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Biguanide Antidiabetic Drugs: Imeglimin Exhibits Higher Proton

Basicity but Smaller Lithium-Cation Basicity than Metformin in
Vacuo
Ewa D. Raczyńska,*,† Jean-François Gal,*,‡ Pierre-Charles Maria,‡ and Fabien Fontaine-Vive‡
†
Department of Chemistry, Warsaw University of Life Science (SGGW), ul. Nowoursynowska 159c, 02-776 Warszawa, Poland
‡
Université Côte d’Azur, CNRS, Institut de Chimie de Nice, UMR 7272, 06108 NICE, France
*
S Supporting Information
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ABSTRACT: Compounds containing biguanide moiety, such

as buformin, phenformin, and metformin are well recognized
for their antihyperglycaemic action. Imeglimin is a dihydro-
Downloaded via 148.63.163.1 on February 11, 2021 at 18:35:39 (UTC).

1,3,5-triazine that can be considered as a cyclic metformin

derivative, which has been tested as a promising new
antidiabetic drug. Quantum-chemical calculations have been
carried out to examine its structure and its gas-phase basicity
toward the proton and the lithium cation. Owing to various
structural isomeric rearrangements possible for imeglimin, 23
isomers have been considered for the neutral molecule in
vacuo at the B3LYP/6-311+G(d,p) level. Four isomers (two
major and two minor) have been selected and their
exceptional energetic stabilities additionally confirmed by the
G2, G2MP2, and G4 methods. The major isomers (>95%) correspond to the push−pull biguanide systems, which are similar to
those for neutral metformin. The minor isomers (<5%) have nonanalogous metformin structures. The basicity properties in the
gas phase have been examined by computing the energetics of protonation and adduct formation with Li+. The same protocol
(starting by density functional theory, then Gn procedures) used for the neutral molecule was applied to the monoprotonated
and monolithiated forms of imeglimin to select the favored isomers. When compared to metformin, the proton affinity of
imeglimin is larger by more than 10 kJ mol−1, this increase being attributed to the effect of the additional >CH−CH3 group.
The cyclic form of imeglimin precludes the possibility of chelation effect by two imino groups as it occurs for metformin.
Consequently, imeglimin has a lower lithium-cation affinity than that of metformin by ca. 30 kJ mol−1. The lithium cation seems
however to be weakly chelated by the neighboring imino and amino N atoms of imeglimin, an effect that is weaker than that of
the two terminal imino N atoms of metformin. Gas-phase proton basicity of imeglimin falls between that of bicyclic amidine
DBU and guanidine TBD, whereas lithium-cation basicity is situated between that of bicyclic guanidine MTBD and tricyclic
vinamidine TTT. Electron delocalization in the biguanide moiety of imeglimin is analogously related to isomerism as that in the
parent biguanide and metformin.

■ INTRODUCTION
Diabetes constitutes a worldwide public health problem that
affected 382 million people (8.3% of the world’s population) in
2013, and recent projections suggest that this prevalence is
likely to increase in the next 20 years, affecting 592 million
people (10.1%) in 2035.1 An increase of occurrence of diabetes
from environmental effects is anticipated.2 The first-line
treatment of type 2 diabetes is metformin, a biguanidic oral
drug still used for its mechanism of action3−5 and for its
structure and basicity properties.6 It also reduces cardiovas-
cular and cancer risks.7,8 Because of lactic acidosis risk as a
secondary effect, the other oral antidiabetic biguanidic drugs,
phenformin and buformin, were withdrawn from most
markets. A new class of dihydro-1,3,5-triazine derivatives,
glimins, has the advantage of avoiding lactic acidosis risk.7
From experiments in vitro and in vivo, imeglimin emerges as a
promising molecule.9−18 Clinical trials on imeglimin are in
progress.19,20
Imeglimin possesses a cyclic 1,3,5-triazine structure.
Containing a biguanide substructure, it bears a similarity
with metformin (Figure 1). At least three possible prototropic
tautomers can be proposed for derivatives with the biguanide
moiety. These isomers are a consequence of amino−imino
tautomeric conversions. For metformin, we found recently that
two tautomers possessing a central imino N atom are pivotal in
determining the stable structures.6 Metformin (C4N5H11) is an
acyclic dimethyl derivative of the parent biguanide (C2N5H7),
whereas imeglimin (C6N5H13) possesses two additional C
Received: September 25, 2018
Accepted: December 6, 2018
Published: December 19, 2018

