Unusual reactivities of acridine derivatives in catalytic hydrogenation. A combined experimental and theoretical study

Article abstract of DOI:10.1016/j.molcata.2013.01.015

Hydrogenation of acridine derivatives over Rh/Al₂O₃, has been studied. Strong influence of the pyrrolidino-substituent on the reduction pathway and reductions products was found. When, the reaction was performed on the unsubstituted acridine nucleus full conversion was obtained in 8 h. Under the same conditions, when a pyrrolidine substituent was settled on the central ring of acridine (9-position), a pure product was obtained with the two lateral carbocycles reduced whereas the central heterocyclic ring was not reduced. When the pyrrolidine substituent was at the 1-position, pure partially reduced central heterocyclic ring was obtained, but the compound was rapidly re-oxidized by air. In order to clarify such substituent effect, theoretical calculations were performed. Considering the energies and thermodynamic values of each intermediate and product as well as the interaction with the catalyst surface, the selectivity and diversity in the reduced product formation were partially explained and different reaction pathways were drawn according to the substitution pattern on the acridine scaffold.

Full text of DOI:10.1016/j.molcata.2013.01.015

Journal of Molecular Catalysis A: Chemical 371 (2013) 63–69
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Unusual reactivities of acridine derivatives in catalytic hydrogenation.
A combined experimental and theoretical study
Pierre Mignona, Martin Tianob, Philippe Belmontb,c, Alain Favre-Réguillond,
Henry Chermettea, Fabienne Fachee,∗
a Université de Lyon – Université Lyon1, Laboratoire des Sciences Analytiques, UMR5180, Equipe Chimiométrie et Modélisation, 43 boulevard du 11 novembre 1918, Villeurbanne
F-69622, France
b Université de Lyon – Université Lyon1, Laboratoire de Synthèse et Méthodologie Organiques (LSMO), ICBMS, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, 43
boulevard du 11 novembre 1918, Villeurbanne F-69622, France
c Institut Curie et CNRS, UMR 176, Equipe Chimie Organométallique, Hétérocycles et Cibles Biologiques (COHCB), Institut Curie, 26 rue d’Ulm, 75248 Paris cedex 05, France
d Laboratoire des Transformations Chimiques et Pharmaceutiques (LTCP), Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France
e Université de Lyon – Université Lyon1, UMR 5246 CNRS, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Bât. Raulin, 43 boulevard du 11 novembre 1918,
Villeurbanne F-69622, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydrogenation of acridine derivatives over Rh/Al2O3, has been studied. Strong influence of the
pyrrolidino-substituent on the reduction pathway and reductions products was found. When, the reac-
tion was performed on the unsubstituted acridine nucleus full conversion was obtained in 8 h. Under the
same conditions, when a pyrrolidine substituent was settled on the central ring of acridine (9-position),
a pure product was obtained with the two lateral carbocycles reduced whereas the central heterocyclic
ring was not reduced. When the pyrrolidine substituent was at the 1-position, pure partially reduced cen-
tral heterocyclic ring was obtained, but the compound was rapidly re-oxidized by air. In order to clarify
such substituent effect, theoretical calculations were performed. Considering the energies and thermo-
dynamic values of each intermediate and product as well as the interaction with the catalyst surface, the
selectivity and diversity in the reduced product formation were partially explained and different reaction
pathways were drawn according to the substitution pattern on the acridine scaffold.
Received 23 October 2012
Received in revised form 8 January 2013
Accepted 19 January 2013
Available online 9 February 2013
Keywords:
Aromatic hydrogenation
Acridine derivatives
Hydrogenation pathway
DFT calculations
© 2013 Elsevier B.V. All rights reserved.
1. Introduction
Furthermore, the hydrodenitrogenation reaction (HDN), where
nitrogen is removed from the heteroaromatic nitrogen ring of com-
Acridine derivatives are compounds of interest due to their
broad biological activities against bacteria, parasites or tumours
[1–7]. Their properties depend mainly on the nature and the posi-
tion of the substituents on the acridine nucleus [8].
pounds found in fossil fuels, is one of the most important and highly
studied reaction [20–22]. HDN is a complex process that involves
a variety a chemical sequences and among then, reduction of the
aromatic carbocycles [22]. Numerous studies have been published
on the acridine as a model of polynuclear heteroaromatic fuel prod-
ucts. The reduction pathway depends on the nature of the metal,
on the support and on reaction conditions. Two different compet-
ing pathways for the reduction of acridine have been suggested,
differing by the fact that the heterocyclic ring of acridine is being
reduced first, before the lateral carbocycles, or the inverse [23–28].
In homogeneous catalysis, the reduction catalyzed by ruthenium
or boron complexes [29,30] also showed that the pathway can be
different depending on the catalysts. The reduction by H2 over
metal/oxide surfaces has been the subject of several theoretical
works, studying the selectivity brought by the metal nature and/or
the oxide support [31–36]. All the calculations indicate that hydro-
genation proceeds through dissociated hydrogen (i.e. atomic H·)
which attacks the chemisorbed substrate over the surface allowing
In the course of our studies on hydrogenation of aromatic com-
pounds [9–11], we found of interest to study the reduction of
acridine derivatives with the aim of controlling the chemioselectiv-
ity of the reaction which should lead to new families of potentially
biologically active molecules. In particular, hydrogenation of
9-amino acridine gave access to tacrine (1,2,3,4-tetrahydro-9-
amino-acridine), a reversible acetylcholine inhibitor, which has
been the first drug approved for the treatment of Alzheimer dis-
ease [12] in 1993/1994 and new derivatives are still sought after,
although tacrine is now out of the market [13–19].
∗
Corresponding author.
E-mail address: fache@univ-lyon1.fr (F. Fache).
1381-1169/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2013.01.015

