Mechanochemical Friedel-crafts acylations

Article abstract of DOI:10.3762/bjoc.15.130

Friedel-Crafts (FC) acylation reactions were exploited in the preparation of ketone-functionalized aromatics. Environmentally more friendly, solvent-free mechanochemical reaction conditions of this industrially important reaction were developed. Reaction parameters such as FC catalyst, time, ratio of reagents and milling support were studied to establish the optimal reaction conditions. The scope of the reaction was explored by employment of different aromatic hydrocarbons in conjunction with anhydrides and acylation reagents. It was shown that certain FC-reactive aromatics could be effectively functionalized by FC acylations carried out under ball-milling conditions without the presence of a solvent. The reaction mechanism was studied by in situ Raman and ex situ IR spectroscopy.

Full text of DOI:10.3762/bjoc.15.130

Mechanochemical Friedel–Crafts acylations
Mateja Đud, Anamarija Briš, Iva Jušinski, Davor Gracin and Davor Margetić*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1313–1320.
Ruđer Bošković Institute, Bijenička cesta 54, HR-10002 Zagreb,
doi:10.3762/bjoc.15.130
Croatia
Received: 22 February 2019
Accepted: 24 May 2019
Published: 17 June 2019
Email:
Davor Margetić* - margetid@irb.hr
* Corresponding author
This article is part of the thematic issue "Mechanochemistry II" and is
dedicated to Professor Koichi Komatsu on the occasion of his 77th
birthday.
§ Tel.: +385-1-468-0197; fax: +385-1-456-1008
Keywords:
ball milling; Friedel–Crafts reaction; mechanochemistry
Guest Editor: J. G. Hernández
© 2019 Đud et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Friedel–Crafts (FC) acylation reactions were exploited in the preparation of ketone-functionalized aromatics. Environmentally more
friendly, solvent-free mechanochemical reaction conditions of this industrially important reaction were developed. Reaction param-
eters such as FC catalyst, time, ratio of reagents and milling support were studied to establish the optimal reaction conditions. The
scope of the reaction was explored by employment of different aromatic hydrocarbons in conjunction with anhydrides and acyl-
ation reagents. It was shown that certain FC-reactive aromatics could be effectively functionalized by FC acylations carried out
under ball-milling conditions without the presence of a solvent. The reaction mechanism was studied by in situ Raman and ex situ
IR spectroscopy.
Introduction
The Friedel–Crafts reaction (FCR) is a very powerful tool in tions which are carried out in solid state by mortar and pestle
organic chemistry for the synthesis of aromatic ketones. It is of [3-5]. We are aware of only a few examples of FCRs employ-
great industrial importance and widely used in fine chemicals ing manual grinding: reserpine acylation with AlCl3 [6] and
production [1,2]. In recent years, public awareness of the nega- acylation reaction of aromatics [7]. One of the reasons for this
tive impact of chemical processes on the environment insti- scarcity is the hygroscopic nature of the aluminum trichloride
gates chemists to improve processes by the reduction of waste catalyst [8-12] when exposed to air humidity. This problem
material, energy consumption and reagents (materials). In this could be easily avoided by conducting the reaction in a closed
respect, carrying out FCR at room temperature without the use vessel, by the aid of automated ball milling, which became a
of solvents, which are usually highly toxic (halogenated hydro- very effective synthetic method in recent time [13-18]. The first
carbons) will improve the eco-friendliness of the process. Until account on mechanochemical FC alkylation by Borchardt [19]
now, FCRs have been rarely applied to organic functionaliza- demonstrates the utility of the mechanochemical method in the
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synthesis of covalent triazine frameworks. Herein, we report
related results on solvent-free FC acylation reactions conducted
in a ball mill, which is the continuation of our program in
organic mechanosynthesis [20-24].
Table 1: Reaction of pyrene with phthalic anhydridea.