© 2018 American Chemical Society 17842 DOI: 10.1021/acsomega.8b02507

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Figure 1. Selected tautomers of biguanide (BG), metformin (M), and
imeglimin (I).
atoms, one closing a six-membered ring between the two
terminal N atoms of the biguanide moiety and the other
providing the exo Me group. These structural similarities and
differences between imeglimin and metformin affect their
physicochemical properties, in particular their Brönsted−
Lowry and Lewis basicities.
To our knowledge, structure and physicochemical properties
of neutral imeglimin have neither been reported in the gas
phase, in solution, or in the solid state. Therefore, a rational
approach is to identify the stable structure(s) of this molecule.
In this work, all possible imeglimin isomers have been
examined with the aim to identify those that are energetically
favored in the gas phase. Owing to the similarities with the
biguanide frameworks, in Figure 1, imeglimin is expected to
display strong Brönsted−Lowry and Lewis basicities. Imegli-
min is anticipated to be a “superbase” because of the push−
pull mechanism21−27 that is operating in conjugated forms.
Curiously, a literature search did not give reports on
experimental or calculated basicity data such as pKa, gas-
phase proton affinity (PA), or lithium-cation affinity (LiCA)
for adduct formation with a Lewis acid. Another aspect of the
imeglimin reactivity relates to its possible oxidation, leading to
an aromatic system by dehydrogenation. We have not found
mention of such degradation in the literature, probably because
its usual form is a salt, which may be more stable than the free
base. The aromatization of imeglimin is nevertheless an aspect
that is worth further studies.
The drug action of a molecule is largely determined by its
acid/base characteristics.28 In this study, we attempted to shed
light on this aspect of imeglimin properties by calculating the
gas phase basicity toward the proton (GB) and the lithium-
cation (LiCB). The structure and energetics of monoproto-
nated and monolithiated forms have been analyzed, and we
estimated the corresponding basicities in the gas phase that
model apolar environment. For our studies, we employed the
quantum-chemical methods {DFT B3LYP/6-311+G(d,p), G2,
G2MP2, and G4} and the procedures as described previously
for metformin.6 The selected density functional theory (DFT)
method has been considered as a good compromise in terms of
accuracy and computer time for nitrogen-containing strong
bases being also tautomeric systems.24−26,29,30 In spite of their
higher costs, the Gn methods were tested because they are
expected to be state-of-the-art computational levels for gas-
phase thermochemistry. Comparison with related results
17843
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reported previously for metformin gives insights on the
following phenomena: effect of cyclization (Figure 1),
tautomeric equilibria, and intrinsic Brønsted and Lewis
basicity.
■ RESULTS AND DISCUSSION
Major and Minor Isomers for Neutral, Monoproto-
nated, and Monolithiated Imeglimin. Looking for the
composition of the isomeric mixture of neutral imeglimin, all
reasonable types of isomerism have been considered, including
prototropic conversions between conjugated sites and geo-
metric isomerism about CN double bond. Enantiomers were
not considered because R and S isomers have the same
thermochemistry. Particular attention must be paid to
prototropy,31−34 a particular kind of tautomerism in which
tautomeric forms differ only in the position of protons and π
bonds. Various prototropic rearrangements are possible for
imeglimin (Figure 1). For example, labile protons at the endo
and exo amino N atoms can move to the endo imino N atoms
(and vice versa) according to amino−imino rearrangements.
These proton transfers are analogous to those possible for the
parent biguanide and its dimethyl derivative, metformin.6
Imeglimin has additionally a labile proton at the endo C atom.
This proton can move to the other endo C atoms. After the
1,3- or 1,5-proton shift, the formed isomers have a labile
proton at the exo C atom in the NC−Me group. This
proton can move to the imino N atom according to imino−
enamino tautomerism. Since tautomeric sites (N and C atoms)
are conjugated, intramolecular proton transfers are always
accompanied by changes of π-electron positions. Prototropic
conversions lead to isomers, called tautomers, without
separation of charge. None of the tautomers is zwitterionic.
For tautomers possessing the exo NH group, two geometric
isomers are possible. Taking all types of isomerism into
account, DFT calculations have been carried out for 23
imeglimin isomers (Figure S1 in the Supporting Information).
Each of them has been found to correspond to an energy
minimum exhibiting real vibrational frequencies (Tables S1
and S2 in the Supporting Information).
The lowest electronic energy (E at 0 K) at the DFT level has
been found for the isomer I3 (Figure 2 and Table S1 in the
Supporting Information). The E value of I1 is higher than that
of I3 by only 0.4 kJ mol−1. When zero point energies are taken
into account, the difference between the electronic energies of
I1 and I3 is even smaller (0.2 kJ mol−1). Their enthalpies are
almost equal, but the Gibbs energy is slightly higher by 1.0 kJ
mol−1 for I1 (Table S2 in the Supporting Information), due to
a small difference between their entropies. Similar conclusions
can be derived on the basis of results found at the G2, G2MP2,
and G4 levels (Tables 1 and S5 in the Supporting
Information). The relative Gibbs energy between I1 and I3
remains close to 2 kJ mol−1 at all levels of theory. The two
imeglimin isomers (I1 and I3) are favored in the gas phase
(>95%). Their structures resemble those of the favored
isomers of acyclic metformin (M3a and M1a, respectively, in
Figure 2).6 The major isomer, I3 and M1a, contains the labile
proton at the amino N atom placed near the C atom with the
NMe2 group.
The isomeric mixture of neutral imeglimin includes also two
minor isomers, I6 and I13 (<5%). Regardless of the level of
calculation, their relative Gibbs energies are higher than those
of I3 by about 7−13 kJ mol−1 and contribute marginally to the
isomeric mixture. The other imeglimin isomers given in Figure
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Information) for the four selected imeglimin isomers, I1, I3,

I6, and I13. At the DFT level, the isomer I1/I3H+ (Figure 3;

