Novel"N(’L)2 species with two lone pairs on nitrogen:

systems isoelectronic to carbodicarbenesw

Dhilon S. Patel and Prasad V. Bharatam*

Received (in Cambridge, UK) 22nd September 2008, Accepted 13th November 2008

First published as an Advance Article on the web 5th January 2009

DOI: 10.1039/b816595e

A new bonding environment has been identified for nitrogen in

chemical species with the general formula "N(’L)2 (I), in

which the N atom is characterized by two lone pairs.

Many novel bonding environments of carbon are being reported,

for example, stable ‘bottlable’ carbenes,1 pentacoordinate and

hexacoordinate carbon,2 divalent C(0) carbons with two lone

pairs, etc.3,4 In this article, we report a new class of chemical

species with the general formula "N(’L)2 (I), with a new

bonding environment of nitrogen. Electronic structure analysis

indicates that this class of compounds possess two lone pairs of

electrons on a nitrogen atom with a formal positive charge. The

central core of this class of molecules is isoelectronic to the

central core of carbodicarbenes C(’NHC)2 (II),4—which are

characterized by (i) a divalent C(0) carbon, (ii) the presence of

four electrons in two lone pairs on the central carbon atom which

occupy the two highest occupied molecular orbitals, (iii) s and pelectron donating ability to Lewis acids and (iv) the involvement

of their two lone pairs in the complexation with transition metals.

The "N(’L)2 systems reported in this work are clearly different

from the nitrenium ion, "NR2, systems,5 which are isoelectronic

to carbenes. Several known molecules such as metformin hydro-

chloride (2-(N,N-dimethylcarbamimidoyl)guanidine�HCl),6 and

proguanil hydrochloride (1-(4-chlorophenyl)-2-(N0-propan-2-

ylcarbamimidoyl)guanidine�HCl)7 belong to this hitherto

unrecognized class "N(’L)2. Generating many species with

the general formula (III and IV) is an important challenge and

offers ample opportunities for basic research in chemistry.

N+ is isoelectronic to carbon, and thus the systems with the

general formula R2CQNQCR2+ become isoelectronic to

allenes.8 They are expected to be linear and the two p bonds

in these systems are expected to be orthogonal. However,

crystallographic structures show that metformin�HCl

[(NMe2)(NH2)CQNQC(NH2)2]+ is bent with C2–N1–C3 angle

122.61 and C2–N1–C3 angle in biguanide�HCl (2-carbamimidoyl-

guanidine�HCl) [(NH2)2CQNQC(NH2)2]+ is 122.81.6,9 Com-

putational analysis10 of R2CQNQCR2+ (IV) showed that the

C–N–C angle decreases with an increasing number of pelectron donating substituents (NH2).

A linear C–N–C arrangement in H2CQNQCH2+ becomes

highly bent in 1 ((H2N)2CQNQC(NH2)2+). Fig. 1 shows the

3D structures of the protonated biguanide (1), protonated

metformin (2), the NHC coordinated N+ species (3) and the

corresponding carbodicarbene (4). The geometrical features of

1–3 are quite similar to that of 4. In particular the C–N–C

angles in 1–3 (125.8, 125.8, 123.91) are very similar to the

central C–C–C angle of 4 (122.41). The torsional angles across

the central unit in these systems are also comparable (132.31 in

3 vs. 123.71 in 4). The central nitrogen carries a partial negative

charge in IV (R = H) and it increases with an increase in the

number of NH2 groups.11 The N inversion barrier in these

systems increases with the number of NH2 groups.11 This

analysis indicates that with an increase in the p-electrondonating substituents, electron density gets accumulated on

the central nitrogen, and the electronic structure at the central

nitrogen atom becomes different from that of the simple

H2CQNQCH2+.

Molecular orbital analyses of 1–3 indicate that they are

characterized by two lone pairs of electrons on the central

nitrogen. Natural localized molecular orbital (NLMO) and

Fig. 1 Optimized 3D structures of 1–4. The geometric parameters are

as per the B3LYP/6-31+G* calculations. Distances are in A and

angles in degrees.