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P. Mignon et al. / Journal of Molecular Catalysis A: Chemical 371 (2013) 63–69
a favourable interaction with the atomic hydrogen bound to the
metal
2.4. Computational details
In this article, we present our work on the catalytic hydrogena-
tion of pyrrolidine-substituted acridine derivatives, synthesized
according to a method published by some of us where pyrroli-
dine serves as a trigger for a cyclo-isomerization reaction leading
to pyrrolidino-aryl moieties [37,38]. However the reactivity of the
substrates over Rh/Al2O3 catalyst was found to be strongly depend-
ent of the substituant position and could not be easily explained.
Thus, the hydrogenation of the unsubstituted acridine was carried
out, as a model compound, under the same experimental conditions
to study the reduction pathway with Rh/Al2O3 catalyst. Experimen-
tal data combined with a theoretical approach based on gas phase
calculation of the energies and thermodynamic values of the inter-
mediate products allow us to propose a reaction pathway for the
reduction of the acridine derivatives. Thus, most of the unusual
reactivity of pyrrolidine-substituted acridines in catalytic hydro-
genation over Rh/Al2O3 catalyst could be explained.
Density Functional Theory calculations were performed with
the ADF [39] code using the PBE functional [40] and Triple Zeta plus
polarization basis sets. For all given compounds, various stereoiso-
mers were calculated. In each case, frequencies were computed and
we always considered the stationary points with the lowest energy.
The corresponding electronic energy and zero point energy were
used to compute the relative changes in electronic energy, enthalpy
and free energy (ꢀE, ꢀH and ꢀG) against the acridine and H2
isolated molecules. The thermodynamic functions, including free
energies, were calculated at 298.15 K and 1 atm.
3. Results and discussion
3.1. Reduction of substituted acridine derivatives
Hydrogenation of acridine derivatives over Rh/Al2O3, has been
studied. For the reduction of compound 1, only compound 2 was
isolated (Scheme 1). However in the case of product 3, only com-
pound 4 was obtained and underwent a fast re-aromatisation when
left in the NMR tube (CDCl3). The re-aromatisation of 4 was slower
in C6D6.
2. Experimental part
2.1. Chemicals
These observed selectivities for compounds 1 and 3 are quite
surprising and the role of the pyrrolidine substituent uncertain. To
clarify the unexpected reactivity of acridine derivatives 1 and 3,
the reduction of the unsubstituted acridine 5 was reinvestigated
experimentally and theoritically.
All commercially available reagents were used as received.
Rh/Al2O3 (5%) and acridine were purchased from Acros.
2.2. Instrumentation
3.2. Reduction of unsubstituted acridine 5
Hydrogenation experiments were performed in a stainless steel
autoclave. NMR spectra were recorded with a Bruker AMX 300
spectrometer. Mass data were also acquired on a Shimazu QP2010
GCMS apparatus, with injection on a SLB-5ms column lined with a
mass EI detection system.
Standard conditions were applied to acridine 5 (Rh/Al2O3 with
40 bar H2, 100 ◦C, methanol as solvent). Product distribution as the
function of time is given in Fig. 1. After 30 min, the reaction mix-
ture was analyzed by both 1H NMR and mass spectrometry. The
conversion was already high (50%) and the major product was 6,
with only the central ring being reduced (compound 7 being the
minor product). After 1 h, the conversion was slightly higher (60%),
but the distribution of the products was different. The major reduc-
tion product was this time 8 with the external rings reduced. After
8 h of reaction, the conversion was total. We obtained a mixture of
the fully reduced product 9 (80%) and the partially reduced prod-
uct 8. From these data, it appears that products 6 and 7 are rapidly
formed and that after 1 h they are converted into 8. An accumu-
lation of 8 before the formation of 9 can also be noticed. Finally
these results show that the first reduction occurs on the central ring.
2.3. General procedure for the hydrogenation under H2 pressure
The acridine derivative 1, 3 or 5 (0.046 mmol) and Rh/Al2O3
(2 mg, 0.0008 mmol) in 0.4 mL of MeOH were put in a stainless
steel autoclave. The solution was degased 3 times under hydro-
gen. The reaction mixture was then stirred at 40 bar H2 and heated
at 100 ◦C, for requested time (the final pressure was 45 bar). The
reaction mixture was filtrated through celite, the solvent evap-
orated and the crude product analyzed by NMR without further
purification.
N
N
N
H2 40 bar
Rh/Al2O3
2
100%
MeOH, 100°C, 8h
N
1
N
N
N
H2 40 bar
r.t.
p.atm
t1/2= 4h
Rh/Al2O3
N
N
N
H
MeOH, 100°C, 8h
3
3
4
conv. 70%
selectivity 100%
Scheme 1. Reduction outcome of 9- or 1-pyrrolidino-acridine derivatives (1 or 3).

