Guanidine Superbases
1131
C10
Table 2. Gas phase and solution basicities (in acetonitrile) of peralky-
lated triguanides 4a–b and biguanides 5a–b calculated using the
IEFPCM/B3LYP/6–3111G(d,p)//B3LYP/6–31G(d) approach[12]
C9
C8
C5
Cl1
C4
C2
Molecule GBgas(B) GBg0 as(B)
DG(X)AN
[kcal molꢀ1
GBA0 N(B)
pKAa
C14
]
N4
C7
[kcal molꢀ1
]
X ¼ B X ¼ BHþ [kcal molꢀ1
]
C6
N2
C18
C13
4a
4b
5a
5b
262.2
264.5
253.1
255.3
268.5
270.8
259.3
261.6
16.91 ꢀ12.75
16.52 ꢀ12.58
6.95 ꢀ27.11
6.73 ꢀ26.65
298.2
299.9
293.4
295.0
28.4
29.4
25.4
26.4
N5
N7
C3
C1
N3
ACalculated using Eqn 1.
C17
C15
N6
N1
C12
The intermediate biguanides 5a–b have gas phase basicities
of 253.1 and 255.3 kcal molꢀ1 and pKa values of 25.4 and 26.4 in
acetonitrile (Table 1), respectively, making them ,6-7 pKa units
stronger base than 2-tolylbiguanide (pKAa N 19.66).[18] Concom-
itantly, it was expected that 5a–b would form the corresponding
chloride salts under the applied reaction conditions. Since
protonated guanidines and biguanides are poor nucleophiles,
the need for an external base to drive the reaction towards a
polyguanide product is obvious. The pKa value of DIPEA in
acetonitrile, which was used here as a base, was estimated to be
19.4 employing Eqn 1. Although the equilibrium between
[5a–b]H1 and DIPEA is shifted towards the biguanide bases,
DIPEA effectively deprotonates [5a–b]H1 because the follow-
ing formation of triguanides 4a–b as the strongest bases in the
system act as the driving force for the reaction.
The introduction of the second guanidine subunit in 5a–b to
yield 4a–b increased the basicity by ,10 kcal molꢀ1 and the pKa
value by three units. This follows the general principle of
building up basicity in polyguanides where the extension by a
C(NR’R’’)2 fragment, coupled with a proper choice of substi-
tuents, leads to stronger bases.[4] For example, the order of
GBgas values going from 1,1,3,3-tetramethylguanidine (TMG,
240.7 kcal molꢀ1) to biguanides 5a–b and triguanides 4a–b fully
conforms to this principle. Based on the GBgas and pKa values,
both 4a–b and 5a–b can be considered as organic superbases.[1]
Furthermore, unlike 5a–b which undergo deprotonation during
the synthesis, triguanides 4a–b after being formed remain in the
form of chloride salts, witnessing the inability of DIPEA to
effectively deprotonate such strong bases.
C11
C16
Fig. 2. A distorted triguanide cation in the crystal structure of the chloride
salt [4aH]Cl. The displacement ellipsoids are drawn at the 40 % probability
level, while the hydrogen atoms are omitted for clarity.
corresponding nitrogen atoms. The pyramidalization for atoms
N1, N2, N4, N6, and N7 amounts to 5.1, 0.5, 1.1, 4.1, and 1.0 %,
respectively, and is consistent with the protonated state of 4a.
The gas phase structure of 4aH1 optimized with B3LYP/6–31G
(d) is also in agreement with the solid-state one, with dihedral
angles of 146.0 and 49.18, respectively, and bond lengths of
˚
1.326 to 1.374 A in the triguanide (Fig. SM14 and Table SM2).
Upon protonation, the three double bonds in 4a (C1–N3, C2–N4,
and C3–N5) undergo an increase in length, and the distances of
the remaining triguanide core bonds slightly decrease.
The only proton in the molecule is involved in a hydrogen
bond to a neighbouring chloride anion (N4–H1N4ꢂꢂꢂCl1
˚
3.184(1) A). The chloride anion also interacts with the surround-
˚
ing methyl, benzyl, and phenyl protons (3.514(2)–3.706(2) A),
while the triguanidium cations interact with each other through
weak van der Waals contacts between methyl groups, as well as
between the benzene C–H proton and adjacent CH3 group. This
arrangement gives rise to a two-dimensional array of triguanide
cations bridged by chloride anions, as shown in Fig. SM17 in the
Supplementary Material.
The calculated basicity of peralkylated triguanides from 262
to 265 kcal molꢀ1 in the gas phase and pKa values in acetonitrile
between 28 and 30 render these compounds as candidates for
base-catalyzed reactions, such as the transesterification of
vegetable oil[14,19] which is an important transformation in the
biodiesel production.[20] For this purpose, we followed a stan-
dard procedure and tested the benzyl triguanide derivative 4a in
a transesterification reaction with methanol (see the Supple-
mentary Material for details). Although the synthesized trigua-
nides are predicted to be very strong bases, the catalytic activity
of 4a in the transesterification reaction is lower than, for
example N1,N2-dicyclohexyl-N4,N4,N5,N5-tetramethylbiguanide
(DCTMB) or 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD),[7]
which are weaker bases (Fig. 3).
Single crystals of the benzyl triguanide chloride salt [4aH]Cl
were grown by slow evaporation of ethyl acetate–ethanol mix-
ture over a few days. The title compound crystallizes in ortho-
rhombic Pbca space group with unit cell parameters a 15.9304
˚
˚
˚
(4) A, b 14.0589(3) A, and c 19.0244(4) A. In the crystal struc-
ture, the triguanidium cation is heavily distorted (Fig. 2) as
evidenced by N1–C1–N3–C2 (149.86(2)8) and C2–N5–C3–N6
(60.84(2)8) dihedral angles. Despite such a pronounced non-
planarity, the bond lengths within the triguanide core lie in the
˚
range from 1.3204(2) to 1.3584(2) A (Table SM4 in the Supple-
mentary Material). Since a typical carbon–nitrogen double bond
˚
˚
is 1.27A and a single C–N bond is 1.47 A, all the bonds in the
triguanide framework are highly delocalized, confirming that the
resonant stabilization of the positive charge in 4aH1 is not
affected by its twisted geometry. This observation is in line with
the reported crystal structure of pentasubstituted triguanide
sulfate salt.[9] The three guanidine subunits containing C1, C2,
and C3 atoms are essentially planar, where the carbon atoms are
Nevertheless, 33 % conversion at 0.5 mol-% loading, 53 %
at 1.0 mol-%, and 61 % at 2.0 mol-%, respectively, places
triguanide 4a above TMG (pKAa N 23.3), PMG (pKaAN 25.0), or
P1-phosphazene (pKAa N 28.27) as organocatalysts in this type of
transformation.[14] Whereas catalyst 4a lacks protons directly
attached to nitrogen atoms, DCTMB and TBD possess one such
proton. In the protonated form, they are capable of forming
˚
displaced by 0.010–0.053 A from the mean plane defined by the