Divalent N(I) Compounds with Two Lone Pairs on Nitrogen

Published: June 08, 2011

r 2011 American Chemical Society 7645 dx.doi.org/10.1021/jp111017u | J. Phys. Chem. A 2011, 115, 7645–7655

ARTICLE

pubs.acs.org/JPCA

Divalent N(I) Compounds with Two Lone Pairs on NitrogenDhilon S. Patel and Prasad V. Bharatam*

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar(Mohali), Punjab 160 062, India

bS Supporting Information

’ INTRODUCTION

Bonding environments with low oxidation states are typicallyfound in transition metal complexes, where the donor ligands“push” electron pairs into the empty orbitals of acceptor metals.Main group elements are not generally considered as electronacceptors, a search for such bonding environments is facilitatedby the novel chemistry of N-heterocyclic carbenes (NHCs).Recently, a novel bonding environment of carbon was reportedby Frenking and co-workers in carbones1 with divalent C(0)having the general formula ::C(rL)2 . These are characterizedby two lone pairs of electrons on carbon and are different fromcarbenes, i.e., divalent C(II) compounds.2 Experimentally knowncarbodiphosphoranes C(PR3)2 (I) (Figure 1) were shown to bedivalent C(0) systems that were earlier erroneously consideredas carbenes or ylides or allenes.3 Computational analysis ofC(PR3)2 suggested that bonding in C�PR3 bonds should beconsidered in terms of donor�acceptor interactions ::C(rPR3)2between the phosphorus lone pair electrons and empty valenceorbitals of carbon.1a In search of more divalent carbon(0)compounds, species with structure ::C(rNHC)2 (II) weresuggested in which the bonding interaction between the centralcarbon and NHCs are due to the donation of lone pair ofelectrons from NHC to the empty valence orbitals of centralcarbon, making all the four electrons available in the form of twolone pairs on the central carbon atom.1b Bertrand et al. experi-mentally generated species with ::C(rNHC)2 (III) and com-plexed them with transition metals to provide the experimentalproof for the existence of species with divalent C(0) carbon.4

Wang et al. reported divalent silicon(0) compounds stabilizedby NHC ligand (IV).5 X-ray crystal structure of this compoundconfirmed that the C�Si�Si�C backbone deviates from the

linearity that was presumed to be linear for Si2þ. Thus, the zerooxidation state for silicon was established on the basis of the bondangles and distances found to be slightly larger than those in Si2þ

state. In continuation of the earlier experimental work, Frenkingand co-workers reportedmore detailed computational analysis toestablish the donor�acceptor interactions between silicon andNHCs, justifying a new bonding environment for silicon andcharacterized as divalent Si(0) compounds, silylones.1g Establish-ing more examples in this series of low oxidation state ofelements they have further provided theoretical evidence forthe divalent E(0) compounds (where E = Ge (germylones) andSn (stanylones)). All these compounds showed the followingmajor characteristics: (i) high proton affinity, (ii) two lone pairson central atom E, and (iii) strong σ donation capacity to Lewisacids.1h Ellis et al. reported the generation of divalent phosphorusP(I) (V) in which the low valent phosphorus atom acceptselectron density fromNHCs. Molecular orbital analysis of V clearlydemonstrated the π based HOMO.6

Considering that divalent C(0), divalent Si(0), and divalentP(I) compounds in low oxidation states are known, compoundswith divalent N(I) arrangement can also be expected. A prelimin-ary communication of the divalent N(I) arrangement waspublished,7 a few new compounds were synthesized8 later withthe divalent N(I) arrangement and shown to belong to a novelclass ::N(rL)2

x (VI).7 Bruns et al. reported the synthesis andcoordination chemistry of LfN�R systems and showed them topossess characteristics similar to ::N(rL)2

x systems.9 In this

Received: November 18, 2010Revised: April 18, 2011

ABSTRACT: Carbon with the C(0) state has been reported recently,examples of which were known for the past decades. Silicon in theSi(0) state and phosphorus in the P(I) state are also known experi-mentally. This prompted us to search for divalent N(I) compounds,which resulted in the identification of ::N(rL)2

x systems withbicoordinated nitrogen in the N(I) formal oxidation state. It wasfound that several biguanide derivatives (especially in their protonated state) belong to this class. Quantum chemical analysisprovided the structural details, molecular orbitals, charge localization (vs delocalization) trends, etc. This class of compounds hasbeen found to be characterized by two lone pairs on the central nitrogen, very similar to the central carbon in divalent C(0)compounds (::C(rL)2). The new bonding environment for nitrogen reported in this article, divalent nitrogen N(I), is clearlydifferent from the nitrenium ions NR2

x. The electronic structure and reactivity of representative examples of this novel class ofdivalent nitrogen N(I) systems (::N(rL)2

x) have been analyzed in detail, in terms of molecular orbitals, atomic charges,protonation energies, complexation energies with Lewis acids like BH3, AlCl3, and AuCl and compared with those of divalent C(0)systems.