Figure 3. B3LYP/6-311+G(d,p) structure of the favored monop-

rotonated imeglimin isomer compared to those6 for monoprotonated
Figure 2. Structures of the major and minor isomers for neutral metformin.
imeglimin compared to those for metformin selected at the B3LYP/6-
311+G(d,p) level. The numbering of metformin is that used in ref 6.
protonation of I1 or I3 at the N-imino bonded to the CH-CH3
Table 1. Relative Enthalpies, Gibbs Energies (ΔH298 and moiety) is favored for the imeglimin monoprotonated form
ΔG298, Respectively, in kJ mol−1),a and Percentage (Tables S3 and S4 in the Supporting Information). The
Contents (x298 in %) at 298.15 K for Major and Minor structure of this isomer resembles the twisted shape of MH+1a
Isomers of Neutral Imeglimin Estimated at Various (Figure 3), found for monoprotonated metformin in the gas
Theoretical Levels phase.6
To the best of our knowledge, there is only one structure
isomer method ΔH298 ΔG298 x298 determination related to imeglimin derivatives. The crystal
I1 DFT b
0.0 1.0 38.7 structure of 2,4-dichlorophenylacetate methanol solvate has
G2 0.2 1.8 31.5 been determined by X-ray diffraction.35 The crystal structure
G2MP2 0.0 1.6 32.8 displays the same tautomer as that found for the most stable
G4 1.1 2.5 25.3 monoprotonated imeglimin in vacuo (I1/I3H+). Because of
I3 DFTb 0.0 0.0 58.8 the cyclic structure of the biguanide skeleton in imeglimin,
G2 0.0 0.0 65.0 there is no imeglimin analog structure to MH+1b (Figure 3).
G2MP2 0.0 0.0 63.3 The other possible isomers for monoprotonated imeglimin
G4 0.0 0.0 70.0 possess Gibbs energies higher than those of I1/I3H+ by more
I6 DFTb 12.0 8.5 1.9 than 30 kJ mol−1 (Table S4 in the Supporting Information).
G2 14.0 13.4 0.3 Since they can be neglected in the isomeric mixture of the
G2MP2 13.6 13.0 0.3 imeglimin monoprotonated form, they have not been
G4 14.0 11.9 0.6 considered for calculations at higher levels of theory (G2,
I13 DFTb 11.5 11.7 0.5 G2MP2, and G4).
G2 4.2 7.5 3.1 Nitrogen bases interacting with the lithium-metal cation in
G2MP2 3.9 7.1 3.5 the gas phase can form noncovalent mono- or polydentate
G4 4.2 7.0 4.1 adducts29,30,36−38 For imeglimin, the Li+ adduct structure
a
ΔH298 and ΔG298 are referenced to the lowest value for the most depends on substituents. For the major isomer I3, containing
stable structure I3. bB3LYP/6-311+G(d,p)//B3LYP/6-311+G(d,p). the endo imino and exo amino groups, a stable monodentate
adduct is not found. During DFT optimization, the geometry
shift to a bidentate adduct with a four-membered ring (Figure
S1 (Supporting Information) can be considered as not S2 in the Supporting Information). However, for the isomer
contributing significantly to the mixture. At the DFT level, I1, the monodentate adduct I1Li+1a (also in Figure S2 in the
their Gibbs energies, relative to those of I3, are higher than 17 Supporting Information) is found to be stable. As shown by
kJ mol−1, corresponding to percentages lower than 0.1%, and DFT calculations (Tables S3 and S4 in the Supporting
may be neglected in the imeglimin isomeric mixture in the gas Information), the electronic and Gibbs energies of I1Li+1a are
phase. It is likely that this conclusion is valid in apolar higher than those of the corresponding bidentate adduct
environments. I1Li+1b by 9.2 and 7.2 kJ mol−1, respectively. Taking these
As previously shown for the parent biguanide and energetic differences into account, monodentate adducts have
metformin,6 the strong n−π conjugation reduces the basicity not been considered for the minor isomers I6 and I13.
of the N-amino site in favor of the N-imino ones. This effect is In bidentate imeglimin−Li+ adducts, the lithium cation can
common to the whole family of push−pull amino-imines interact with two N atoms, the endo imino and exo amino.
(amidines, guanidines, vinamidines, and phosphazenes) for Considering all possible interactions for each selected
which the N-imino atom is the favored site of protonation.26 imeglimin isomer, 12 bidentate adducts have been chosen for
For this reason, we considered hereafter only the N-imino DFT calculations (Figure S2 in the Supporting Information).
monoprotonated forms (Figure S2 in the Supporting For all of them, energetic minima with real frequencies have
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been found (Tables S3 and S4 in the Supporting Information).
Among them, I3Li+1 (Figure 4) displays the lowest Gibbs
metformin-Li+ adduct (MLi+2a), where the lithium cation
noncovalently interacts with two terminal imino N atoms and
favors the otherwise very rare tautomeric form (Figure 4). For
imeglimin, the cyclic structure impedes the formation of an
adduct analog to the 6-membered ring chelate MLi+2a, with
the lithium cation chelated by two N-imino groups. This
structural difference is responsible for the large difference
between lithium-cation basicities (LiCBs) of imeglimin and
metformin (vide infra).
Proton Basicity of Imeglimin in the Gas Phase. DFT
calculations performed for selected monoprotonated isomers
of imeglimin together with those for neutral isomers give the
possibility to estimate the gas-phase microscopic basicities
(Table S6 in the Supporting Information), as defined in the
Methodology section. Microscopic basicities correspond to the
virtual protonation reaction of a given neutral isomer,
calculated here at each potential N-imino basic site. Chart 1

