Diversion of the Arbuzov reaction: Alkylation of C-Cl instead of phosphonic ester formation on the fullerene cage

Article abstract of DOI:10.1039/c9ob00593e

We report an "inversed" Arbuzov reaction of the fullerene derivatives C₆₀Ar₅Cl with trialkyl phosphites P(OR)₃ producing alkylated fullerene derivatives C₆₀Ar₅R (R = Me, Et, iPr, nBu) with almost quantitative yields. This reaction provides a convenient synthetic route for the preparation of a large variety of functionalized fullerene derivatives with tailored properties, e.g. water-soluble compounds demonstrating promising antiviral activities against HCMV, HSV1, HIV and several influenza virus strains.

Full text of DOI:10.1039/c9ob00593e

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Ershova, V. M. Martynenko, S. Claes, A. A. Kushch, S. Kostyuk, D. Schols, A. F. Shestakov and P. Troshin,
Org. Biomol. Chem., 2019, DOI: 10.1039/C9OB00593E.
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DOI: 10.1039/C9OB00593E
ARTICLE
Diversion of the Arbuzov Reaction: Alkylation of C-Cl Instead of
Phosphonic Ester Formation on the Fullerene Cage
Received 00th January 20xx,
Accepted 00th January 20xx
a,b
c
d
c
Ol’ga A. Kraevaya, Alexander S. Peregudov, Sergey I. Troyanov, Ivan Godovikov, Natalya E.
e
e
f
f
f
Fedorova, Regina R. Klimova, Vasilina A. Sergeeva, Larisa V. Kameneva, Elizaveta S. Ershova,
Vyacheslav M. Martynenko, Sandra Claes, Alla A. Kushch, Svetlana V. Kostyuk, Dominique
DOI: 10.1039/x0xx00000x
b
g
e
f
g
b,h
a,b
Schols, Alexander F. Shestakov and Pavel A. Troshin*
5 3
We report “inversed” Arbuzov reaction of the fullerene derivatives C60Ar Cl with trialkyl phosphites P(OR) producing
alkylated fullerene derivatives C60Ar R (R=Me, Et, iPr, nBu) with almost quantitative yields. This reaction provides a
5
convenient synthetic route for preparation of a big variety of functionalized fullerene derivatives with tailored properties,
e.g. water-soluble compounds demonstrating promising antiviral activities against HCMV, HSV1, HIV and several influenza
virus strains.
Introduction
Chemical functionalization of fullerenes delivered a broad
range of their functional derivatives with valuable properties
Selective arylation of C60Cl
conditions producing C60Ar
reactions reported for halofullerenes. Interestingly, similar
fullerene derivatives C60Ar H can be produced directly from C60
5
and organolithium or organomagnesium reagents in the
6
under Friedel-Crafts reaction
5
Cl compounds was among the first
8
1
and potential for practical application in medicine or
2
electronics. The developed approaches to modification of the
4
2
presence of CuI*Me S as a catalyst. However, the use of
fullerene cage include cycloaddition, radical, nucleophilic and
transition metal-catalyzed addition reactions involving one or
few double bonds on the carbon cage. However, the products
of double, triple or multiple functionalization of the fullerene
sphere formed in these reactions typically represent hardly
separable mixtures of isomers with a few notable exceptions.
The most selective are reactions of radical halogenation of
fullerenes, which proceed under thermodynamic control and
usually produce just a single or very few isomers of the target
highly active organometallic precursors narrows considerably
the range of functional groups, which can be introduced on the
fullerene cage following that approach.
3
Recently, highly selective reactions were also reported for
9
4
chlorofullerene C60Cl
aminoacids, alcohols and hydroxyacids as well as esters of
arylalkylcarboxylic acids,
6
with thiols and thioacids, amines and
1
0
11
1
2
which provided convenient
pathways for preparation of various water-soluble fullerene
derivatives with promising biological activities. Particularly
interesting was the Arbuzov-type reaction of C60Cl
5
6
6
C60 or C70 halides. Among them, chlorofullerene C60Cl is the
6
with
most frequently used precursor for the synthesis of highly
functionalized fullerene derivatives with unique arrangement
of all addends at one hemisphere of the carbon cage.
trialkylphosphites
derivatives C60[PO(OR) ] H. Notable is the fact that only five
2 5
producing
pentaphosphonic
ester
1
3
7
chlorine atoms are replaced with phosphonate addends, while
the sixth undergoes reductive substitution with H due to the
steric hindrances. A similar reaction was reported previously
a. Skolkovo Institute of Science and Technology, Nobel St. 3, Moscow, 143026,
Russia
5 5
for C60Ar Cl (1a-4a) compounds producing C60Ar H (1b-4b)
b.