7646 dx.doi.org/10.1021/jp111017u |J. Phys. Chem. A 2011, 115, 7645–7655

The Journal of Physical Chemistry A ARTICLE

article, we report the electronic structure of many organic mol-ecules that may be considered as divalent N(I) compounds.Several experimentally known cyclic systems are shown to belongto this class; examples are VII�XI (Figure 1). The electronicstructures of these species are also explored and shown to possesstwo lone pairs at the central nitrogen. A detailed quantum chemicalanalysis of divalent N(I) class of compounds and comparison withdivalent C(0) compounds is included in this article. The proton-ation energies and complexation energy of novel ::N(rL)2

x

systems with Lewis acids such as BH3, AlCl3, and AuCl usingquantum chemical methods are also estimated.

’COMPUTATIONAL DETAILS

Ab initio MO10 and density functional theory (DFT)11

calculations were carried out using the GAUSSIAN03 package.12a

Complete optimizations without any symmetry constraints wereperformed on acyclic as well as cyclic ::N(rL)2

x systems usingB3LYP,13 and MP2(full)14 methods with the 6-31þG* basis setand compared with ::C(rNHC)2 and ::P(rNHC)2

x systems.Rotational and inversion processes were studied on acyclic ::N(rL)2

x systems. Frequencies were computed analytically forall optimized species at both levels to characterize each stationarypoint as a minimum or a transition state, and also to estimate thezero point vibrational energies (ZPE). The calculated ZPE values(at 298.15 K) were scaled by a factor of 0.9806 and 0.9661 forB3LYP and MP2(full) levels, respectively.15 The discussion ofrelative energies and geometrical parameters are based on theMP2(full)/6-31þG* optimized structures unless otherwise spe-cifically mentioned. The NBO analyses16 using the MP2(full)/6-31G* level of theory were performed on the model systems1�15. NBO analysis was employed to estimate partial atomic

charges and the second-order interaction energy (E(2)) betweendonor (i) and acceptor (j)NBOs. To estimate the nucleophilicityof the ::N(rL)2

x systems (1�15), absolute proton affinityvalues (APA) were calculated at B3LYP and MP2(full) methodswith the 6-31þG* basis set. Complexation energies with BH3,AlCl3, and AuCl were also estimated for each member of thisclass. Complexes of 1�15 with AuCl were optimized with mixedbasis set 6-31þG* plus def2-TZVPP.17 Atoms in molecules(AIM)18 analysis was performed using AIM2000 package19

and electron localization function (ELF) analysis20 was carriedout using TopMod software21 to evaluate the electronicstructure.

’RESULTS AND DISCUSSION

Biguanides (carbamimidoylguanidines) are neutral species(A, Scheme 1) characterized by (i) 4π electron conjugation,(ii) an intramolecular hydrogen bond, and (iii) resonancestabilization due to low 1,5-H shift barriers.22 Many medicinallyimportant species like metformin, phenformin, proguanil, cyclo-guanil, pyrimethamine, WR99210, etc. possess biguanidemoiety.23 It was shown that these biguanide derivatives adopt atautomeric state in which an H atom is absent at the centralnitrogen.22 All biguanide drugs/leads act in their protonatedstate (for oral bioavailability).24 Quantum chemical analysisshowed that the preferred site of protonation in A is N6(which form N6-protonated biguanide (1)) rather than thecentral nitrogen N1.22,25 The protonation at N6 leads to (i)breakdown of electron conjugation, (ii) breaking the intramole-cular hydrogen bond, (iii) loss of resonance stability due to 1,5-Hshift, and (iv) reduction of molecular rigidity.22a Even though somany negative factors are associated with protonation at N6, thisis the preferred site of protonation inA (Scheme 1). This leads tothe questions related to the stabilizing factors responsible forprotonation atN6 inA. Ab initioMOandDFT calculations indicatethat charge localization at nitrogen, accumulation of two lone pairsat the central nitrogen, increased flexibility due to easy C�Nrotations, and N-inversion process are the advantages experiencedby the biguanide derivatives during the protonation at N6.7

The geometric features for computed structure of protonatedbiguanide (1, Figure 2) are quite comparable to its crystalstructure,26 it adopts a C2 symmetric arrangement. MO analysisshowed that 1 is characterized by two lone pairs of electrons onthe central nitrogen similar to that in divalent C(0) compounds(::C(rL)2). HOMO�3 in 1 is a σ type lone pair and HOMO isa π type of lone pair (Figure 3). NBO analysis also shows twolone pairs of electrons on the central nitrogen N1 in 1 (Table 1)with electron occupancies of 1.87 and 1.55 units, respectively.The contour map of HOMO (Figure 3) clearly shows that thisorbital is predominantly localized on the central nitrogen N1, thep-orbital of which is involved in antibonding interactions with thep-orbitals of the adjoining carbon atoms. The estimated (NBO)partial atomic charge at N1 in 1 is �0.772 units.