P. Mignon et al. / Journal of Molecular Catalysis A: Chemical 371 (2013) 63–69
65
Table 1
Energies and thermodynamic values of reduction products of compound
5
(kcal/mol).
From compound 5
ꢀE
ꢀH
ꢀG
6
7
8
9
−23.1
−44.2
−84.7
−122.8
−16.7
−31.8
−60.0
−79.3
−8.4
−14.9
−25.9
−18.2
ring. The reduction by H2 over metal/oxide surfaces has been
the subject of several theoretical works, studying the selectivity
brought by the metal nature and/or the oxide support [31–36]. All
the calculations indicate that hydrogenation proceeds through dis-
sociated hydrogen (i.e. atomic H·) which attacks the chemisorbed
substrate over the surface allowing a favourable interaction with
the atomic hydrogen bound to the metal. As a result for compound
9, hydrogen atoms were added in the cis position on the central
ring. The corresponding electronic energies and thermodynamic
values are given in Table 1 and free energy changes are shown in
Fig. 2.
From 5 to 9, the hydrogenation of aromatic molecules leads
to more and more stable compounds (see ꢀE and ꢀH values,
Table 1). From ꢀG values one can see that the formation of each
intermediate is favourable, except for the final product 9. Indeed
from 5 to 8, the change in free energy is negative in the range of
−6 to −10 kcal/mol for each step. From 8, the positive change in
free energy (+7.7 kcal/mol) shows that the formation of 9 is not
favoured, although it is observed experimentally. According to the
experimental conditions, H2 is present at high pressure (40 bar)
which can influence drastically the equilibrium towards 9. More-
over the positive change in free energy suggests that the reduction
from 8 to 9 is less easy than the previous ones. This may explain
why the reaction is delayed and why accumulation of 8 (54% after
1 h, see Fig. 1) is observed before the formation of 9.
Fig. 1. Product distribution as the function of time for the reduction of acridine by
Rh/Al2O3 with H2.
This confirms one of the two suggested mechanisms that were pro-
posed in earlier works [23,27] for catalysis on Pd, Pt or Rh supported
materials.
3.3. Theoretical calculations
In order to understand the reduction mechanism of com-
pounds 1 and 3 we have performed DFT calculations from the
simplest model, the unsubstituted acridine 5 (Fig. 2). For each
intermediate, different isomers can be formed through the hydro-
genation/adsorption process. For the observed compounds 5–9,
all possible structures were computed. In the present work we
have considered that the dominant role of the surface, as discussed
below, consists in a geometrical constraint towards the hydrogena-
tion mechanism by hydrogenation on the same side of the aromatic
Fig. 2. Gas-phase reaction profiles of the reduction of unsubstituted acridine 5. (Gibbs free energies, in kcal/mol) and distances, in Å, of axial hydrogen and pyrrolidine
hydrogen atoms above/below the plane of the aromatic ring.