IPCP RAS, Semenov Prospect 1, Chernogolovka, 141432, Russia
INEOS RAS, Vavylova St. 28, B-334, Moscow, 119991, Russia
Department of Chemistry, Moscow Lomonosov State University, Leninskie gory,
with quantitative yields when treated with Ph P, which is a
3
c.
1
4
commonly used reducing agent.
Here we explored for the first time the reaction of C60Ar
with trialkylphosphites P(OR) and revealed an unusual
pathway: Cl atom is replaced neither with phosphonic ester
residue nor with hydrogen but undergoes a facile substitution
with alkyl groups forming C60Ar R compounds with almost
5
quantitative yields. Similar “inversed” Arbuzov reaction is very
rare and was reported previously for specific substrates such
d.
Moscow, 119991, Russia
Honored Academician N.F.Gamaleya National Research Centre for Epidemiology
5
Cl
e.
3
and Microbiology of the Ministry of Health of the Russian Federation, Gamaleya
st. 18, 123098, Moscow, Russia
Research Centre for Medical Genetics RAMS, Moskvorech’e St. 1, Moscow,
f.
1
15478, Russia
g.
h.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000, Leuven,
Belgium
Faculty of Fundamental Physics & Chemical Engineering, Moscow Lomonosov
State University, GSP 1,1-51 Leninskie Gory, Moscow 119991, Russia
as
hexachlorocyclopentadiene,
1,2,3,4,5-
and
Electronic Supplementary Information (ESI) available: general experimental
procedures, selected crystallographic data for 1c (CCDC 1893318), details of DFT
computational study, biological assays, HPLC profiles, NMR spectra. See
DOI: 10.1039/x0xx00000x
pentachlorocyclopentadiene
hexabromocyclopentadiene. Additionally, alkyl fluorides and
15
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Journal Name
phosphites are known to react with the formation of abnormal Thus, 13C NMR spectra can confidently reveal theVietwypAreticloefOntlhinee
products under Arbuzov conditions. To the best of our substituents attached to the carbon cageD.OI: 10.1039/C9OB00593E
16
knowledge, we report the first examples of very efficient The molecular structure of 1c was revealed unambiguously
“inversed” Arbuzov reaction of the halide R’Cl and using X-ray single crystal diffraction. Top and side views of the
trialkylphosphite P(OR) leading to the formation of a new C-C 1c molecule are shown in Fig. 1. Five residues of methyl ester
3
bond in the target R’-R product on the fullerene cage. This of phenylpropionic acid are attached symmetrically to one
unusual reaction provided a convenient route to the synthesis five-membered ring on fullerene cage. Methyl group is
of a variety of highly functionalized fullerene derivatives as attached to the central pentagon completing the
shown in Scheme 1.
cyclopentadienyl-type framework.
X
X
X
X
X
X
R
Cl
P(OR)3
PhCH3, reflux
X
X
X
X
1a-4a
R = Me (c), Et (d), iPr (e), nBu (f)
X =
1
COOCH3
1
c: 95% 1d: 92% 1e: 80% 1f: 95%
COOCH3
COOCH3
COOCH3
2c: 95% 2d: 94% 2f: 85%
3d: 91%
Figure 1. Two projections of the molecular structure of 1c according to the single
crystal X-ray diffraction data. Hydrogen atoms of organic addends are omitted
for clarity.
2
3
4
4c: 94% 4d: 92%
COOCH3
The revealed in this work “inversed” Arbuzov reaction on the
fullerene cage is exceptionally interesting from the
fundamental point of view. To gain a deeper understanding of
the mechanism of this unique reaction, we performed
COOCH3
Scheme 1. Introduction of alkyl groups on the fullerene cage using the
inversed” Arbuzov reaction.