N1—C2 (and N1—C3) rotational barrier in 1 is 3.8 kcalmol�1 (Table 1, Figure S1, Supporting Information12b), which isvery small compared to a regular CdN rotational barrier (∼30kcal mol�1).27 The N1—C2 (and N1—C3) bond length in 1 is1.332 Å, which is in the range of a regular double bond. This veryweak π strength and shorter bond lengths indicate that N1—C2and N1—C3 bonds in 1 can be considered as coordinationbonds as CrC bonds in divalent C(0) compounds.1 Theelectronic structure of biguanide undergoes significant change

Figure 1. Examples of the compounds representing donor�acceptorbonding environment.



upon protonation. Before protonation the C3—N6 π* bond wasinvolved in nN7fπ*C3—N6 second-order delocalization in bi-guanide (A, Scheme 1). Due to protonation at N6, the C3—N6π orbital as well as theπ* orbital disappear and hence nN7fπ*C3—N6

second-order delocalization is not possible any more. Theimidamidine C3(NH2)dNH group becomes a :C3(NH2)2group (a diaminocarbene). On the other hand the C2(NH2)2group, which was involved in double bond with N1, afterprotonation at N6 starts behaving like a diamino carbene. In 1,the two diamino carbenes (on the two sides of N1) donateelectrons through coordination bonds (as shown inC, Scheme 1).The two lone pairs on N1 in 1 are similar to the two lone pairs at

the C(0) carbon in carbodicarbenes and carbodiphosphoranes.1,2

Also this electronic structure is similar to that of P(I) in V(Figure 1).6 Considering these facts, the N1 atom in 1 can betreated as a divalent N(I) system.

The antidiabetic block buster drug, Metformin hydrochloride28

(2, Figure 2) is a biguanide derivative and it is also characterized byhigh negative charge accumulation at N1 (�0.774), and two lonepairs of electrons at the central nitrogen N1 according to the MOanalysis, and other characteristics similar to 1. The only differencebetween the electronic structures of 1 and 2 arise from the loss ofsymmetry in 2 in relation to 1. Hence, 2 should also be consideredas a species with C2fN1 and C3fN1 coordination bonds as in

Scheme 1. Schematic Representation of the Resonance Form (B, C, D) of Protonated Biguanide (1)

Figure 2. 3-D structures of compounds 1�15 optimized atMP2(full)/6-31þG* level of theory and for 16 B3LYP/6-31þG* optimized geometries wasused. All distances are in angstrom units (Å) and angles are in degrees. All the structures are at the global minima on their respective potential energysurfaces and are characterized by zero negative frequencies. The central nitrogen atom is considered as the N1 atom, in all the species (1�16); theattached carbon atoms are treated as C2 and C3 as in Scheme 1.



divalent C(0) species; similarly, all other biguanide derivativesshow two lone pairs on central nitrogen in their protonated state.

Considering that the electronic structure of 1 and 2 arecomparable to that of divalent C(0) compounds (II) and alsothat of V, compounds with structure VI (Figure 1) weredesigned7 (and later synthesized).8 Compound 3 (Figure 2) isthe simplest example of the compounds represented by VI, and

compound 4 is one of the simplest models of divalent C(0)systems II. The geometric features of 3 and 4 are quite compar-able. The CrN rotational barrier in 3 is 2.8 kcal mol�1,12b whichis quite comparable to the CrC rotational barrier in 4 (4.2 kcalmol�1). Similarly, the N-inversion process in 3 (Figure S2,Supporting Information)12b requires 14.9 kcal mol�1, which isonly slightly larger than the C-inversion process in 4 (9.2 kcal

Figure 3. Comparison of shapes of molecular orbitals of 1�15 generated on theMP2(full)/6-31þG* optimized geometries. For 16, B3LYP/6-31þG*optimized geometries were used.



mol�1; through structures with two negative frequencies). 3 ischaracterized by two lone pairs of electrons, π-type (HOMO)and σ-type (HOMO�2) again comparable to the correspondingMOs of 4 (Figure 3). NBO analysis of 3 also shows two lone pairsof electrons on central nitrogen occupying σ and π orbitals withelectron occupancies 1.87 and 1.55, respectively (Table 1).These are much larger than the electron occupancies in theσ and π lone pairs in 4 (1.51 and 1.11, respectively),1c indicatingthat the lone pair electrons are much strongly localized on centralnitrogen in 3 in comparison to the central carbon in 4.

