-10-3w

N-13-3w

N-1-4w

N-10-4w

N-13-4w

N-1-2w

Fig. 4 M06-2X/6-31+G(d,p) optimized geometries of microsolvatedclusters of enamine (N-1), imine (N-10) and nitronic acid (N-13)tautomers.


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nitronic acid (N-13) tautomers is determined in the presence of 1-4 microsolvating water molecules. Two/three alternative structures for water clusters were identified for N-1, N-10 and N-13 after complete optimization. Of which, the relative energies of lowest energy clusters are given in Table 2 (others higher energy 5

clusters are given in supporting information, Fig. S1 - Fig. S4, Table S2). Optimized structures of N-1-nw, N-10-nw and N-13-nw clusters are given in Fig. 4. In the lowest energy configuration N-1-1w of N-1, a single water molecule bridges between the nitro and amino groups. The lowest energy water 10

cluster, N-10-1w, contains a water molecule which forms three H-bonds by interacting with the nitro and amino groups. In N-13-1w water molecule is localized at the aci-nitro center by two intermolecular H-bonds. In the presence of one water molecule, the relative stability of N-10-1w is not changed while the stability 15

of N-13-1w is increased by 2.46 kcal/mol compared to bare conformation at M06-2X method. In N-1-2w, a two water chain is preferred between the nitro and amino (N6-H) groups. In two water clusters of nitronic acid, both the water molecules are localized at the aci-nitro group (N-20

13-2w). In other alternative structures interaction of water molecules at the amino group is found. In the lowest energy two water cluster of N-10, interaction of a water chain with the nitro (O4) and amino (N6-H) groups is found. In addition, this N-10-2w cluster is not characterized by O5…N6-H intramolecular H-25

bond as it found in bare conformation. Data shown in Table 2 indicates that addition of second water molecule has decreased the stability of N-10-2w by 2.72 kcal/mol and has improved the stability of N-13-2w by 2.10 kcal/mol from the corresponding bare structures at M06-2X/6-31+G(d,p) level of theory. 30

In N-1-3w and N-13-3w clusters, a chain of three water molecules bridges across nitro or aci-nitro groups. In N-1-3w one of the terminal water molecules is H-bonded with both oxygen atoms of nitro group. In the structure of N-10-3w orientation of two water molecules is similar to N-10-2w and interaction of 35

third water molecule is favorable at amino group (N-7H). Data given in Table 2 indicates that addition of third water molecule on two water clusters is disfavored by about 0.67 kcal/mol for N-10-3w and favoured by 1.89 kcal/mol for N-13-3w compared to the corresponding two water clusters at M06-2X method. 40

In N-1-4w two water molecules are directly H-bonded to nitro group and remaining two water molecules connecting amino group (N-6H) to two water chain which is associated with nitro group. In N-10-4w cluster, a chain of three water molecules connects amino group (N6-H) to nitro group (O4) and fourth 45

additional water molecule bridges to this chain. In the lowest energy conformation of N-13-4w, a ring of four water molecules bridges to aci-nitro group by three intermolecular H-bonds. In the presence of four water molecules improvement in stability of N-13-4w is about 4.42 kcal/mol whereas decrease in stability of N-50

10-4w is about 2.86 kcal/mol over their corresponding bare conformations at M06-2X level of theory. It is worth noting that in all the imine clusters shown in Fig. 4, water molecules interacting together with amino and nitro groups are preferred however, configuration where water interacting with only nitro 55

group is not found on potential energy surface. Explicit water medium calculation indicated that in aqueous medium also enamine tautomers are the most preferred tautomers

than the alternative tautomers. In smaller water clusters imine and nitronic acid tautomers are quite competitive; however, in larger 60

water clusters nitronic acid tautomer is preferred over imine tautomers. As the number of water molecules is increased in explicit model, nitronic acid may be more preferred. This may be origin of observed nitronic acid tautomer of NED, leading to polymorphic differences. It is interesting to note that mutually 65

opposing results are obtained from studies using implicit and explicit water conditions on the relative energy of nitronic acid tautomer of the NED species. The relative preference of nitronic acid tautomer is decreased by ~7 kcal/mol under implicit condition whereas the relative preference of nitronic acid 70

tautomer is increased by 5 kcal/mol under explicit water conditions. Such observation indicates that the implicit solvent analysis methods need to be made more robust in the case of nitro compounds to give more reliable results. This observation is found in the solvation study of zwitterions of several amino 75

acids,60-63 pyridine sulfonylurea,64 etc.