Chart 1. Comparison of the DFT-Calculated Microscopic

PAs (in kJ mol−1) for Imino N Atoms in Selected Isomers of
Biguanides (Favored Site Indicated in Red)
Figure 4. B3LYP/6-311+G(d,p) structures of major and minor
imeglimin−Li+ adducts compared to those6 of the most stable
metformin-Li+ adduct.

Table 2. Relative Enthalpie, Gibbs Energies (ΔH298 and

ΔG298, Respectively, in kJ mol−1)a and Percentage Contents
(x298, in %) at 298.15 K for Selected Imeglimin−Li+ Adducts
Estimated at Various Theoretical Levels
isomer method ΔH298 ΔG298 x298
I1Li+1b DFTb 9.5 10.0 1.4 shows the microscopic PAs calculated for the imino N atoms
G2 6.5 8.2 3.4 in selected three amino−imino tautomers of imeglimin. They
G2MP2 6.8 8.4 3.1 are compared with those previously estimated for the open-
G4 6.5 6.9 5.5 chain biguanides, unsubstituted biguanide, and its dimethyl
I3Li+1 DFTb 0.0 0.0 83.6 derivative, metformin.6
G2 0.0 0.0 93.5 For the major imeglimin isomers containing the labile
G2MP2 0.0 0.0 93.5 proton at one of the terminal amino N atom, the other
G4 0.0 0.0 89.9 terminal imino N atom exhibits stronger basicity than the
I3Li+3 DFTb 13.5 13.5 0.4 central imino N atom. Analogous trends occur for parent
G2 13.7 14.0 0.3 biguanide and metformin.6 These PA differences are slightly
G2MP2 13.8 14.1 0.3 larger for imeglimin (60−70 kJ mol−1) than those for
G4 12.1 11.7 0.8 biguanide (41 kJ mol−1) and metformin (40−50 kJ mol−1),
I6Li+3 DFTb 5.5 4.3 14.6 probably because of cyclization and lack of rotation of the
G2 9.1 8.8 2.7 guanide moieties in imeglimin. This limited structural
G2MP2 8.7 8.4 3.1 flexibility of imeglimin enhances the n−π conjugation in the
G4 8.5 7.8 3.8 biguanide system as compared to that of biguanide and
a
ΔH298 and ΔG298 are referenced to the lowest value for the most metformin with open and twisted chains. The N-imino atoms
stable structure I3Li+1. bB3LYP/6-311+G(d,p)//B3LYP/6-311+G- of the third amino−imino imeglimin isomer (Chart 1) display
(d,p). PAs smaller by about 40 kJ mol−1 than those of the major
isomers.
energy (Table 2). It is favored for imeglimin−Li+ adduct In the case of imeglimin, four isomers, two major (I1 and
(>80%). The same structure is favored (>90%) at the G2, I3) and two minor ones (I6 and I13), have been taken into
G2MP2, and G4 levels (Tables 2 and S5 in the Supporting account for the neutral base (Figure 2), and one isomer (I1/
Information). The amounts of three other selected adducts I3H+), for its monoprotonated conjugate acid (Figure 3). The
(I1Li+1b, I3Li+3, and I6Li+3) are also significant (<20% at the percentage contents of selected neutral isomers (given in Table
DFT level and <10% at the G2 and G2MP2 levels), and they 1) are calculated at the DFT, G2, G2MP2, and G4 levels from
should also be considered for the estimation of basicity relative their relative Gibbs energies, as described in the Supporting
to Li+. Information. For the ‘ideal’ deprotonation reaction 1 from the
Interestingly, the structure of the major isomer I3Li+1 is monocation I1/I3H+ to the isomeric mixture of the four
completely different from that found previously for the neutral imeglimin isomers I1, I3, I6, and I13, its enthalpy and
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Table 3. Comparison of the Calculated Macroscopic Proton Gas-Phase Basicity Quantities (GB and PA at 298.15 K in kJ
mol−1) for Biguanides with Experimental and Computational Data for Selected Reference N Bases

a
B3LYP/6-311+G(d,p)//B3LYP/6-311+G(d,p). bRef 6. cThis work. dRef 26. eValue calculated for metformin according to the procedure from ref
6 taking the percentage contents of the neutral mixture into account at the G2, G2MP2, and G4 levels, respectively. fIn the Supporting Information
of ref 39. Values from ref 39 appear to be in error, as they do not follow the increasing polarizability effect of the CH2 groups in the series of bicyclic
amidines DBN, DBD, and DBU; this effect is observed in the experimental values and well reproduced in our calculations. gValue calculated for
reaction 1 taking the percentage contents of the neutral isomeric mixture into account at the DFT, G2, G2MP2, and G4 levels, respectively.