The compound 3 may be treated as in E (Scheme 2), aheteroallene with CdNdCx arrangement.22c However, becausethere are no π bonds across C and N, and also because the C2—N1—C3 angle is strongly bent, E cannot be the most represen-tative structure of 3. Alternatively, structure F may be appro-priate; however, two lone pairs of the electron are clearly visiblein 3 as per NBO as well as MO analysis. A large negative chargeon N1 indicates that 3may be represented as inG. However, theC—N bond lengths are too short in comparison to C—N singlebond lengths. Considering that NHCs are electron donatingspecies, and nitrogen is in the N(I) state, structure H is arepresentative electronic structure of 3. Such a descriptionmakes3 isoelectronic to 4, which is found to be true on many counts asdiscussed above. This indicates that the N(I) atom should indeedbe a positively charged center. However, because it is acceptingelectron density from two NHCs, the actual charge on N1 in 3 isbecoming negative; thus H may be the resulting resonatingstructure of resonance forms E�G for compound 3.

The divalent N(I) environements for the central N1 atoms of1�3 are clearly different from the divalent N(I) environment ofnitrenium ions, which are designated as xNR2 systems.29 Nitre-nium ions are isoelectronic to carbenes, where singlet�tripletchemistry dominates.29b NBO analysis of the 1,2,3-triazolium ion(TRZ, a model cyclic nitrenium ion which is isoelectronic tosimplest NHC, Figure S3, Supporting Information)12b showedthe presence of only one lone pair on the central N1 atomwith anoccupancy of 1.97 unit. MO analysis of TRZ showed that twounbounded electrons on central N1 atom occupying σ-type(HOMO�2) orbital and LUMO is characterized by π-typeorbital (Figure S4, Supporting Information).12b

To further validate the hypothesis (two lone pairs on centralN1), AIM and ELF calculations were performed. The contourline diagrams of the Laplacian obtained in AIM analysis(Figure 4) shows a continuous area of charge concentrationaround N1 in 1 and 3, corresponding to σ and π lone pairs verysimilar to that in divalent C(0) compound 4.1c ELF analysis(Figure 5) showed a bean shaped isosurface at N1 correspondingto two lone pairs. The population of the V(N1) basin is 3.28 e in1 and 3.32 e in 3, confirming the presence of two lone pairs ofelectrons at N1 in these molecules.

The crystal structure of VI is available8 and a phosphorusequivalent (V) of it is known.6 The electronic structure analysisof 5 (a model of V) suggested that the best representation of thiscation shows two lone pairs of electrons on the phosphrous atomand it should be considered as a system with donor (NHC) andacceptor P(I). NBO analysis of 5 supports the presence of two

Table 1. Charge and NBO Analysis for Compounds 1�16 Calculated at MP2(full)/6-31þG* Level of Theorya

sr no.

charge on

N1/P1/C1

charge

on C2/P2

charge

on C3/P3

LP(N)σoccupancy

LP(N)πoccupancy

C�N/P

rotational barrier

N1/C1

inversion barrier

1 �0.772 0.841 0.841 1.87 1.55 3.8 12.3

2 �0.774 0.861 0.834 1.87 5.2 13.1

3 �0.748 0.785 0.785 1.87 1.55 2.8 14.9

4 �0.698 0.581 0.581 1.51d 1.11d 4.2 9.2

5 0.217 0.233 0.233 1.95 1.65 1.2

6 �1.615 1.999c 1.999c 1.85 1.82

7 �0.750 0.478 0.852 1.85 1.0 11.1

8 �0.634 0.807 0.803 1.89 5.3 14.9

9 �0.746 0.481 0.493 1.86 1.9 9.5

10 �0.758 0.490 1.001 1.81 2.0 8.8

11 �0.756 0.853 0.857 1.91 1.51

12 �0.801 0.839 0.814 1.92

13 �0.798 0.830 0.830 1.92 1.53

14 �0.739 0.849 0.849 1.91 1.48

15 �0.728 0.850 0.850 1.91 1.49

16b �0.688 0.628 0.628 1.89 1.45

TRZ 0.066 �0.344 �0.344 1.97a Partial charges and occupancies are given in electrons. C�N rotational barriers (for 1�10) and N1 inversion barriers (for 1�4, 7�10) in kcal mol�1

are calculated at theMP2(full)/6-31þG* level of theory. bData calculated at the B3LYP/6-31þG* level of theory. cCharge on phosphorus (P2 and P3).d Enforced NBO used for locating two lone pairs on central carbon.

Scheme 2. Schematic Representation of the Resonance Form of 3



lone pairs on central phosphorus and the electron occupancies inthe σ and π orbitals are 1.95 and 1.65, respectively.