Department of Medicinal Chemistry, National Institute ofPharmaceutical Education and Research (NIPER), Sector 67,S. A. S. Nagar (Mohali), 160 062 Punjab, India.E-mail: pvbharatam@niper.ac.in; Fax: (+) 91-172-2214692;Tel: (+) 91-172-2214685w Electronic supplementary information (ESI) available: The coordi-nates of the optimized geometries of 1–10 and IVa–e along with their3D structures, absolute and relative energies of these species. SeeDOI: 10.1039/b816595e

1064 | Chem. Commun., 2009, 1064–1066 This journal is �c The Royal Society of Chemistry 2009

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natural bond orbital (NBO) analyses12 show that 1–3 are

characterized by two lone pairs of electrons on the central

N, similar to the two lone pairs of electrons on the central

carbon in carbodicarbenes.3,4 Fig. 2 shows the contour maps

of the occupied orbital representing the s and p type lone pairs

of 3 and 4, showing considerable similarities. This suggests

that 3 and 4 show analogous characteristics in terms of both

structure (geometric parameters) and electronic structure.

NLMO analysis shows full (2.0) integer occupancies for two

lone pairs s and p at the central nitrogen of 3. The NBO

analysis shows electron occupancies in the s and p lone pairs

in 1 are 1.87 and 1.55, respectively; the same values for 3 are

1.87 and 1.55, respectively. These values are larger than the

electron occupancies in the s and p lone pairs in 4 (1.51 and

1.11, respectively),4 indicating that the lone pair electrons are

more strongly localized on the central nitrogen in 1 and 3 in

comparison to those in 4.

The presence of two lone pairs on the central nitrogen atom

in 1–3 indicate that these systems may be treated as divalent

N(I) systems similar to divalent C(0) systems, carbodicarbenes

(II). The striking similarities in the geometric parameters as

well as molecular orbital shapes support the above argument.

The calculations on "N(’PMe3)2 also show two lone pairs

on the central nitrogen similar to C(’PMe3)2 and the nitrogen

atom in "N(’PMe3)2 should also be considered as a divalent

N(I) system.13 Compound 5, a phosphorus equivalent of

3 is known to exist14 and the electronic structure analysis of

5 also shows two lone pairs of electrons on the phosphorus

atom.11

Characteristic features of carbodicarbenes include their

strong single and double proton affinities.4 They also show

strong Lewis basic character as indicated by the strength of

their coordination with Lewis acids such as BH3 and the

formation of complexes with metals.4 The proton affinities10

of 1–3 (108–122 kcal mol�1) (Table 1) are much smaller than

that of 4, this may be attributed to the fact that 1–3 are already

positively charged. The proton affinities of 1–3 are more

closely comparable to the second proton affinities of carbo-

dicarbenes (in the range of 148–162 kcal mol�1).4

The complexation energies10 of 1–3 with BH3

(11–15 kcal mol�1) are much smaller than that of 4

(68 kcal mol�1), indicating that the Lewis basic character of

1–3 is very weak. This novel electronic structure (two lone

pairs on divalent nitrogen) is not limited to 1–3. Protonated

cycloguanil (1-(4-chlorophenyl)-6,6-dimethyl-1,3,5-triazine-

2,4-diamine) 6 (R = 4-ClC6H4, an anti-malarial drug),15 7

(R = –CH2CH2Si(CH3)2Ph, R0 = –SiMeH(CH2)2Si(CH3)2Ph,

R00 = alkyl or phenyl, a pentavalent silicon system)16 and

8 (a boron complex of a biguanide unit)17 are also character-

ized by two lone pairs on nitrogen as per molecular orbital

analysis.11 A formal positive charge can be attributed to the

central nitrogen atoms in 7 and 8, while the localized negative

charge on pentavalent Si (in 7) and tetravalent B (in 8) make

these molecules neutral. The proton affinity of cationic species

6 is 121.67 kcal mol�1 comparable to that of 1–3. On the

other hand the proton affinities of 7 and 8 are 220.39 and

214.76 kcal mol�1 respectively, which are much larger than that

of 1–3. The complexation energies of 7 and 8 with BH3 are 25.52

and 25.90 kcal mol�1 respectively, indicating that the Lewis

acidity of 7 and 8 is much larger than that of 1–3, further

indicating that the coordination chemistry of "N(’L)2 systems

can be experimentally verified by generating species similar to (V).