Protonation in Nitroethylenediamines

NED species are basic, they are known to form HCl salts.17, 19 There are three important sites of protonation in N-1 i.e. O4, C2 and O5 leading to the three different isomers (HN-1, HN-2 and 80

HN-3) of HNED, the structures of these are shown in Fig. 5. Protonation at O4 is most preferred with a proton affinity of -220.41 kcal/mol (Table 3). Protonation at C2 is the next preferred site with a proton affinity of -216.48 kcal/mol. Proton affinity for protonation at O5 is -215.30 kcal/mol. HN-1 and HN-3 are 85

nitronic acid analogs whereas HN-2 should be treated as a derivative of nitromethane RCH2NO2, where R is the diaminocarbenium ion ((NR2)2C

+). The small energy difference between the three isomers of HNED indicates that under acidic conditions, isomerization in NED is quite possible and the 90

various polymorphic states are reported for the NED derivatives are under acidic conditions. From this data, it can be concluded that all the drugs based on NED moiety prefer protonation at O4 site in the gas phase. However, in the continuum conditions, the most preferred site of protonation is C2 due to its highest proton 95

affinity in water medium compared to other sites. Therefore the relative stability of HN-1 is reversed with HN-2 in water medium and it is found to be about 3 kcal/mol less stable than HN-2. Dumanovic et al.29 in their study indicated low heat of formation for the C2 and O5-protonated species. Whereas, several other 100

groups expected protonation of nitro group of NED moiety.65 From this data it can be concluded that in the gas phase O4 is preferred while in aqueous medium C2 is preferred site of protonation. However, possibility of existence of both structures (HN-1 and HN-2) can't denied due to low energy differences in 105

proton affinity (2 kcal/mol) and the relative stability (3 kcal/mol).

HN-1 HN-2 HN-3

Fig. 5 B3LYP /6-31+G(d,p) optimized geometries of HN-1 to HN-3.


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In order to understand chemical behavior of NED tautomers, N-1 and N-13 were explicitly treated in the presence of one water molecule and one hydronium ion. In the starting geometry of N-1, hydronium ion and water molecules are attached through 5

intermolecular H-bonds to nitro group and N7, respectively while in N-13 at opposite sites. In cluster H2O-N-1-H3O

+ during optimization, proton from hydronium ion is transferred to the

nitro group leading to the formation of protonated nitronic acid tautomer which is stabilized by two water molecules (Fig. 6). 10

Similarly, in H2O-N-13-H3O+ cluster also proton from

hydronium ion is transferred to N7 and resulting protonated nitronic acid-water complex. This clearly established the preference for O4 protonated nitronic acid (HN-1) isomer under acidic condition. In addition, 15

dimeric model of N-13 with HN-1 leads to spontaneous transfer of proton from HN-1 to N-13 (Fig. S5). While similar proton shift is not observed in the dimeric model of HN-1 with N-1 (proton shift may require some amount of energy). This indicates the low and high kinetic stability of neutral nitronic acid (N-13) 20

and protonated nitronic acid (HN-1) tautomers, respectively in acidic condition. This further support the conclusion that under acidic condition, nitronic acid tautomers can be easily observed which probably lead to the observed polymorphic states of drugs with NED moiety.25

Table 3. Protonation behaviour of N-1 enamine tautomer. a

Rel. E (kcal/mol) (Proton affinity kcal/mol)

Gas phase Solvent phase Gas phase Solvent phase

Entry Protonation site

Protonated tautomer

CPCM SMD CPCM SMD

B3LYP b B3LYP c B3LYP c B3LYP b B3LYP c B3LYP c

N-1

O4 HN-1 0.00 0.00 0.00 0.00 -220.41 -220.09 -254.01 -258.28

C2 HN-2 3.64 3.31 -3.00 -3.03 -216.48 -216.46 -256.27 -260.31

O5 HN-3 5.18 4.78 3.37 3.31 -215.30 -215.39 -251.27 -255.53

a All energies are corrected for zero-point vibrational energy. b Basis set 6-31+G(d,p) and c basis set 6-311+G(d,p) are used for optimizations.