Electronic structure analysis of carbodiphosphoranes ::C-(rPR3)2 (II) reported by Frenking et al. showed two lone pairs,σ- and π-type, on the central carbon.1a Extending this calculationon the Nþ analogue, ::N(rPme3)2

x (6, Figure 2), also showstwo lone pairs on central nitrogen similar to ::C(rPme3)2. Suchspecies are experimentally known and they are considered asR3PdNdPR3

x systems.30 The bonding situation in xN�PR3

bonds should be considered in terms of donor�acceptor inter-actions between the phosphorus lone pair electrons and emptyvalence orbitals of N(I) as in ::C(rPme3)2. NBO analysis of 6also supports the presence of two lone pairs on the centralnitrogen occupying σ and π orbitals with the correspondingoccupancies 1.85 and 1.82, respectively (Table 1). Moreover,charge analysis on 6 showed high negative charge (�1.615 units)is concentrated on the central nitrogen along with high positivecharge 1.999 on phosphorus. MO analysis of ::N(rPme3)2

x

also showed π based HOMO and σ type HOMO�1 (Figure 3).All these arguments support the hypothesis that the nitrogenatom in ::N(rPR3)2

x should also be considered as a divalentN(I) system. Incidentally, Kerkines et al.31 have studied

::N(rNH3)2x and reported an electronic structure similar

to that of 6.Recently we have studied the mechanism and energy profile

for alkylation of GTU leading to the formation of S-alkylatedproduct, which includes the involvement of positively chargedintermediate (7; Figure 2).32 7 is characterized by two lone pairsof electrons on the central nitrogen, which facilitates alkylationreactions.32 On the same lines the protonated states of biuret (8),thiobiuret (9), dithiobiuret (10) (Figure 2) and their derivativesare pharmacologically important molecules.33 These protonatedstates help the tautomerism in the corresponding neutralanalogs.34 Calculations indicated that the protonated intermedi-ates of biuret (8), thiobiuret (9), and dithiobiuret (10) belong tothe novel ::N(rL)2

x class. Incidentally 7�10 are the moststable isomers on the respective potential energy surfaces. MOanalyses of 7�10 also showed the presence of two lone pairs ofelectrons present in σ and π type orbitals on the central nitrogen(Figure 3). Electronic structure similarity with those observed forprotonated biguanides supports the consideration of thesecompounds under novel ::N(rL)2

x class, divalent N(I) species.Compounds 1�3 and 6�10 are examples of acyclic systems

with ::N(rL)2x electronic structures. Such electronic structure

Figure 4. Contour line diagramsr2F(r) of divalent N(I) compounds 1 and 3 in comparison to those for divalent C(0) compound 4 andN-heterocycliccarbene (NHC). AIM analysis shows a continuous area of charge concentration aroundN1 in 1, 3, and 4 corresponding to σ andπ lone pairs while NHCthat are supposed to have one lone pair on carbon show discontinuous charge area and/or hole in the charge distribution, confirming the presence of onlyone σ lone pair.

Figure 5. Electron localization function (ELF) of 1, 3, and 4 (isosurface value 0.85).



can also be found in cyclic biguanide derivatives VII�XI(Figure 1).VII (R = 4-Cl-Ph) is a general structure of protonatedcycloguanil and other antimalarial species; all of them are knownto be biologically active in the protonated state. X-ray diffractionas well as neutron diffraction data are reported for cycloguanil,35

the N1�C2 andN1�C3 distances are 1.33 and 1.35 Å, which arequite comparable to that in 1. Compound 11 is a model system ofVII, with comparable geometric parameters (Figure 2). MOanalysis of 11 indicated that two lone pairs on central nitrogenare characterized as σ (HOMO�3) and π (HOMO) type oforbitals (Figure 3). NBO analysis of 11 also supports thepresence of two lone pairs on the central nitrogen that occupyσ- andπ-type orbitals with electron occupancies of 1.91 and 1.51,respectively (Table 1). This electronic structure of 11 indicatesthat the bridging nitrogen (N1) in protonated cycloguanil shouldbe considered a divalent N(I) system. NBO charge on N1(�0.756) in 11 is quite comparable to that of 1�3 (Table 1).

In an attempt to synthesize novel pentacoordinate siliconcompounds [Si�N�C�N�C�N], Kumar and Shankar re-ported a series of four compounds with the general formula VIII(Figure 1, R = CH2CH2SiR1R2; R0 = Ph, nPr; R00 = SiH-MeCH2CH2SiR1R2; R1 = Ph, Me; R2 = Me, Ph).36 Computa-tional analysis of the 12 (a model system of VIII, Figure.2)showed a pentacoordinate Si atom with trigonal bipyramidalarrangement in which the coordinating NfSi and Si�H bondsare in the axial position. N1�C2 and N1�C3 bond distances(∼1.34 Å) in 12 are quite similar to those of 1, 2, 3, and 11.Though NBO analysis does not show the two lone pairs, it showsthat the negative charge is localized on N1. The central nitrogenN1 in 12 is characterized by two lone pairs according to the MOanalysis; Figure 3 includes HOMO andHOMO�5 depicting thetwo lone pairs in 12. The NBO charge on N1 is, �0.801 units,quite high as in 1, 2, 3, and 11. These facts further corroborateour hypothesis to consider the N1 in 12 (and hence in VIII) as adivalent N(I) arrangement.