Neutral biguanides upon deprotonation produce anions

which form metallic complexes such as VI.18 A comparative

analysis of deprotonation energies19 of 3 (234.7 kcal mol�1)

and 4 (341.1 kcal mol�1) (leading to species 9 and 10,

respectively) indicates that deprotonation is highly favourable

in both cases. The deprotonation energy of 4 is the same as

that of acetic acid (341.4 kcal mol�1) indicating that acidity of

4 may be quite comparable to that of acetic acid.7 Double

deprotonation in 4 is also possible (446.89 kcal mol�1), the

corresponding anion (42�) may form complexes with metals as

Fig. 2 Comparison of shapes of molecular orbitals of 3 and 4

containing s and p lone pair electrons (calculated at MP2(full)/

6-31+G*//B3LYP/6-31+G* level of theory). There is a clear node

between NHC and N in the HOMO of 3 whereas partial delocalization

is present in the central (NHC)C–C–C(NHC) in the HOMO of 4;

suggesting that the second lone pair in 3 is localized on N in

comparison to that on C in 4.

Table 1 Proton affinities (EPA) at central N and complexationenergies with BH3 (EBH3

) are calculated at B3LYP/6-31+G* (kcal mol�1)a

EPA EBH3EPA EBH3

1 108.29 10.94 6 121.67 16.372 119.15 12.00 7 220.39 25.523 121.48 15.18 8 214.76 25.90

a The proton affinity of 4 at the central carbon is 292.3 kcal mol�1 and

the complexation energy with BH3 is 68.00 kcal mol�1.4

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shown in VII, leading to the generation of several novel and

stable carbodicarbene complexes. Similarly, deprotonation/

double deprotonation of 3 also may lead to many new

examples of the title compounds.

Hydrochloride salts of metformin and proguanil are known

to be orally bioactive, and possess two lone pairs on central

nitrogen, while their neutral counterparts are not charac-

terized by two lone pairs on central nitrogen. Upon proton-

ation in the neutral biguanide derivatives, (i) intramolecular

electron conjugation breaks down, (ii) intramolecular hydrogen

bond breaks down, (iii) two lone pairs get localized on the

central nitrogen, (iv) allene like character is induced and (v)

dynamism increases through N-inversion as well as C–N

rotation. The activation of biguanide derivatives through

protonation seems to have significance in terms of their

therapeutic potential, which needs to be explored in detail.

Synthesis of compound 3 and its derivatives shall provide an

important handle in exploring the chemistry of "N(’L)2systems. Many anti-malarial and anti-diabetic leads, biurets,

thiobiurets, guanylthiourea derivatives (in their protonated

states) are examples of this class (IV); electronic structure

studies of these systems is in progress in our lab.

In conclusion, a new class of "N(’L)2 species has been

identified for the first time from among the existing and well

known chemical species with the help of electronic structure

analysis. Further exploration of the novel phenomenon of

these systems is worth pursuing; especially because of their

wider application in organic, medicinal as well as coordination

chemistry.

This work is supported by Department of Science and

Technology (DST), New Delhi. The authors also thank Pansy

D. Patel, a former member of their lab for in-depth discussion.

Notes and references

1 A. J. Arduengo, Acc. Chem. Res., 1999, 32, 913; D. Bourissou,O. Guerret, F. P. Gabbaı and G. Bertrand, Chem. Rev., 2000, 100, 39.

2 K.-y. Akiba, Y. Moriyama, M. Mizozoe, H. Inohara, T. Nishii,Y. Yamamoto, M. Minoura, D. Hashizume, F. Iwasaki,N. Takagi, K. Ishimura and S. Nagase, J. Am. Chem. Soc., 2005,127, 5893; T. Yamaguchi, Y. Yamamoto, D. Kinoshita,

K.-y. Akiba, Y. Zhang, C. A. Reed, D. Hashizume andF. Iwasak, J. Am. Chem. Soc., 2008, 130, 6894; J. Z. Davalos,R. Herrero, J.-L. M. Abboud, O. Mo and M. Yanez, Angew.Chem., Int. Ed., 2008, 47, 381.