E/Z isomerization

The conversion of one enamine isomer into other requires rotation across C1-C2 double bond. For example, conversion of 30

N-1 into N-8, takes place as a result of rotation across C1-C2 bond and breaking of intramolecular H-bond. The estimated barrier for this conversion is near about 23 kcal/mol (Table 4). Similarly, C1-C2 rotational barrier of N-3 (to N-4) is 24.20 kcal/mol. On the other hand, conversion of N-6 to its Z isomer 35

(N-5) requires only 16 kcal/mol energy. However, barriers in water solvent are low compared to gas phase, for example ~13.8 kcal/mol barrier is found for each N-1 and N-3. Rotational barrier in N-6 is 6-7 kcal/mol lower than N-1 (and N-3). This is due to the absence of intramolecular H-bond in N-6, which provides 40

extra barrier to rotation in N-1 and N-3. This indicates that barrier for C1-C2 rotation is ~16 kcal/mol and the strength of intramolecular H-bond is ~6-7 kcal/mol in NED. Energy barriers are lower in water due to weakening of intramolecular H-bond by polar solvent. The C=C rotational barrier in ethene (1a) (Fig. 7) is 45

expected in the range of 60-61 kcal/mol66, 67 but in N-1 and N-6, it is very low (~16-24 kcal/mol). Jarowaski et al.66 reported that methyl, ethynyl and vinyl substitutions reduce C=C rotational barriers in alkenes, significantly. For example, barrier in 3,4-divinyl-1,3,5-hexatriene (1,1-divinyl-2,2-divinyl-ethene) across 50

C=C double bond is 18.8 kcal/mol. This indicates that in NED,

bond is weakened compared to ethene with an increase in the electron delocalization, the C=C rotation barriers are reduced. In NED, the amino groups donate electron density to the C=C bond molecular orbital and hence C=C double bond strength 55

decrease, reducing the rotational barrier to smaller values.68 In order to understand this behavior, various smaller analogs (1b-1g) of NED are considered and the rotational barrier in each case was calculated. This C=C rotational barrier in ethene (~61 kcal/mol) is reduced by ~6 kcal/mol upon an amino substitution 60

1d

1a 1b 1c

1e 1f 1g

Fig. 7 B3LYP/6-31+G(d,p) optimized geometries of various amino and nitro substituted ethylenes (1b-1g).

N

O

O

N N

H

H

OH

H

OH H

N

O

O

N N

HO

H

H

OH H

N

O

O

N N

H

OH

H

OH H

H

H

H2O-N-1-H3O+ H2O-N-13-H3O

+

1.57

2.00

H H H

Fig. 6 Schematic representation of NED behavior in acidic aqueous medium (Distances in Å).


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in 1b, due to the pushing of electron density from N to antibonding orbital of bond (E2 = 8.32 kcal/mol) (Table 4). In the presence of another amino substitution in 1c (ethene-1,1-diamine), barrier is reduced by ~21 kcal/mol. In 1c, second order delocalization energies (E2) due to nN→ delocalizations from 5

each amino group is about 25 kcal/mol, which strongly weakens the strength of C=C bond. On the other hand, in 1d (ethene-1,2-diamine) (positional isomer of 1c) C=C rotational barrier is not affected significantly by the presence of second amino substitution. In 1e, (nitroethene) the C=C rotational barrier is 10

reduced by ~13 kcal/mol, this can be attributed to the decrease in the electron density. Nitro group substitution significantly lowers barrier than single amino group. Trans disubstitution of ethene with nitro and amino groups (1f, 2-nitroenamine) significantly reduces the C=C rotational barrier to 38.63 kcal/mol. 15

This indicates that combination of one electron donor group and one electron withdrawing group (as in 1f) is slightly more effective compared to two electron donor groups (1c, ethene-1,1-diamine) in lowering the C=C barrier. In 1f, second order delocalization energy (E2) due to nN→C=C delocalization is 20

51.08 kcal/mol. In 1g estimated barrier is about 27 kcal/mol, which is higher only by 4 kcal/mol with respect to that of N-1. This increase in barrier in 1g compared to N-1 is due to the absence of alkyl group attached to amino groups which are responsible for inductive effect. This is indicated in lower values 25

of second order delocalization in 1g than N-1(Table 4).