A set of boron complexes of biguanide (IX, Figure 1) arereported, some of which are characterized crystallographically.37

In these species, the boron center carries a formal negativecharge, leaving positive charge to be distributed in the biguanideframework. MO analysis of 13 (a model of IX) showed thepresenceof two lonepairs on central nitrogen asσ-type (HOMO�4)and π-type (HOMO) orbitals (Figure 3). NBO analysis of 13also showed the presence of two lone pairs on the centralnitrogen occupying σ- and π-type orbitals with the electronoccupancies of 1.92 and 1.53, respectively (Table 1). The chargeon N1 (�0.798) in 13 is quite comparable to that of 1, 2, 3, 11,and 12. All the above data suggest that the N1 in 13 is associatedwith divalent nitrogen N(I) character; with two lone pairs onnitrogen, and the species should be considered as an example of a::N(rL)2

x system, while the B(OH)2 unit is assigned the formalnegative charge in this neutral molecule.

Synthesis of 3,5-diaminothia-2,4,6-triazine derivatives (X,Figure 1) has been reported.38 Calculated positively chargedmodel systems 14 and 15 are given in Figure 2. Electronicstructure analysis based on MOs showing the two lone pairs onN1 in 14 and 15 are given in Figure 3. NBO analysis also indicatesthe presence of two lone pairs on N1, with the electronoccupancies of 1.91 and 1.49 (Table 1) in the σ- and π-typeorbitals, respectively, in 15. The high negative charges onN1 (�0.739 and �0.728 units in 14 and 15, respectively)also support the divalent N(I) state of central N1 atom in 14and 15.

Several transition metal complexes (XI) with chelating bigua-nide ligands are reported.39 The complexes reported thus farinclude the transition metals Tc, V, Mn(II), Mn(VI), Cu(II),Pd(II), Ni(II), etc. in these complexes. The deprotonated (loss ofhydrogen from N4 of neutral biguanide) and negatively chargedform of biguanides (big-) are involved in bidentate coordinationwith the positively charged transition metals.39 In a few casesbigH (protonated at N1) is also shown as a ligand. 16 is a modelneutral Ni complex with two biguanide (big) units, each inchelating mode with the metal may be taken as a model of thisclass of transition metal complexes. The 3D structure of 16obtained using the B3LYP/6-31þG* level is shown in Figure 2and MOs depicting σ-type (HOMO�4) and π-type (HOMO)orbitals on N1 are shown in Figure 3. NBO analysis showedthat the electron occupancies in σ and π orbitals are 1.89and 1.45, respectively (Table 1). The NBO charge analysison N1 in 16 is �0.688. The presence of two lone pairs on N1and comparable geometric parameters (C�N distance 1.341 Å)to that of 11�15, indicates the central nitrogenN1 in themetalliccomplexes (XI) should be treated as a divalent N(I) nitrogen.

’PROTON AFFINITIES AND LEWIS BASE CHARACTEROF ::N(RL)2

X SPECIES

Proton affinity is a measure of nucleophilicity of any species.Divalent C(0) compounds show very strong proton affinities andare labeled as superbases.1d,f Divalent C(0) compounds are alsoknown to show strong second proton affinity due to the presenceof a second lone pair of electrons on the carbon.1b,d Similarly, dueto the presence of two lone pairs on nitrogen, ::N(rL)2

x

systems may be expected to show strong proton affinity valuesat N1. However, because this class of molecules already carries apositive charge, the proton affinity would be much weaker thanthe corresponding divalent C(0) compounds. The crystal struc-ture of the salts of biguanide withH2SO4 and 2HClmolecules arereported.26d,e Kunetskiy et al.8 reported the N-protonation of VI,forming symmetrical dication. These experimental data clearlyshow that protonation of ::N(rL)2

x class of compounds at N1is known even though they are already positively charged.

To obtain a quantitative estimation of the proton affinities,B3LYP/6-31þG* and MP2(full)/6-31þG* calculations werecarried out on 1�15, and the results are listed in Table 2. Theoptimized 3D structures of protonated 1�15 (i.e., 1-H�15-H)along with selected geometric data (calculated at MP2(full)/6-31þG*) are given in Supporting Information (Figure S5).12b Theproton affinity of 1, 2, and 3 are 106.7, 117.7, and 127.6 kcalmol�1,respectively. The NHC coordinated system (3) shows greaterproton affinity in comparison to 1 and 2. The ability of NHC ringsto accommodate the positive charge is responsible for this greaterproton affinity. The proton affinity of 3 (127.6 kcal mol�1) ismuch weaker than that of divalent C(0) compound 4 (279.3 kcalmol�1). This clearly indicates that though both species (3 and 4)are characterized by two lone pairs on their central atoms and theirbasicities are quite different, 4 is a superbase whereas 3 is weaklynucleophilic. The proton affinities at the central N1 atom of 1�3are much larger than the proton affinity at central N1 atom ofnitrenium ion, TRZ (44.6 kcal mol�1, Table 2, Figure S3,Supporting Information).12b In 1-H, 2-H, and 3-H the newlyintroduced proton is coplanar with the C2�N1�C3 unit; i.e., theprotonation is along the σ type lone pair of 1, 2, and 3. Thebonding environment in 1-H, 2-H, and 3-H should be consideredas (Lf)2NH

2x, but not as (þR)2NH. This is because no



pyramidalization is observed at N1 and the C�N1 bond lengthcontinues to be much shorter than a regular C�N single bondlength. This further lends support to the argument that there is anLfN coordination bond in 1, 2, and 3. Similar values of weakerproton affinities are estimated for 6 � 11, 14, and 15. However,the proton affinities of the neutral species 12 and 13 are very high(209.2 and 212.0 kcal mol�1, respectively) in comparison to thosefor 1, 2, and 3 but still much smaller than that of 4.