Gibbs energy changes correspond, respectively, to the confirm the monodentate lithium-cation adducts for selected
macroscopic PA and GB, as defined in the Methodology cyclic push−pull imines. Their favored structures are included
section. The DFT-, G2-, G2MP2-, and G4-calculated macro- in Figure 5.
scopic basicity quantities are summarized in Table 3 together
with those estimated previously for the parent biguanide and
its dimethyl derivative, metformin.6 Theoretical proton
basicities estimated here for push−pull reference N bases are
also included in this table.

I1/I3H+ → [I1 F I3 F I6 F I13] + H+ (1)

As expected from its push−pull structure, imeglimin is an

exceptionally strong base in vacuo. Together with unsub-
stituted biguanide and its methyl derivative, metformin, it can
be grouped with the family of superbases in the gas
phase24−26,40 with PA > 1000 kJ mol−1 (Table 3). The
macroscopic GB and PA estimated for imeglimin at the DFT
level are higher than those of metformin by 14 and 16 kJ
mol−1, respectively. This basicity GB and PA increase is a
consequence of the favorable polarizability effect of the >CH−
CH3 group, which closes the six-membered cycle of imeglimin.
Additionally, the biguanide moiety in the cyclic imeglimin
monoprotonated form is less twisted than in the protonated
metformin, favoring the n−π conjugation and the push−pull
effect. The estimated GB and PA for imeglimin appear to be
close to those for bicyclic push−pull N bases, bicyclic amidine
DBU and bicyclic guanidine TBD, for which experimental data
are available.26 GB and PA experimental determination may be Figure 5. Favored structures for selected monodentate lithium-cation
adducts of mono- and polycyclic push−pull imines and for bidentate
foreseen using DBU and TBD as reference bases.
adducts of biguanides found at the DFT level.
Lithium Gas-Phase Basicity of Imeglimin. For mono-
and polycyclic push−pull imines containing the amidine (>N−
C(R)N−) or guanidine {(H2N)2CN−} group and also Generally, the distances between the lithium cation and the
for vinamidines, the lithium cation is supposed to interact with imino N atom in monodentate adducts of selected push−pull
the most basic N-imino site and to form monodentate adducts imines correlate well with gas-phase lithium-cation basicity
in the gas phase analogously, as for unsubstituted formamidine data (Table S7 in the Supporting Information). Stronger
(H 2 NCHNH···Li + ) and unsubstituted guanidine imine−Li+ interaction leads to higher basicity parameters and
{(H2N)2CNH···Li+}.29,30,41 Indeed, our DFT calculations to smaller N···Li+ distance. Figure 6 shows a linear trend
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Figure 6. Linear trend between lithium-cation basicities (LiCBs in kJ
mol−1) and N···Li+ distances (in Å) for selected monodentate imines,
both calculated at the DFT level.
between DFT-calculated lithium-cation basicities (LiCBs) and
N···Li+ distances for monocyclic (imidazole, imidazoline, and
HP), bicyclic (DBN, DBD, DBU, TBD, and MTBD), tricyclic
(TTT), as well as acyclic bases (Z-formamidine and
guanidine).
It should be also noted here that for monodentate push−pull
imines, the lithium-cation basicity data, LiCBs and lithium-
cation affinities (LiCAs), are almost parallel to the proton
basicity data, GBs and PAs, respectively, all estimated at the
same level of theory (Table S7 in the Supporting Information).
For a set of 10 selected push−pull bases (Table S7), both
LiCBs and LiCAs correlate well with PAs and GBs,
respectively. Figure 7 presents the linear relationship between
Figure 7. Strong deviations of biguanide and metformin from the
linear relationship between lithium and proton basicity data (LiCB
and GB in kJ mol−1) for monodentate push−pull imines calculated at
the DFT level.
LiCBs and GBs for monodentate push−pull imines. Calculated
gas-phase basicity data for unsubstituted formamidine and
guanidine (acyclic bases) fit well this relationship.
Quite a different situation takes place for open-chain
biguanides.4 For the parent biguanide and its dimethyl
derivative, metformin (Figure 5), the lithium cation,
interacting with two terminal N atoms, changes the tautomeric
preferences in biguanides by forming very stable bidentate
adducts. This interaction reveals their exceptionally strong
lithium-cation basicities (Table 4) in comparison to their
proton basicities (Table 3), both computed at the DFT level.
Hence, the two points in Figure 7 corresponding to biguanide
and metformin deviate from the linear relationship found for
monodentate imines. The large increase of lithium-cation
basicity for open-chain biguanides when compared to that in
monodentate bases (ca. 50−60 kJ mol−1) gives an indication of
the chelation effect of Li+ by the open-chain biguanides. The
adduct formation involves a less favored tautomer and
additional destabilization by geometry constraint (formation
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of a cyclic adduct), but these unfavorable effects are
overcompensated by Li+ chelation.
For the cyclic imeglimin, both the change of the tautomeric
and conformational preferences and the chelation of the
lithium cation by two imino N atoms are not possible. The
only possible Li+ chelation in imeglimin adducts is by
proximate N-imino and N-amino atoms, as shown in Chart
2. This chart shows the structures of selected mono- and
Chart 2. DFT-Calculated Microscopic LiCAs (in kJ mol−1)
for Selected Imeglimin−Li+ Adducts
bidentate imeglimin−Li+ adducts and the microscopic LiCAs
calculated at the DFT level. According to DFT calculations
performed for selected isomers of lithium-cation adducts,
monodentate imeglimin displays considerably smaller LiCA
and LiCB than imeglimin acting as a bidentate base. To the
best of our knowledge, no systematic studies of rotational
barriers for the NR2 (R = H, Me) groups in imeglimin were
found. Only a few mentions of rotational barriers in open-chain
biguanides and metformin may be found in the study of
Bharatam and co-workers.27 Although this dynamic effect is
partly related to chelation, we have not included this reactivity
aspect in our thermochemical study.
The interaction of the lithium cation with the imino and
amino N atoms in imeglimin, forming a formally four-
membered ring chelate, is much less efficient than a 5- or 6-
membered ring chelation by two imino N atoms in open-chain
biguanides.6 Consequently, imeglimin has a smaller lithium
gas-phase basicity than metformin (Table 4). The presence of
a >C−Me group in imeglimin is not sufficient to counteract
the weaker chelation effect. Deviation (ca. 20 kJ mol−1) of its
macroscopic (weighted average) LiCB from the linear
relationship found for cyclic monodentate imines is smaller
than that for open-chain biguanides (Figure 7). The macro-
scopic lithium-cation basicity data have been estimated as the
enthalpy and Gibbs energy changes of reaction 2.
[I1Li+1b F I3Li+1 F I3Li+3 F I6Li+3]
→ [I1 F I3 F I6 F I13] + Li+ (2)
Although the estimated macroscopic LiCB and LiCA for
bidentate imeglimin (Table 4) are smaller than those for
metformin, they seem to be higher than those for monodentate
bicyclic guanidine MTBD. The higher range of the LiCB
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Table 4. Comparison of the Calculated Macroscopic Lithium Gas-Phase Basicity Data (LiCB and LiCA at 298.15 K in kJ
mol−1) for Biguanides with Experimental and Computational Data for Selected Push−Pull N Bases