66
P. Mignon et al. / Journal of Molecular Catalysis A: Chemical 371 (2013) 63–69
Table 2
the intermediate 2 on the catalyst surface and thus prevent the
hydrogenation of the central ring to give product 12 (Fig. 3).
Energies and thermodynamic values of reduction products of compound
(kcal/mol).
1
From compound 1
ꢀE
ꢀH
ꢀG
3.5. Reduction of substituted acridine derivative 3
10
11
2
−23.5
−43.5
−84.0
−111.5
−16.9
−31.5
−59.1
−67.9
−8.3
−13.0
−24.8
−7.3
For compound 3 (Scheme 3) two routes were computed for the
reduction of 4, the only detected intermediate.
12
We distinguish the formation of 13 and 14, depending on
whether the reduction occurs on the substituted aromatic cycle
or not. Energies and thermodynamic values show that after the
formation of compound 4 the reduction would rather lead to
13 than to 14. Thus, the reduction is easier when it occurs on
an unsubstituted aromatic cycle. From 13, the formation of 15
would be favoured, if we considered the ꢀꢀG (6.5 kcal/mol),
but the difference is rather low compared to the ꢀꢀG for 7–8
(11 kcal/mol) and 11–2 (11.8 kcal/mol) (see Tables). Nevertheless,
these data could not explain why products 15 or 16 were not
formed.
In previous theoretical studies on the hydrogenation of aro-
matic molecules the loss of aromaticity or resonance energy,
measured as the change in enthalpy upon addition of H2 on
double bonds, was found to be a measure of the reactivity of the
substrate [41,42]. In the present work the loss in aromaticity,
going from one intermediate to the following one, is quite similar
3.4. Reduction of 1-pyrrolidino substituted acridine 1: theoretical
calculation
The same reduction pathway was considered for the substituted
product 1 even if only intermediates 11 and 2 have been detected
by NMR (Scheme 2).
The reduction reactions are still favourable and lead to stable
compound 11, up to molecule 2. From 2, the formation of 12 is
not favourable at all, the difference between the free energy values
being of +17.5 kcal/mol. This value is 10 kcal/mol higher than the
difference between 8 and 9. Moreover, the electronic energy and
enthalpy values of 12 are about 10 kcal/mol less than those of 9 (see
Tables 1 and 2).
Furthermore, steric interactions between the pyrrolidine sub-
stituent and the external cycles could prevent the adsorption of
N
N
N
N
H
1
10
N
N
N
N
N
N
H
2
12
11
Scheme 2. Reduction of compound 1.
Fig. 3. Gas-phase reaction profiles of the reduction of 9-pyrrolidino substituted acridine 1. (Gibbs free energies, in kcal/mol) and distances, in Å, of axial hydrogen and
pyrrolidine hydrogen atoms above/below the plane of the aromatic ring.