Divalent C(0) compound 4 is highly nucleophilic1d and itscomplexation energy with BH3 is about 59.7 kcal mol�1. Incomparison, the BH3 complexation (Figure S6, SupportingInformation)12b energies of 1 and 2 are quite weak (15�18 kcalmol�1). The BH3 complexation energy of 3 is better (21.3 kcalmol�1) than that of 1 and 2 butmuchweaker than that of 4. Thesevalues aremuch better than the complexation energy of the centralN1 of TRZ with BH3 (6.4 kcal mol�1, Table 2, Figure S3,Supporting Information).12b The BH3 complexation energies ofthe neutral species 12 and 13 (26.1 and 29.1 kcal mol�1,respectively) are the only values worth mentioning, all otherspecies show very poor complexation energies. This clearly impliesthat the nucleophilicity of ::N(rL)2

x system is quite low;however, when the N(I) arrangement is found in neutral species(as in 12 and 13), nucleophilic character is found to be sufficientlyhigh. Similar conclusions can be drawn from the data on AlCl3complexation (Figure S7, Supporting Information).12b To studythe complexation of 1�15with transition metals, AuCl complexa-tion is considered (Figure S8, Supporting Information).12b AuCloffers thye least possible steric influence and hence allows clearestimation of electronic influence. The neutral species 12 and 13show strong complexation energies (35.5 and 36.0 kcal mol�1,respectively, at the B3LYP/6-31þG* level with def2-TZVPP basisset for Au, Table 2). All other species show very weak complexa-tion energies. This confirms that the weak nucleophilicity of::N(rL)2

x species arises from their positive charge.Divalent C(0) species show second proton affinities and also

the ability to bind to two Lewis acids. It is desirable to estimatethe second proton affinity 1�15 and the complexation energies

of these speices with two units of BH3 and two units of AuCl.Complete optimizations of doubly protonated 1�central N1atom (each compound carrying three units of positive charge)are not stable, and the structures break up; this can be attributedto the low necleophilicity and positive charge on these systems.Calculations have been performed to estimate the complexationenergies of 1�15 with two units of BH3 and two units of AuCl.Upon complete optimization, all the positively charged divalentN(I) compounds (1�11 and 14, 15) show breaking up of oneunit of BH3 (and one unit of AuCl) from the central N1. This canbe clearly attributed to the low nucleophilicity of these species,which is already established. This low nucleophilicity in additionto the positive charge on the species makes the complexesunstable. Complexes of 12 and 13 (for which overall charge iszero) show stable complexes with the second BH3 (∼ 9 kcalmol�1 complexation energies) and with two units of AuCl (∼18kcalmol�1 complexation energy). It is interesting to note that theAuCl units in 12�2AuCl and 13�2AuCl (Figure 6) are alongthe directions of the σ and π lone pairs on N1 of 12 and 13,respectively; i.e., N1 nitrogen adopts trigonal pyramidalarrangement.12b The corresponding 4�2AuCl adopts almost atetrahedral arrangement.

1�15 show mild reactivity. Only when the positive charge isneutralized due to negative charge at a different center (far fromN1) within the molecule, as in 12 and 13, does the reactivity duethe two lone pairs become evident. This low reactivity is an addedadvantage for this class of compounds; i.e., these species foundtherapeutic applications because of the low nucleophilicity. It isquite possible that ::C(rL)2 may not find any therapeuticapplication because of their high reactivity. It is important toestablish how the two lone pairs of electrons on N1 play a role indrug action, which is being pursued in our laboratory.

’SUMMARY AND OUTLOOK

Divalent C(0), Si(0), and P(I) compounds with low oxidationstate at main group elements are well established; Ge(0) and