3 O. Kaufhold and F. E. Hahn, Angew. Chem., Int. Ed., 2008, 47,4057.

4 R. Tonner, F. Oxler, A. Neumuller, W. Petz and G. Frenking,Angew. Chem., Int. Ed., 2006, 45, 8038; S. Marrot, T. Kato,H. Gornitzka and A. Baceiredo, Angew. Chem., Int. Ed., 2006,45, 2598; R. Tonner and G. Frenking, Angew. Chem., Int. Ed.,2007, 46, 8695; R. Tonner and G. Frenking, Chem.–Eur. J., 2008,14, 3260; R. Tonner and G. Frenking, Chem.–Eur. J., 2008, 14,3273; C. A. Dyker, V. Lavallo, B. Donnadieu and G. Bertrand,Angew. Chem., Int. Ed., 2008, 47, 3206; M. M. Deshmukh,S. R. Gadre, R. Tonner and G. Frenking, Phys. Chem. Chem.Phys., 2008, 10, 2298; A. Furstner, M. Alcarazo, R. Goddard andC. W. Lehman, Angew. Chem., Int. Ed., 2008, 47, 3210.

5 P. G. Gassman, Acc. Chem. Res., 1970, 3, 26.6 M. Hariharan, S. S. Rajan and R. Srinivasan, Acta Crystallogr.,Sect. C, 1989, 45, 911.

7 P. V. Bharatam, D. S. Patel and P. Iqbal, J. Med. Chem., 2005, 48,7615; S. Sundriyal, S. Khanna, R. Saha and P. V. Bharatam,J. Phys. Org. Chem., 2008, 21, 3.

8 To the best of our knowledge, the chemistry of R2CQNQCR2+

has not been explored, though chemistry of heteroallenes has beenstudied: S. Gronert and J. R. Keeffe, J. Org. Chem., 2007, 6343;Reviews on chemistry of allenes and heteroallenes: D. R. Taylor,Chem. Rev., 1967, 67, 317; J. Escudie, H. Ranaivonjatovo andL. Rigon, Chem. Rev., 2000, 100, 3639.

9 S. R. Ernst, Acta Crystallogr., Sect. B, 1977, 33, 237.10 Geometry optimization was carried out using Gaussian03 pro-

gramme.11 B3LYP11/6-31+G* level of theory was employed toobtain geometrical parameters and energy estimates. Performanceof the B3LYP/6-31+G* level of theory was found to be good inestimation of geometrical parameters as found in crystallographicdata for 1 and 2.

11 See ESIw.12 NBO analysis has been calculated at MP2(full)11/6-31+G*//

B3LYP/6-31+G* level of theory.13 The MOs of "N(’PMe3)2 include two lone pairs on N atom, one

of them with sp2 character, the other with p character. The electronoccupancies in these two are 1.85 and 1.82 as per NBO analysis.The proton affinity of this system is 139.46 kcal mol�1 (see ESIw).

14 B. D. Ellis, C. A. Dyker, A. Decken and C. L. B. Macdonald,Chem. Commun., 2005, 1965.

15 C. H. Schwalbe and W. E. Hunt, Chem. Commun., 1978, 188.16 P. Kumar and R. Shankar, J. Organomet. Chem., 2003, 687, 190.17 K. B. Anderson, R. A Franich, H. W. Kroese, R. Meder and C. E.

F. Rickard, Polyhedron, 1995, 14, 1149.18 G. Das, P. K. Bharadwaj, D. Ghosh, B. Chaudhuri and

R. Banerjee, Chem. Commun., 2001, 323; A. Marchi, L. Marvelli,M. Cattabriga, R. Rossi, M. Neves, V. Bertolasi and V. Ferretti,J. Chem. Soc., Dalton Trans., 1999, 1937; L. Coghi, M. Lanfranchi,G. Pelizzi and P. Tarasconi, Transition Met. Chem. (Dordrecht),1978, 3, 69.

19 Vertical ionization energies were calculated using the equationEdeprot = [E(B) � E(BH�)] + [ZPE(B) � ZPE(BH�)].

1066 | Chem. Commun., 2009, 1064–1066 This journal is �c The Royal Society of Chemistry 2009

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