a
B3LYP/6-311+G(d,p)//B3LYP/6-311+G(d,p) for 298 K. bThis work. cAveraged value calculated for reaction 2 taking the percentage contents of
the neutral and lithiated isomeric mixtures of imeglimin into account at the DFT, G2, G2MP2, and G4 levels, respectively. dRef 6. eB3LYP/6-
311+G(d,p)//B3LYP/6-31G(d,p) for 298 K. fRef 43. Difference between Exp. and DFT LiCB was discussed in ref 6. gAveraged value for
metformin calculated according to the procedure from ref 6, the percentage contents of the neutral isomeric mixture taken into account at the G2,
G2MP2, and G4 levels, respectively.

scale30 is currently limited to about 200 kJ mol−1 and
potentially up to 230 kJ mol−1 using diaminoalkanes as
chelating ligands,42 including 2-(β-aminoethyl)-pyridine
(AEP) and histamine (HA).43 The development of the LiCB
scale by relative basicity determinations may benefit from the
close relative basicities estimated for monodentate and
bidentate ligands listed in Table 4.
Electron Delocalization in the Biguanide Moiety for
Selected Isomers of Neutral, Protonated, and Lithiated
Imeglimin. Only five imeglimin tautomers (I1−I5) possess
the conjugated biguanide moiety −HN−C(NH2)N−C-
(NMe2)N−, which is also present in open-chain metformin
tautomers. The isomers I1−I5 (Figure S1 in the Supporting
Information) contain a 10-electron system, i.e., three pairs of
n-electrons at the amino N atoms and two pairs of π-electrons
in the imino CN group, which are conjugated in a different
way; I1, I3, and I5 are doubly n-π-cross-conjugated system,
whereas I2 and I4 possess two differently bonded Y-
conjugated fragments. Various resonance structures (Scheme
S1 in the Supporting Information) can be proposed for the
biguanide moiety to illustrate its high electron delocalization.
The transfer of the labile proton from the C atom bonded with
Me to the C atom bearing NH2 (I6−I10) or NMe2 (I11−I18)
excludes the NH2 or NMe2 group (and their n-electrons) from
the conjugated system. These isomers do not belong to the
biguanide family. They are singly n−π-cross-conjugated (I6,
I7, I12, I13, and I15) or Y-conjugated compounds (I8−I11,
I14, and I16−I18).
Analogous n−π conjugation in the biguanidinium moiety
takes place for monoprotonated forms, for which the positive
charge is additionally delocalized. For the lithium-cation
adducts, the strength of n−π conjugation strongly depends
of the type of interaction. For monodentate adducts, it may be
seen as similar to that for monoprotonated isomers, but the
participation of N-amino electron pairs in bidentate adducts
may alter the conjugation by changing the out-of-plane twist
angle of the amino group. All of these changes in electron
17848
delocalization for neutral, protonated, and lithiated imeglimin
isomers are well illustrated by variation of the CN bond lengths
that vary from 1.27 to 1.48 Å.
The geometry-based harmonic oscillator model of electron
delocalization (HOMED) index44,45 takes into account
quantitatively all changes in the bond lengths and consequently
in electron delocalization of the system. This index is based on
computed bond lengths and mathematically compared to
reference bond lengths computed at the DFT level of theory,
B3LYP/6-311+G(d,p), as described in the Supporting
Information. The impact of resonance energies on basicities
may be estimated by considering the thermochemistry of
isodesmic reactions, which may be deduced from the H and G
data reported in the Supporting Information data, and
indirectly from the PA and LiCA values of the isomers in
Charts 1 and 2. We chose the geometric descriptor (HOMED)
as a complementary approach for the quantitative analysis of
resonance stabilization in biguanides, because the geometric
parameters of all structures examined for basicity in the gas
phase were available.
The HOMED indices have been estimated for the biguanide
moiety (six bonds, HOMED6) in selected neutral (I1−I5),
protonated (I1/I3H+, I1/I2H+, and I2/I3H+), and lithiated
(I1Li+1−I1Li+3 and I3Li+1−I3Li+3) imeglimin isomers
(Table S8 in the Supporting Information). The estimated
HOMED6 indices were also previously estimated for
unsubstituted biguanide and metformin at the same DFT
level. In Figure 8, trend plots between HOMED indices and
the relative stabilities of individual isomers are shown. There is
a clear tendency that a high delocalization (large HOMED)
favors a high stability (low ΔG). An exception is the neutral
isomer I2 (HOMED6 = 0.579), which deviates from the linear
tendency found for other neutral biguanides isomers. There are
no stable isomers for unsubstituted biguanide and metformin
similar to I2, and it is difficult to propose some general
explanation.