Rotational barrier in N-6 is lower by 7 kcal/mol compared to N-1 due to lack of intramolecular H-bond, indicating that barrier because of bond is about 16 kcal/mol. Implicit solvent phase calculation at B3LYP/6-311+G(d,p) level using CPCM indicated 30

that E/Z isomerization barrier in polar solvent is 1-3 kcal/mol lower than that in nonpolar solvent.

This data indicates that while moving from 1a to NED, the second order delocalization is increasing therefore electron density from the lone pairs of amino groups is pushed to C-C 35

which weakens the bond. This shifting is also intensified by the presence of the strong electron withdrawing nitro group in NED moiety. The nitro group withdraws electron density from C-C bond. The excess electron pumping to orbital and removal of electron density from C-C bond, reduce the strength and 40

decrease the rotational barrier to ~27 kcal/mol in 1g. The effect of amino and nitro substitution follows addition effect. Therefore, it can be concluded that all the drugs based on NED moiety exhibit in E/Z equilibrium due to push-pull effects of amino and nitro groups, and thus contribute to the polymorphic forms. N-13 and 45

N-14 are nitronic acid tautomers and estimated C1-C2 barriers are 5.48 and 1.94 kcal/mol, respectively. In addition, in N-13 and N-14 conjugative interaction across C-C bond is almost absent. This energy data shows that in N-13, intramolecular H-bond is stronger than in N-14. This implies that interconversion of 50

nitronic acid isomers is easier compared to enamine isomers.

Table 4. Rotational energy barriers of enamines and nitronic acids across C1-C2 bond.a

Entry

Rotational barrier (kcal/mol) Donor-acceptor

Interactions

E2(e)

(kcal/mol)

Gas phase Solvent phased

H2O CHCl3

B3LYPb MP2 Fullb

B3LYPc MP2 Fullc

B3LYPc

1a 60.72f -- -- -- -- -- -- --

1b 54.42 59.33 54.47 58.27 47.04 49.15 nN→*C=C 8.32

1c 39.98 44.05 40.01 43.73 31.60 33.94 nN→*C=C nN→* C=C

24.86 24.99

1d 60.43 64.31 60.93 64.51 55.97 57.45 nN→*C=C nN→* C=C

7.99 7.98

1e 48.11 51.97 49.32 53.88 47.20 47.87 -- --

1f 38.63 42.12 39.30 43.25 29.97 32.89 nN→*C=C 51.08

1g 27.35 28.27 27.54 29.60 17.15 19.70 nN→*C=C nN→* C=C

35.54 50.48

N-1 23.07 21.52 23.18 22.84 13.75 16.21 nN6→*C=C nN7→* C=C

49.34 64.40

N-3 24.20 25.22 24.42 26.38 13.77 16.33 nN6→*C=C nN7→* C=C

27.47 60.56

N-6 16.06 16.84 16.43 18.72 7.55 9.65 nN6→*C=C nN7→* C=C

39.83 47.78

N-13 5.48 3.55 5.24 3.74 3.39 3.89 -- --

N-14 1.95 -- -- -- -- -- -- --

a All energies are corrected for zero-point vibrational energy. b Basis set 6-31+G(d,p) is used for optimizations. c Basis set 6-311+G(d,p) is used for optimizations. d Implicit solvent analysis, using CPCM method. e Second order interaction energy. f Value of rotational barrier for ethylene (1a) is taken from reference for comparison.67