Table 2. Proton Affinities and Complexation Energies (with BH3, AlCl3, and AuCl in kcal mol�1) of 1�15 Calculated at theB3LYP and MP2(full) Level of Theory Using the 6-31þG* Basis Set

proton affinity BH3 complexation AlCl3 complexation AuCl complexation

B3LYP MP2(full) B3LYP MP2(full) B3LYP MP2(full) B3LYP

1 108.3 106.7 10.9 15.1 13.2 28.0 16.8

2 119.2 117.7 12.0 19.0 16.9 37.0 17.5

3 121.5 127.6 15.2 21.3 20.2 40.3 18.9

4 282.1 279.3 55.3 59.7 70.3 83.8 72.5

5 132.8 151.8 21.6 29.0 22.2 38.8 23.6

6 129.6 126.8 7.6 16.0 8.2 27.8 16.0

7 102.4 101.1 9.7 15.6 11.9 28.4 14.0

8 89.3 87.1 9.7 13.2 7.4 23.2 14.0

9 91.7 90.3 7.8 12.3 8.3 24.6 11.9

10 95.9 94.8 6.7 13.0 8.3 25.8 10.1

11 121.7 119.7 16.4 26.2 16.6 34.6 20.3

12 220.4 209.2 25.5 26.1 32.0 46.2 35.5

13 214.8 212.0 25.9 30.0 32.4 49.5 36.0

14 105.9 118.0 14.1 18.6 12.9 28.3 16.9

15 94.9 91.8 11.1 14.8 8.4 24.3 12.7

TRZ 48.0 44.6 5.3 6.4 11.3



Sn(0) systems were computationally explored. Computationalexploration of divalent N(I) systems lead to the identification ofseveral acyclic and cyclic systems, which are shown to belong tothe ::N(rL)2

x class.7 This class of compounds are quitecomparable to carbones ::C(rL)2, silylones ::Si(rL)2, germy-lones ::Ge(rL)2, stanylones ::Sn(rL)2, and the ::P(rL)2

x

systems in terms of their electronic structure. Following thetrend, this new class of divalent N(I) compounds may be labeledas nitreones and the corresponding phosphorus analogs; i.e.,divalent P(I) compounds may be labeled as phospheones.

Divalent N(I) systems are characterized by (i) low oxidationstate N(I), (ii) two lone pairs on the central nitrogen, and (iii)nitrogen involved in coordination bonds with electron donatinggroups. Many well-known compounds and recently synthesizedcompounds belong to this class. They may be in cationic state::N(rL)2

x, as exemplified by protonated biguanide and the::N(rNHC)2

x and ::N(rPR3)2x compounds,8,30 or may be in

neutral state ::NR(rL) state, as exemplified by ::N(Mes)(rbis-(diisopropylamino)cyclopropenylylidene).9 This set of com-pounds are clearly different from the previously well-knownnitrogen compounds like amines (NR3), quaternary ammoniumsalts (NR4)

xXQ, and nitrenes (NR). They are clearly differentfrom nitrenium ions NR2

x, which are characterized by only onelone pair on central nitrogen and comparable to carbenes CR2.

Cationic divalent N(I) compounds show low nucleophilicityand do not coordinate with metals easily. They also showrelatively low proton affinities, though a few examples are knownwith reasonable proton affinity. Neutral divalent N(I) com-pounds can show high proton affinity at the central nitrogenand can form transition metal complexes by donating electrons.Experimental evidence suggests base resistance and phase trans-fer catalytic activity for the highly substituted divalent N(I)compounds.

Divalent N(I) compounds found many therapeutic applications.Metformin hydrochloride ::N(rC(NH2)2)(rC(NH2)NMe2)

x

is a block buster antidiabetic drug that also is implicated withanticancer properties.22 Pyrimethamine and cycloguanil areantimalarial agents; in the biologically active state, they aredivalentN(I) species. Though the protonated biguanides containtwo lone pairs of electrons on N1, they are weakly nucleophilic.This property appears to be an added advantage in theirapplication as drugs; these species may help in proton exchange

in body fluids while remaining mildly active. Considering theirphase transfer catalytic role and coordination chemistry, there issignificant interest in this class of divalent N(I) compounds. Theacademic and industrial interest in this class of compounds isenormous, and further exploration of this new class of com-pounds is highly desirable.

’ASSOCIATED CONTENT

bS Supporting Information. 3D structures for optimizedgeometries of rotational (Figure S1) and inversion transitionstates (Figure S2) of 1�10 at the MP2(full)/6-31þG* level oftheory, 3D structures for optimized geometries of protonatedspecies and species complexed with BH3, AlCl3, and AuCl(B3LYP/6-31þG* plus def2-TZVPP) of 1�15 (Figure S3,S5�S8), molecular orbitals (Figure S4), absolute energies ofall the geometries under consideration (Tables S1�S5) thecoordinates of the optimized geometries of 1�15 at MP2-(full)/6-31þG* level of theory and 16 at B3LYP/6-31þG* levelof theory along with their protonated species, complexation withBH3, AlCl3 and AuCl (B3LYP/6-31þG* plus def2-TZVPP).Coordinates for rotational and inversion transition states are alsoincluded in Supporting Information. This material is availablefree of charge via the Internet at http://pubs.acs.org.

’AUTHOR INFORMATION

Corresponding Author*E-mail: [email protected].

’ACKNOWLEDGMENT

We thank the Department of Science and Technology (DST),New Delhi, for financial support.

’REFERENCES

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Divalent N(I) Compounds with Two Lone Pairs on Nitrogen

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