“
quantum-chemical simulations for the model system “C60Ph
5
Cl
+
P(OMe) ” using the electron density functional method (DFT,
3
see details in ESI).
It was found that C60Ph Cl can interact with P(OMe) and form
5 3
Results and Discussion
The experimental procedure to perform the reaction was quite a complex with much smaller dipole moment (5.0 D) than the
simple. Typically, C60Ar Cl compound was dissolved in a dry sum of the dipole moments of the reagents (7.7 D) due to a
5
toluene together with a large excess of P(OR)
3
(25 eq.) and partial transfer of the electron density from the phosphorous
heated at reflux under inert atmosphere for 1 h.
atom to the fullerene cage despite the large Cl-P distance of
However, introducing bulky isopropyl group proceeds with a 3.40 Å (see Scheme 2). A complete electron transfer produces

-
+
bit lower yield (~80%) due to the formation of 5-12% of the ion pair C Ph Cl P(OMe) , which is short-living due to
6
0
5
3
-
.+
C60Ar
5
H impurity. Moreover, though the reaction of C60Ar
with P(OBu-n) proceeds smoothly and produces C60Ar Bu-n in results in the formation of a radical pair C Ph …СlP(OMe) ,
high yields, the isomeric product C60Ar CH(CH )C
detected as a 5-14% impurity. The observation of this side PСl(OMe) while forming a new C-P bond or undergo the
5
Cl the transfer of Cl anion to the radical cation P(OMe) . This
3


3
5
6
0
5
3
5
3
H
2 5
is which can give either a recombination product C Ph -
60 5
3
-
+
product is important for the discussion of the reaction second charge separation and yield the C Ph …ClP(OMe)
6
0
5
3
mechanism presented below.
High purity of the isolated C60Ar
ion pair. The corresponding recombination product and the ion
R compounds was revealed by pair have almost the same energies of 12.2 and 12.3 kcal/mol,
5
HPLC, while their composition was confirmed by ESI mass respectively, vs. the initial “C Ph Cl + P(OMe) ” state.
6
0
5
3
spectra. Molecular structures of all synthesized fullerene While considering the first route, the C Ph -PСl(OMe)
6
0
5
3
derivatives were proved by 1D and 2D correlation NMR intermediate can undergo elimination of CH Cl with the
3
spectroscopy (Figs. S3-S76, ESI). The alkyl groups attached to formation of the classical Arbuzov reaction product
1
3
the fullerene cage revealed typical chemical shifts in the
C
60 5 2
C Ph PO(OMe) . This monomolecular reaction can proceed
NMR spectra: ~33 ppm (Me); 9 ppm and 33 ppm (Et); 22 ppm through a four-term transition state, which has a high
and 35 ppm (iPr); 14, 22, 27 and 40 ppm (nBu). The signals of activation energy of ~32.2 kcal/mol. Most probably, the first
3
the sp carbon atoms of the fullerene cage bearing alkyl stage is a heterolytic dissociation of the P-Cl bond, which has a
addends R demonstrated very characteristic chemical shifts: more decent activation barrier of 19.4 kcal/mol. However, the
~
62 ppm (R=Me), ~66 ppm (R=Et), ~72ppm (R=iPr) and ~65 specific structure of the intermediate product C Ph -
60 5
ppm (R=nBu). For comparison, similar compounds with PСl(OMe) does not allow for a significant elongation of the P-
3
halogen (R=Cl) or hydrogen (R=H) addends showed chemical Cl bond required for its heterolytic cleavage due to short van
shifts of ~76 ppm and ~63 ppm, respectively (Fig. S77, ESI). der Waals contacts of the Cl atom with neighboring H and C
2
| J. Name., 2012, 00, 1-3
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atoms (2.7 and 3.9 A). Thus, the steric hindrances induced by While considering possible practical applicatiVoienwsArtioclfe Ontlhinee
the phenyl substituents surrounding the chlorine atom block revealed reaction, we explored its poteDnOtiIa:l10f.o10r3t9h/Ce9sOyBn0t0h5e9s3iEs
the classical pathway of the Arbuzov reaction.