Entry Conditions
Work-upb
Yield (%)c
1
1 h
B
78
2
1 h, ratio 1:1:1
1 h
A
44
Results and Discussion
3
A
76
Mechanochemical FCR of pyrene (1) and phthalic anhydride (2)
producing 1-(o-carboxybenzoyl)pyrene (3) was selected for the
optimization of reaction conditions since all reagents and cata-
lyst are solids (Scheme 1, Table 1) [25]. In solution, this reac-
tion is facile and the product could be obtained in quantitative
yield (Table 1, entry 15). The results on optimization of reac-
tion conditions in the ball mill indicate that FC acylation could
be effectively carried out mechanochemically. The best
mechanochemical reaction conditions (Table 1, entry 4): 2 h,
equimolar amount of phthalic anhydride and 2.5 equivalents of
AlCl3, afforded product 3 in high yield (79%). Identical yields
were obtained by the change of reaction time to 1 h and alterna-
tive work-up procedures (Table 1, entries 1 and 4). When the
catalyst amount was decreased to one equivalent, a significant
decrease of yield was attained (Table 1, entry 2). Addition of
various grinding additives to improve mass transfer and prevent
pasting of the reaction mixture [26-28] (Table 1, entries 5–8)
was detrimental to reaction yields. The addition of a small
amount of solvents which was reported to facilitate several ball
milling reactions (liquid assisted grinding, LAG) [29-32], also
decreased yields (Table 1, entries 9 and 10). The reaction
carried out in a planetary mill (Table 1, entry 11) afforded
yields comparable to the MM400 vibrational mill. We have also
performed screening of efficacy of various Lewis acid catalysts
[33-38] (Table 1, entries 18–23), which did not lead to forma-
tion of products.
4
2 h
A
A
79
5
1 h, silicagel 1 g
1 h, dry silicagel 0.5 g
1 h, dry NaCl 0.5 g
1 h, dry Na2SO4 0.5 g
1 h, LAG dry DCM
1 h, LAG dry THF
1 h, planetary milld
1 h, teflon jar
n.r.
42
6
A
7
A
37
8
A
43
9
A
51
10
11
12
13
14
15
16
17
A
16
A
79
A
71
3 h, reflux, dry DCM
1 h, reflux, dry DCM
1 h, reflux, dry DCM
1 h, rt, dry DCM
B
94 [39]
98
B
A
83
A
99
10 min, melt, 180 °C,
dry NaCl
C [40]
n.r.e
18
19
20
21
22
23
24
1 h, FeCl3
1 h, ZnCl2
1 h, ZnI2
A
A
A
A
A
A
A
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
73f
1 h, ZnBr2
1 h, CuBr2
1 h, CuCl2
3 h, scale-up
aRetsch MM400 ball mill, 16 mL stainless steel vial, 1 × 12 mm stain-
less steel ball, 30 Hz, substrate/anhydride/AlCl3 ratio 1:1:2.5; bWork-up
A: mixture suspended in H2O, pH adjusted with conc. HCl, chromatog-
raphy; work-up B: identical to work-up A, but recrystallisation from
AcOH instead of chromatography; work-up C: suspended in aq oxalic
acid, extracted with DCM, chromatography; cisolated yields; dRetsch
planetary ball mill PM-200, 500 rpm, 25 mL stainless steel vial,
30 × 3 mm steel balls; emelted in open flask; fscaled up to 500 mg of
pyrene.
variety of aromatic substrates was subjected to FC acylation
(Scheme 3).
Acylation reagents shown in Scheme 2 were less reactive in
comparison to phthalic anhydride. Benzoic anhydride was used
as a substitute for benzoyl chloride and the reaction proceeded
in better yield. The observed disparity in reactivity might be as-
sociated with the difference in the physical state of the reagents.
Furthermore, succinic anhydride poorly reacted with pyrene,
Scheme 1: FCR of pyrene and phthalic anhydride.