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Figure 8. Comparison of the plots between electron delocalization in
the biguanide moiety (measured by the HOMED6 index, Table S8)
and relative Gibbs energies (ΔG, Tables S2 and S4), both estimated
at the DFT level for neutral, monoprotonated, and monolithiated
isomers of unsubstituted biguanide, metformin, and imeglimin. Data
for biguanide and metformin taken from ref 6.
Generally, monoprotonated biguanides display a stronger
electron delocalization of the biguanide moiety than the
neutral forms. For the most stable monoprotonated isomers,
the HOMED6 indices (0.983 for biguanide, 0.972 for
metformin, and 0.984 for imeglimin) are close to unity
whereas they are slightly smaller for the most stable neutral
isomers (0.851 for biguanide, 0.868 for metformin, and 0.856
for imeglimin). In the case of the lithium-cation adducts, the
HOMED6 indices depend on the type of imeglimin−Li+
interaction. For the monodentate adduct I1Li+1a, the
HOMED6 index is close to unity (0.963) similar to that for
the major isomer of monoprotonated imeglimin (0.984 for I1/
I3H+), whereas the HOMED6 values are considerably smaller
(0.764 for I1Li+1b and 0.791 for I3Li+1) for bidentate
17849
Article
adducts. Electron delocalization does not seem to dictate the
isomeric preferences for Li+ adducts, and the plot of HOMED6
vs ΔG shows a large scatter for cyclic imeglimin, analogously,
as that for open-chain biguanides. The chelating power of two
N atoms appears to strongly affect the stability of biguanide-Li+
adducts.
■ CONCLUSIONS
Despite advanced clinical tests on imeglimin, very little is
known about its structure and properties. Imeglimin
prototropy and its Brønsted−Lowry and Lewis basicity were
not documented. For the neutral molecule, we identified 18
tautomers, including geometric isomerism about CN bond;
the isomeric mixture consists of 23 isomers for which the gas-
phase thermochemistry was investigated computationally at the
B3LYP/6-311+G(d,p) level. From the calculated Gibbs
energies, it appears that four isomers dominate the equilibrium
mixture at 298.15 K, a trend confirmed at the G2 and G4
levels. The push−pull electronic structure of the two most
stable tautomers indicates that imeglimin is expected to be a
very strong Brønsted−Lowry base. Quantum-chemical calcu-
lations were carried out on the gas-phase basicity of imeglimin
toward the proton and the lithium cation. The proton affinity
of imeglimin is even larger than that for the similar antidiabetic
drug metformin, and imeglimin can be designated as a
superbase. Comparative calculations on bases known to be
very strong in the gas phase support this conclusion. The
thermochemistry of bonding to the lithium cation was
examined for comparison with metformin. The imeglimin
affinity for Li+ was found to be weaker than that for metformin.
This difference can be attributed to a strong chelation of the
cation in metformin, this effect being much less efficient with
imeglimin. Our exploration of the intrinsic properties of
imeglimin is a necessary first step to the understanding of the
behavior of this promising drug under physiological conditions.
After completion of this work, we became aware of two
publications relevant to our study. Metformin protonation, its
solvation by water, and interactions with DNA were
investigated from the experimental (NMR, IR, UV−vis) and
theoretical (DFT, molecular dynamics) point of views.50 The
basicities in the gas phase and in acetonitrile solution of seven
substituted biguanides have been measured using mass
spectrometric methods, and DFT calculations at a simple
level were used for comparison with previous studies.51
■ METHODOLOGY
Quantum-chemical calculations at the B3LYP/6-311+G(d,p)
level have been performed for all possible isomers of isolated
neutral imeglimin and for selected isomers of its monoproto-
nated and monolithiated forms (Figures S1 and S2 in the
Supporting Information), as described previously.6 Additional
calculations have been carried out at the G2, G2MP2, and G4
levels for major and minor isomers selected on the basis of the
DFT results. Toomsalu et al.46 made an extensive study
regarding the performances of DFT and Gn methods for
calculations of gas-phase basicities and acidities defined from
Gibbs energies of deprotonation (reaction 3). The B3LYP/6-
311+G(d,p) is one of the most widely used method for
structural and thermochemical studies. Although a few other
DFT methods perform better in general,46 this level of DFT
was chosen for the present study to enable comparisons. For
basicities, the B3LYP, G2, and G4 methods are reported to
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produce average absolute errors of 10, 7.5, and 8.4 kJ mol−1,