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This is in contrast with results of Cholerton et al.6 as they reported that direct interconversion of nitronic acid isomers is difficult and indirectly can interconvert through enamine isomerization. Nitronic acid isomers have rotational hindrance of 5

intramolecular H-bond, while stable enamines have not only intramolecular H-bond but also partial double bond and hence E/Z isomerization becomes much difficult compared to nitronic acid isomerization. Above study on the tautomeric preferences, E/Z isomerization 10

and microsolvation as well as the protonation analysis clearly indicates that isomeric preferences becomes delicately balanced as a function of aqueous and mild acidic conditions. Though in gas phase nitronic tautomer is less favorable, under slightly acidic and microsolvated conditions it is easily accessible. This is 15

evidence from observed polymorphic states in which enamine and nitronic acid tautomers are found in solid state.

Conclusions

Quantum chemical analysis of nitroethenediamine was performed to understand tautomeric preferences of ranitidine like drug 20

molecules. The study indicated that N-1 and N-2 are the most preferred isomers of enamine tautomer. Of which N-2 (Z isomer) is reported in three polymorphs of ranitidine. Quantum chemical analysis revealed that the nitronic acid tautomer represented by a N-13 structure is important. This representation was not 25

considered in previous studies. N-15 is the lowest energy nitronic acid isomer but the presence of this isomer on the potential energy surface is not practical because of 1, 5 H-shift. The choice of quantum chemical methods plays important role in the isomeric preferences of this class of tautomers. For example, at 30

MP2 methods, the imine tautomer is found to be more stable than the enamine tautomer. Higher level calculations at G2MP2 and CBS-Q methods do not support this observation. In microsolvated condition, the energy difference between important tautomers is reduced in comparison to bare tautomers 35

significantly. In the smaller water clusters (1-2 water) imine tautomer (N-10) is preferred over nitronic acid tautomer however; improvement in the stability of nitronic acid is more compared to imine tautomer over their corresponding global minimum isomers. In the presence of 3-4 microsolvating water molecules 40

nitronic acid (N-13) is preferred over imine (N-10). For imine clusters, interaction of two water molecules with the nitro group along with amino group is favourable along with breaking of intramolecular H-bond between amino and nitro group. In nitronic acid, the presence of a four water ring at nitro group is 45

preferred while in enamine a chain of four water molecules spanning from nitro group to amino group is favourable. In the acidic condition energy difference between tautomers is < 5 kcal/mol and nitronic acid tautomer is favoured over imine isomers by 3 kcal/mol in the gas phase. 50

Interconversion barrier for E and Z isomers of enamine, across C1-C2 double bond is low compared to ethene and the estimated barrier is ~24 kcal/mol. This lowering of barrier occurs due to the presence of strong nN→delocalizations. In polar solvents solvent condition barrier is reduced by about 10 kcal/mol. The 55

result indicates that a combination of one electron donor group and one electron withdrawing (1f) is slightly more effective

(push-pull effect) compared to two electron donor groups (1c, ethene-1,1-diamine) in lowering the C=C barrier. The low isomerization energies in nitroethenediamines under aqueous and 60

slightly acidic conditions are responsible for the observed polymorphic differences in these compounds. Acknowledgments 65

Authors are thankful to Council of Scientific and Industrial Research

(CSIR), New Delhi and NIPER, S. A. S. Nagar for providing financial

support.

Notes and references a Department of Medicinal Chemistry, National Institute of 70

Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar - 160 062, Punjab, India. Fax: +91-172-2214692; Tel: +91-172-2292018; E-mail: [email protected]

† Electronic Supplementary Information (ESI) available: Table S1 75

contains relative energy of N-1 and N-10 at different levels of theory. Table S2 has relative energy of various microsolvated water clusters. Fig. S1 - Fig. S4 show optimized geometries of microsolvated water clusters of N-1, N-10 and N-13 in the presence of 1-4 water molecules. Fig. S5 contains geometries of transition states of 1b-1g for C1=C2 double bond 80

rotational barrier. Table S3 - Table5 contain absolute energies of given molecules. S1 – S2 have Cartesian coordinates of various the optimized structures and water clusters. See DOI: 10.1039/b000000x/

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nitro ⇌ aci-nitro tautomerism and e/z isomeric preferences of nitroethenediamine derivatives: a...

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