Experiments collected in Table 1 demonstrate that a FC acyl- but the reaction proceeds well with the more reactive biphenyl
ation reaction could be effectively carried out under ball-milling (69%, see Supporting Information File 1). Di-tert-butyl dicar-
conditions at room temperature without the use of solvent. This bonate and 4-nitrobenzoyl chloride were unreactive under ball-
reaction could be easily scaled up from 94 to 500 mg of pyrene milling conditions. Similary unreactive was 4-nitrophthalic an-
without the decrease in yield (Table 1, entry 24) [41,42]. To in- hydride, which only in forced conditions (by melting at 200 °C)
vestigate the scope of the reaction, several acylation reagents reacted sluggishly with pyrene affording mixture of regioiso-
were employed in conjunction with pyrene (Scheme 2) and a meric products 6 and 7. The advantage of the employment of
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Scheme 2: Scope of acylation reagents in FCR under mechanochemical activation conditions and comparison with other reaction conditions (isolat-
ed yields); aconversion from NMR analysis; bsolution reaction in flask, substrate/acylation reagent/AlCl3 ratio is 1:1:2.5; ball-milling details are given in
Table 1.
Scheme 3: Scope of aromatic substrates in FCR under mechanochemical activation conditions. aIsolated yields.
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mechanochemical conditions is evidenced by solid state milling reaction of milling of photodimer 19 itself for 1 h was con-
of pyrene with succinic anhydride which showed remarkably verted to anthracene in 95% yield. This [4π + 4π] cyclorever-
better performance than the reaction carried out in solution sion in mechanochemical conditions is analogous to previously
(40% vs 6% yield).
described dissociation of labile anthracene/C60 cycloadduct
[52]. When the reaction of 19 with 20 was carried out in solu-
The screening of substrates showed disparate reactivities, tion (DCM, overnight), 60% of dimer was converted to
ranging from quantitative to low (Scheme 3). Most rewarding anthracene, and traces of FC product 22 were observed. Further
are reactions of toluene, o-xylene, naphthalene and tetralin. attempts were made to lower the reaction temperature by
Interestingly, ball milling of 4-ethylanisole provided phenol 12, cryomilling [53] (reaction vessel was cooled down by dipping
in which acylation was accompanied with the cleavage of the into liquid nitrogen every 3–5 min, and ball milled for 30 min in
methoxy group [43-45]. A striking advantage of the automated total). This procedure partially suppressed cycloreversion and
ball milling over manual grinding [46] is evident in the reaction led to the mixture of 19 and 18 (3:2 ratio), accompanied with a
of anthracene with phthalic anhydride which gave no product small amount of 22.
by manual grinding and the yield of the toluene reaction is in-
creased from 68% to 92%.
As a substitute for dianthracene 19, thermally more stable sub-
strate, anthracene-N-methyl maleimide adduct 25 [54] was pre-
When anthracene was subjected to a milling reaction with pared by Diels–Alder reaction under high pressure conditions as
succinic anhydride, 9-substituted product 22 was obtained in well as by microwave-assisted reaction and mechanochemi-
low yield, and accompanied with a small amount of 2-acylated cally (Scheme 5). In this molecule, N-methylmaleimide could
product 23 (Scheme 4), with same regioselectivity to that re- be used as protection of the 9,10-positions of anthracene and
ported in the literature [47,48]. FC acylation at the 2-position of then removed by FVP. We thought that the maleimide moiety
anthracene was achieved by Levy by the employment of 9,10- will not be affected in the FC acylation, since the precedencies
dihydroanthracene and subsequent oxidation to anthracene. To exist in the literature on imide moiety withstanding the FC reac-
direct the acylation towards the 2-position, we devised the use tion [55,56]. However, mechanochemical reaction of 25 with
of anthracene photodimer 19 [49] for the protection of 9,10-po- succinic anhydride and 2.5 equiv of AlCl3 showed no reaction
sitions. The photodimer would act as 9,10-dihydroanthracene, and the increase of the excess of catalyst to 5 equiv gave a very
and 2-acylated product should be regioselectively formed, complex mixture.
which could be converted by thermal retrocyclization via flash
vacuum pyrolysis (FVP) [50,51] to 23. However, ball milling of Phthaloyl chloride was applied in mechanochemical FCR with
19 with 20 provided 95% conversion of 19 to anthracene, with a the goal of obtaining a double reaction leading to the anthra-
small amount (<5%) of 22. This result indicates that rapid quinone core in a single reaction pot in solid state [57,58].