of a variety of water-soluble fullerene derivatives, which might
demonstrate interesting biological properties. Indeed,
Following the second route, the intermediate ion pair C60Ph -
5
+
…
ClP(OMe)
3
can undergo a transfer of the methyl cation to compounds 1-4 comprise protected carboxylic groups, which
-
C60Ph
5
, which requires just a very little activation energy of 1.3 were released by acidic hydrolysis of methyl esters following
1
2
kcal/mol. The structure of the corresponding early transition the previously reported procedure. The corresponding
state is shown in Fig. 2. The transfer of the methyl cation polycarboxylic fullerene-based acids A1-A4 were obtained in
2 5
results in the formation of ClP(O)(OMe) and C60Ph Me, which quantitative yields (Figure 3). Molecular compositions and
are the products of the “inversed” Arbuzov reaction reveled in structures of the synthesized compounds were confirmed by
this work.
1D and 2D NMR spectra. The potassium salts of the prepared
polycarboxylic fullerene acids showed high solubility in water
(>300 mg/ml) in combination with an excellent stability of
aqueous solutions, which enabled us to perform a range of
biological studies on these compounds.
classical Arbuzov product
C60Ph P(O)(OR)2
5
elimination of RCl
C60Ph (P(OR) Cl)
5
3
COOH
COOH
COOH
recombination
C60Ph Cl
[C60Ph Cl]
5
5
SET
+
+
[C60Ph ] + [P(OR) Cl]
COOH
COOH
COOH
5
3
HOOC
HOOC
HOOC
P(OR)3
[P(OR)3]
R
R
SET
C60Ph ] + [P(OR) Cl]
[
5
3
COOH
COOH
HOOC
HOOC
COOH
HOOC
A1c-f
A2c-d, A2f
R= Me (c), Et (d), nBu (f)
C60Ph R + P(O)(OR) Cl
R= Me (c), Et (d), iPr (e), nBu (f)
5
2
Scheme 2. Proposed mechanism of the “inversed” Arbuzov reaction.
COOH
COOH
COOH
The proposed mechanism involving transfer of the alkyl cation
is experimentally supported by the isolation of the side
HOOC
HOOC
COOH
COOH
HOOC
COOH
R
R
5 3 2 5
product with the secondary butyl group C60Ar CH(CH )C H in
the reaction of C60Ar
5
Cl with P(OBu-n)
3
. It is known that the
+
COOH
COOH
HOOC
secondary butyl cation (C
primary one (CH CH CH CH
for the isomerization. Moreover, since the addition of bulky
2
H
5
+
(CH
3
)CH ) is more stable than the
HOOC
HOOC
HOOC
A3d R= Et
A4c-d
R= Me (c), Et (d)
3
2
2
2
), which provides a driving force
Figure 3. Molecular structures of the synthesized polycarboxylic fullerene-based
acids A1-A4
+
-
(
CH
hindrance, it can undergo elimination of proton leading to the
formation of propylene CH CH=CH and experimentally
isolated C60Ar H. Additionally, the reaction of compound 1a
with P(OPh) leads to the formation of a complex mixture of
products, where the expected C60Ar Ph is identified by mass
3 2 5
) CH cation to C60Ph occurs under a strong steric
First, we explored the toxicity effects induced by two similar
fullerene derivatives A2a (R=Cl) and A2c (R=Me) in human
embryonic lung fibroblasts (HELFs). Compound A2a in
concentration of 0.3-30 µg/mL induces DNA damage while
increasing the amount of double strand breaks by 50-280%
within 1 h after the addition of the fullerene derivative to the
cells. Within 3 h, the amount of γ-foci returns to the control
levels due to the activation of the reparation system:
expression of BRCA1 and BRCA2 genes is increased by 100-
3
2
5
3
5
spectrometry (Fig. S78-79, ESI). To summarize, the results of
the presented theoretical calculations and the obtained
experimental data provide a strong evidence for the proposed
mechanism of the “inversed” Arbuzov reaction.
2
50% and BRCA1 protein level increases by and order of
magnitude (6-14-fold). At the same time, DNA damage
activates apoptosis as revealed by staining with Annexin V and
propidium iodide, while the total number of the cells in the
population decreases. Expression of the pro-apoptotic ВАХ
gene increases by 50-150%, while the activity of anti-apoptotic
BCL2 gene remains on the level of control.