P. Mignon et al. / Journal of Molecular Catalysis A: Chemical 371 (2013) 63–69
67
N
N
N
N
N
N
N
H
N
H
N
N
16
3
4
15
13
N
14
N
Scheme 3. Reduction of compound 3.
for the unsubstituted acridine or the substituted ones, except
for reduction of 2–12. In that case, the resonance energy is only
8.8 kcal/mol (ꢀH, Table 2), as compared to the other molecules
(about 20 kcal/mol; 8–9 and 15–16). Thus molecule 2 is less aro-
matic and less reactive, which can explain why the reduction of 2
into 12 is not observed (Scheme 2). Numerous previous theoretical
studies on the hydrogenation of unsaturated cyclic and non-cyclic
molecules on metal surfaces have been investigated [31–36]. In
all cases on Pt, Pd, Ru–Zn and Ni surfaces the cyclic molecule is
adsorbed on the surface before the hydrogen is being transferred
to the aromatic carbon. Although calculations are performed at the
DFT/GGA level, without a specific exchange-correlation functional
to better describe dispersion forces, it is well established that the
aromatic molecules chemisorb the surface metal atoms via several
carbon atoms. According to the reported mechanisms, the aromatic
molecule is more or less coplanar to the surface and carbon atoms
bind to surface metal atoms before the dissociated hydrogen is
being transferred to the aromatic carbon via cis addition through
the same side of the aromatic ring. The effect of the surface on
the hydrogenation mechanism was respected in our molecular
structure searches. Thus, the unfavourable free energy change
for the hydrogenation from 2 to 12 could be explained by steric
interaction between pyrrolidine and the external cycles (Fig. 3). It
should be noticed that the free energy change is also the highest
observed in our examples (17.5 kcal/mol, Table 2)
On the other hand, the selectivity observed for compound 2 can-
not be simply explained by energy calculations. Thus, we have to
focus on the steric hindrance induced by the pyrrolidine and how
this substituent could modify the chemisorption of the substrates
(Fig. 3).
During the reduction of the unsubtituted acridine 5, hydrogen
˚
atoms lie by about 1.08–1.18 A above the aromatic plane (Fig. 2).
On the contrary, for substituted acridines, the pyrrolidine brings
an important steric hindrance, which prohibits the binding of the
aromatic carbon atoms to the surface and thus the hydrogenation
of the ring. This appears to be clear for compound 1. The pyrroli-
dine prevents the hydrogenation of the central ring and the external
rings of 1 can chemisorb on the surface, leading to 11 and 2 (Fig. 3).
Steric hindrance rather than energy explains that 2 is not reduced
into 12. The same behaviour may be observed for compound 3.
The opposite external ring can be reduced but not the ring carry-
ing the pyrrolidine. Thus in the case of compound 3 the reaction
was stopped to 13 the first intermediate being compound 4 with
the reduced central ring, as expected from Gibbs energy calcula-
tions (Table 3; Fig. 4). From these remarks one may re-examine the
reduction mechanism for compounds 1 and 3.
Fig. 4. Gas-phase reaction profiles of the reduction of 1-pyrrolidino substituted acridine 3. (Gibbs free energies, in kcal/mol) and distances, in Å, of axial hydrogen and
pyrrolidine hydrogen atoms above/below the plane of the aromatic ring.

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P. Mignon et al. / Journal of Molecular Catalysis A: Chemical 371 (2013) 63–69
Table 3
Acknowledgements
Energies and thermodynamic values of reduction products of compound
(kcal/mol).
3
H.C. and P.M. thank the Centre Informatique National de
l’Enseignement Supérieur (CINES) and Grand Equipement National
de Calcul Intensif (GENCI) for computer resources allocation,
project: cpt2130.
M.T. thanks the Ministère Franc¸ ais de l’Enseignement Supérieur
et de la Recherche and P.B. thanks, the “Association pour la
Recherche sur le Cancer” and the “Cluster de Recherche Chimie de
la Région Rhône-Alpes.”
From compound 3
ꢀE
ꢀH
ꢀG
4
−21.7
−37.2
−42.7
−78.3
−119.6
−15.3
−25.1
−30.4
−54.0
−76.4
−7.3
14
13
15
16
−8.5
−13.7
−20.2
−14.4
For compound 1, the reduction of the central ring is excluded
because of the presence of pyrrolidine substituent. As such, com-
pound 10 should not be formed. In that case the hydrogenation
mechanism occurs directly and only on the external rings, following
the pathway described in Scheme 2.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.molcata.2013.01.015.
For compound 3, only compound 4 is observed experimentally
while 13 is not. However 4 is observed to be rapidly re-oxidized
to 3 at normal conditions. This shows that 4 is not stable under
atmospheric conditions although it is showed theoretically to be
stable and its formation favourable. For 13, as compared to 4 it is
an external ring which is hydrogenated. Although it is more stable
and thermodynamically favourable, one might imagine that 13 is
also rapidly rearranged to 4 under atmospheric conditions and then
back to 3. However these hypotheses cannot be answered rigor-
ously from the present results. Additional work would be necessary
in order to assess whether short-living 13 is formed or not, and in
that case if it is very rapidly re-oxidized to 3.
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