[4π – 4π] cycloreversion of 19 takes place, even in solid state Indeed, milling of p-xylene, AlCl3 and phthaloyl chloride led to
ball-milling conditions at room temperature. Produced the formation of a mixture of 10 and intramolecular FC product
anthracene then subsequently participates in FCR. In control 29 [59] in a 1:3 ratio (Scheme 6). The ratio of 1,4-dimethylan-
Scheme 4: Mechanochemical regiodirected FCR of anthracene dimer and succinic anhydride.
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Beilstein J. Org. Chem. 2019, 15, 1313–1320.
Scheme 5: Regioselectivity direction by protection of 9,10-anthracene ring positions.
ppm), and concurrent appearance of singlet for H-3 at δ 9.1
ppm. These experiments demonstrate that quinones could be
prepared by simple one-pot FC protocols in the case of reactive
aromatics.
In situ Raman spectroscopy [60] was applied to study mecha-
nistic aspects of the solid state reaction of phthalic anhydride
with p-xylene. Raman spectra were simulated and positions of
signals for transient reactive intermediates were predicted by
density functional theory method B3LYP/6-31G* (Supporting
Information File 1) [61]. The stretching of the +C≡O bond of
the acylium ion was predicted to be at about 2300 cm−1. Raman
spectroscopy revealed that the complexation of phthalic an-
hydride with AlCl3 is rapid, and within 3 minutes of milling all
anhydride is consumed (Figure 1). After 3 minutes of milling,
high fluorescence prevents further following of the reaction
progress. These spectra indicate that rapid complexation of an-
hydride with AlCl3 takes place, whereas the formation of the
acylium ion intermediate could not be unequivocally verified.
Scheme 6: Double FCR of phthaloyl chloride and aromatics.
Similar conclusions could be drawn from ex situ IR spectrosco-
thraquinone (29) did not increase in the presence of 5 equiva- py [62] which indicates rapid complexation and disappearance
lents of AlCl3. Formation and ratio of these two products could of phthalic anhydride (Supporting Information File 1, Figures
be conveniently established by 1H NMR analysis, due to a S43 and S44). A further study was carried on complexation of
difference in the symmetry of products: there are two methyl phthalic anhydride with AlCl3 (Supporting Information File 1,
signals for 10 and a single methyl line at δ 2.81 ppm in the case Figure S45). Although there are weak signals at 2300 and
of 29. Pyrene and naphthalene were less reactive under the 3050 cm−1 which could be associated with the acylium ion and
same ball milling conditions and reactions stopped at the stage the intermediate cation, the raise of intensities of these signals
of formation of product 3 and 15. One-step preparation of over the time is quite unlikely to come from reactive species
quinone 30 [39], was achieved by melting reactants at 140 °C (time needed to transfer sample from ball mill to IR spectropho-
for 10 min. Under these conditions, a mixture of adducts 3 and tometer and acquire spectra are within several minutes, which
30 (1.5:1 ratio) was obtained. The product ratio was established could be detrimental to reactive species to survive in the open
by 1H NMR analysis of the characteristic H-10 proton signal of air). These signals are not visible after the standard acidic work-
product 3 (peak resonance doublet at δ 9.2 ppm), which is up and further study would require the use of in situ IR spec-
shifted towards lower magnetic field in quinone 30 (δ 10.0 troscopy in solution [63].
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Beilstein J. Org. Chem. 2019, 15, 1313–1320.
Figure 1: In situ Raman monitoring of reaction of phthalic anhydride with p-xylene.
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In conclusion, the experimental results demonstrate that
Friedel–Crafts acylations could be effectively carried out under
solid state ball-milling conditions. The reaction takes place by
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We acknowledge the financial support of the Ministry of
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