Fullerene derivative A2c in concentration of 0.3-30 µg/mL does
not induce DNA breaks in HELF: expression of BRCA1 and
BRCA2 genes and BRCA1 protein level remain unaffected.
Interestingly, within 1 h after addition A2c, the anti-apoptotic
Figure 2. DFT computed structure of the transition state showing the methyl BCL2 gene expression is elevated by 200-400% vs. control. The
+
-
3 5
cation transfer from ClP(OMe) to C60Ph in the “inversed” Arbuzov reaction
level of the BCL2 protein becomes increased by 440-600%,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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while the expression ratio of anti-apoptotic BCL2 to pro- being few times more active against this viVrieuwsArtsiculebOtynlpinee
apoptotic ВАХ genes increases by almost an order of compared to the commercial drugs suchDOaIs: 1z0a.1n0a3m9/Civ9irOB(E0C0 55 09 =33E
magnitude (6-7-fold). These findings clearly indicate that A2c µM) and amantadine (EC50=1.3 µM). Interestingly, compound
inhibits apoptosis in HELF cells.
A2a inhibited three different influenza subtypes with the
The obtained results evidence that a minor modification of the comparable or superior efficiency to the commercial antiviral
chemical structure of the fullerene derivative by replacing Cl in drugs (Table S5, ESI).
A2a with CH in A2c changes completely the action of these Human immunodeficiency virus type-1 (HIV-1 strain NL4.3
3
compounds on HELF cells: A2a behaves as inductor of CXCR-4-tropic and HIV-1 strain BaL, CCR5-tropic) replication
apoptosis, while A2c is a strong suppressor of the apoptotic was inhibited efficiently by a series of compounds A1a-d and
cell death (Fig. S80 ESI).
A2a-d (Table S6, ESI). However, for compounds A2a-d the
Water-soluble fullerene derivatives are known as potent effective EC50 dose was remarkably decreased from 990 nM for
antiviral agents inhibiting viral enzymes such as human A2a (R=Cl) to 150-160 nM for A2c-d (R=Me or Et, Table 1)
1
7
immunodeficiency
virus
(HIV)
protease,
reverse against HIV-1 NL4.3 replication. This example provides an
transcriptase,18 integrase and envelope glycoprotein gp120.
19
additional illustration of the enhanced antiviral activity of the
Recently, we have shown that fullerene derivatives can fullerene derivative induced by the alkyl groups attached to
2
0
effectively inhibit herpesviral infections.
Reported the fullerene cage. The active EC50 concentrations of 150-160
mechanisms of anti-influenza activity of the fullerene nM reported here are within the best results achieved so far
2
1
derivatives include inhibition of neuraminidase and RNA- for the fullerene-based anti-HIV agents.
2
2
polymerase of influenza viruses.
In this work, we have explored antiviral activity of the
synthesized water-soluble fullerene derivatives in vitro to
Table 1. Anti-influenza and anti-HIV activities of several selected water-soluble
reveal how the modification of their chemical structure affects fullerene derivatives
their biological properties. Results of the screening against
Herpes simplex virus (HSV1) and human cytomegalovirus
Comp.
Activity against
Influenza A/H3N2
Comp.
Activity against
HIV-1 NL4.3WT,
EC50, µM
(
HCMV) are presented in detail in ESI. Briefly, all evaluated
compounds have low cytotoxicity in HSV-sensitive Vero cells
50% cytotoxic doses CC50 in the range from 125 to 2100
µg/mL, Tables S1) and in HCMV-sensitive HELF cells (CC50 = 225
1331 µg/mL, Tables S2). The antiviral activity of the
A/HK/7/87, EC50
,
µM
>100
>100
0.5
(
A1a
A1b
A1c
A1d
A2a
A2b
A2c
A2d
0.99
0.35
0.15
0.16
-
compounds was explored in vitro with the schemes
modulating the microbicidal, virulicidal, prophylactic and
therapeutic actions in vivo, and the obtained results showed
no clear correlations with the chemical structures of the
fullerene derivatives. In particular, many compounds showed
effective concentrations EC50 (at which the virus pathogenic
activity is suppressed by 50% vs. untreated virus-infected cells)
in the range of 1-5 µg/mL. The highest selectivity indexes
0.1
Experimental Section
General procedure for the synthesis of С60Ar
c-d.