respectively. In fact, a closer examination of the results
obtained for the strongest bases, i.e., the basicity region
actually investigated, shows that Gn methods perform much
better than DFT. The calculated Gn basicities of the strong
bases examined in this work are therefore expected to be the
closest to the current experimental gas-phase basicity scale and
useful for selecting reference bases for future experimental
measurements.
All computational details and procedures for estimations of
thermochemical quantities, proton and lithium-cation basic-
ities, and geometry-based indices are given in the Supporting
Information. The DFT-optimized structures and electronic
energies for all possible (23) neutral isomers of imeglimin, as
well as their relative thermochemical quantities (298.15 K, 1
atm), are included in Tables S1 and S2 (Supporting
Information), respectively. The DFT-optimized structures
and electronic energies for the selected monoprotonated and
monolithiated forms of imeglimin and their thermochemical
quantities are summarized separately in Tables S3 and S4
(Supporting Information), respectively. Thermochemical
quantities calculated at the Gn levels for selected isomers are
given in Table S5 (Supporting Information). The DFT-
estimated “microscopic” proton affinities and lithium-cation
affinities for selected imeglimin isomers are listed in Table S6
(Supporting Information). Microscopic affinities are defined as
the thermochemistry of the hypothetical protonation or
lithiation of a given neutral isomer. Note that this definition
is valid either in the gas phase (in vacuo) or in solution.
Conversely, a macroscopic affinity corresponds to the result of
a measurement (or a calculation) on a mixture of neutral
isomers present in a sample under given experimental
conditions of temperature and pressure. The DFT-estimated
proton and lithium-cation basicity data for selected push−pull
imines, which form monodentate adducts with the lithium
cation, are given in Table S7 (Supporting Information). Note
that four or five significant figures in tables are not
representative of the expected accuracy on absolute basicities
but are considered useful for comparison of relative basicities.
The geometry-based indices that describe electron delocaliza-
tion in the biguanide moiety of selected neutral, monoproto-
nated, and monolithiated isomers of imeglimin are summarized
in Table S8 (Supporting Information).
Owing to the small number of isomers with Gibbs energies
less than 1 kcal mol−1 (4.184 kJ mol−1) above the most stable
form (Tables S2 and S4 in the Supporting Information), the
entropy of mixing6,47,48 of neutral and protonated or lithiated
imeglimin contributes weakly (TΔmixS < 1.7 kJ mol−1) to the
Gibbs energy of protonation and lithiation. This entropy
contribution is not considered in the estimation of gas-phase
basicities. The Gaussian values of the H and S at 298.15 K for
imeglimin I and for its conjugate acid IH+ have been used for
calculating the enthalpy and Gibbs energy of reaction 3. The
calculated quantities correspond to the proton affinity (PA)
and the gas-phase basicity (GB), respectively.24−26,49
IH+ → I + H+ (3)
In the same way, lithium-cation affinity (LiCA) and lithium-
cation basicity (LiCB)29 for imeglimin I were deduced from
the enthalpy and Gibbs energy for the Li+ adduct dissociation,
reaction 4, calculated from the H and S quantities of I, ILi+,
and Li+.
17850
Article
ILi+ → I + Li+ (4)
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsome-
ga.8b02507.
Possible isomers for neutral imeglimin (Figure S1);
selected isomers for its monoprotonated and mono-
lithiated forms (Figure S2); DFT structures, atom
coordinates, electronic energies, and relative thermo-
chemical quantities for neutral, protonated, and lithiated
isomers of imeglimin (Tables S1−S4); Gn-calculated
thermochemical quantities (Table S5); microscopic
basicity data (Table S6); basicity data for reference
bases (Table S7); resonance structures (Scheme S1),
and HOMED indices (Table S8) for selected imeglimin
isomers (PDF)
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail: ewa_raczynska@sggw.pl. Tel: +48 22 5937623. Fax:
+48 22 5937635 (E.D.R.).
*E-mail: jean-francois.gal@univ-cotedazur.fr. Tel: +33
492076361. Fax: +33 492076189 (J.-F.G.).
ORCID
Jean-François Gal: 0000-0002-5500-5461
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
Support from Université Cô te d’Azur (UCA) and the
computational services of the ICN Technical Platform
(PFTC) for calculations with Gaussian 16 program are
gratefully acknowledged.
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17852 DOI: 10.1021/acsomega.8b02507

ACS Omega 2018, 3, 17842−17852