5
R derivatives 1c-f to
4
(SI=CC50/EC50) of 120-180 were reached in at least two
different schemes of HCMV inhibition for compounds A1c and A triple-neck round-bottom 50 mL flask equipped with a
o
A3a (Table S3). While targeting to HSV1, compounds A3b and magnetic stirring bar, thermometer (0-150 C), stopper and
A4c delivered impressive selectivity indexes of 340-380, while condenser was evacuated and filled with argon three times.
compound A3d was active in all schemes of application Compound С Ar Cl (0.07 mmol) and dry toluene (50 mL) were
6
0
5
delivering the highest SI=259 in a prophylactic scheme. It introduced to the flask in a steam of argon and the mixture
should be emphasized that reaching SI>100 for a certain was stirred for 10 min until complete dissolution of С Ar Cl.
6
0
5
compound is generally considered as a highly positive Phosphite P(OR) (1.75 mmol, 25 eq.) was added in a steam of
3
screening result and the compound can be further explored as argon and reaction mixture was heated at reflux and stirred for
a potential antiviral drug. Therefore, the observed antiviral 1h. Dynamics of the reaction was controlled by HPLC. When
activities against HSV1 and HCMV can be considered as very the signal of С Ar Cl was not observed by HPLC, reaction
6
0
5
promising.
mixture was cooled to room temperature and poured on the
Screening of the fullerene derivatives A1a-d against Influenza top of the silica gel column. The target product was eluted
A H3N2 virus subtype provided quite spectacular results (Table using toluene/methanol mixtures (97-90% : 3-10% v/v). The
1
). The most active were compounds A1d and A1c with alkyl obtained solutions were concentrated at the rotary
groups attached to the fullerene cage (R=Et and Me, evaporator, washed with acetonitrile and dried in air.
respectively), while the fullerene derivatives A1a (R=Cl) and Compounds С Ar R (1c-f, 2c,d,f, 3d and 4c-d) were obtained
6
0
5
A1b (R=H) were completely inactive. It should be emphasized as bright-orange powders.
that A1c-d inhibited influenza virus efficiently in nanomolar General procedure for the synthesis of polycarboxylic acids A1a-f
concentrations (EC50 of 500 and 100 nM, respectively), thus to A4a-d.
4
| J. Name., 2012, 00, 1-3
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Compounds A1(a-f), A2(a-d,f), A3(a,b,d) and A4(a,c,d) were This work was supported by the the Ministry forViSewciAernticcleeOanlninde
synthesized according to the following procedure. Fullerene Education (project No. 0089-2019-0010D).OAI:t10t.h10e39s/tCa9gOeB0o0f5t9h3eE
derivative С60Ar X (Х=H, Cl, Me, Et, iPr, nBu) (0.07 mmol), revision, this work was also supported by Russian Science
5
toluene (25 mL), acetic acid (25 mL) and HCl (5 ml) were Foundation (grant No. 19-13-00411).
introduced into a two-necked round bottom 100mL flask
equipped with
a teflon-coated magnetic stirring bar,
o
Notes and references
condenser and thermometer (0-100 C). The mixture was
o
stirred at 65-70 C for 3-4 days and concentrated using a rotary
1
P. Anilkumar, F. Lu, L. Cao, P.G. Luo, J.-H. Liu, S. Sahu, K.N.
Tackett, Y. Wang and Y.-P. Sun, Curr. Med. Chem., 2011, 18,
evaporator to afford an orange powder, which was washed
with acetonitrile and dried in air. Water-soluble salts of the
fullerene derivatives were obtained as follows. Fullerene-
based polycarboxylic acid (0.07 mmol), distilled water (20 mL)
and stoichiometric amount of anhydrous potassium carbonate
2
2
045; I. Nierengarten and J.-F. Nierengarten, Chem. Asian J.,
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Cl with
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There are no conflicts to declare.
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Organic & Biomolecular Chemistry
Table of contents:
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DOI: 10.1039/C9OB00593E
We report unusual “inversed” Arbuzov reaction of the pentasubstituted fullerene derivatives C Ar Cl
6
0
5
with trialkyl phosphites P(OR) producing alkylated fullerene derivatives C Ar R with an excellent
3
60
5
selectivity.