BiCl3-Facilitated removal of methoxymethyl-ether/ester derivatives and DFT study of -O-C-O- bond cleavage

Article abstract of DOI:10.1039/d1nj00449b

A simple method for the cleavage of methoxymethyl (MOM)-ether and ester derivatives using bismuth trichloride (BiCl₃) is described. The alkyl, alkenyl, alkynyl, benzyl and anthracene MOM ether derivatives, as well as MOM esters of both aliphatic and aromatic carboxylic acids, were deprotected in good yields. To better understand the molecular roles of BiCl₃and water for MOM cleavage, two possible binding pathways were investigated using the density functional theory (DFT) method. The theoretical results indicate the differential initial binding site preferences of phenolic and alcoholic MOM substrates to the Bi atom and suggest that water plays a key role in facilitating the cleavage of the MOM group.

Full text of DOI:10.1039/d1nj00449b

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PAPER
BiCl3-Facilitated removal of methoxymethyl-
ether/ester derivatives and DFT study
of –O–C–O– bond cleavage†
Cite this: New J. Chem., 2021,
45, 7109
a
b
Angela Pacherille,a Beza Tuga,
Dhanashree Hallooman,
Isaac Dos Reis,a
Melodie Vermette,c Bilkiss B. Issack,c Lydia Rhyman,bd Ponnadurai Ramasami
*
bd
´
a
and Rajesh Sunasee
*
A simple method for the cleavage of methoxymethyl (MOM)-ether and ester derivatives using bismuth
trichloride (BiCl3) is described. The alkyl, alkenyl, alkynyl, benzyl and anthracene MOM ether derivatives,
as well as MOM esters of both aliphatic and aromatic carboxylic acids, were deprotected in good yields.
To better understand the molecular roles of BiCl3 and water for MOM cleavage, two possible binding
pathways were investigated using the density functional theory (DFT) method. The theoretical results
indicate the differential initial binding site preferences of phenolic and alcoholic MOM substrates to the
Bi atom and suggest that water plays a key role in facilitating the cleavage of the MOM group.
Received 27th January 2021,
Accepted 16th March 2021
DOI: 10.1039/d1nj00449b
rsc.li/njc
environmentally friendly, inexpensive, commercially available
alternatives for the development of simple synthetic methodologies
1. Introduction
The methoxymethyl (MOM) moiety is a well-known protecting for the scale-up processes and industrial applications is ongoing. In
group for the hydroxyl functionality of alcohols and phenols this respect, one such emerging reagent is bismuth(III) salts
due to its high stability under basic conditions and ease of which have recently been employed in a number of organic
installation.1 In addition to its main use as a protecting group transformations.7 Bismuth is the 83rd element (Group 15) and
in numerous complex natural product syntheses, a recent study the heaviest stable element in the periodic table. Although its
has shown that the protection of the hydroxyl group of Salvi- neighbouring elements such as arsenic, antimony, lead and tin,
norin B as MOM ethers affords highly potent k opioid receptor are known toxicants, bismuth and several of its compounds are
agonists.2 While the MOM protection is a crucial step, the well known to be non-toxic. For instance, salts such as bismuth
cleavage of the MOM moiety under mild reaction conditions is oxychloride and bismuth oxide have median lethal doses (LD50,
required to release the free hydroxyl group. A variety of reagents murine, oral) that are well above that of sodium chloride.8 As a
have been developed for the cleavage of the MOM group, and result, bismuth and its compounds have found wide applications
these reagents can be categorized as Lewis acids,3 Brønsted in medicinal chemistry.9 While bismuth salts have been extensively
acids,4 and solid catalysts,5 among several others.6 However, used as green catalysts in a plethora of organic reactions, the
some of these reagents are difficult to handle, and quite mechanism of bismuth mediated reactions is poorly understood.
corrosive and toxic in nature. Therefore, the search for Our continued interest in exploring bismuth trichloride (BiCl3) as
an effective non-toxic reagent in organic transformations10,11 led us
a Department of Chemistry, State University of New York at Plattsburgh,
Plattsburgh, New York, 12901, USA. E-mail: rajesh.sunasee@plattsburgh.edu
b Computational Chemistry Group, Department of Chemistry, Faculty of Science,
to recently investigate the cleavage of phenolic methoxymethyl
(MOM) ethers mediated by BiCl3.12 These reactions proceeded well
in high yields with 30 mol% of BiCl3 in wet MeCN at 50 1C for
several substituted phenolic MOM ethers (Scheme 1). The cleavage
method was amenable to phenolic substrates having substituent
groups, such as benzyl, nitrile, ester, aldehyde, and the chiral
BINOL molecule.12
To gain insights into the role of water from the solvent
system used in the deprotection reaction, we had previously
investigated the possibility that the in situ HCl generated from
BiCl3 could be responsible for the MOM hydrolysis.12 A control
experiment was performed in which the deprotection of
´
University of Mauritius, Reduit 80837, Mauritius.
E-mail: p.ramasami@uom.ac.mu
c
´
´
´
Departement des Sciences Experimentales, Universite de Saint-Boniface,
Winnipeg, R2H 0H7, Canada
d Department of Chemical Sciences, University of Johannesburg, Doornfontein,
Johannesburg 2028, South Africa
† Electronic supplementary information (ESI) available: Experimental procedure
and characterization data for MOM protection and deprotection products.
1H NMR and 13C NMR spectra of MOM ethers and esters and deprotected
products. Computational data for compounds 19, 20, 21, 22, 2a and 3a. See
DOI: 10.1039/d1nj00449b
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Table 1 Cleavage of alcoholic MOM ethers (BiCl3 (100 mol%) in MeCN–
H2O (5 : 0.1 v/v) at 50 1C)
Time
(h)
Yieldb
(%)
Entry Substrate
1
Producta
12
8
79
84
Scheme 1 BiCl3-Mediated cleavage of phenolic MOM ethers.
2
3
phenolic MOM ether 19 was carried out in the presence of an
equivalent amount of HCl instead of BiCl3. The cleavage of the
MOM ether 19 was observed to proceed providing a lower yield
(64%) than with BiCl3 (95%),12 suggesting that hydrolysis by
HCl is unlikely to play a determining role in the BiCl3-mediated
cleavage of the MOM group. Rather, the observation points out
that BiCl3 as well as the solvent system play a key role in the
deprotection of the MOM moiety.
5
3
3
88
78
81
4
5
In this work, we herein report for the first time the deprotec-
tion of a variety of alcoholic MOM ethers as well as carboxylic
MOM esters in the presence of bismuth chloride. In addition,
we present the findings of DFT studies investigating the mole-
cular role of BiCl3 in the key carbon–oxygen bond breaking of
the MOM ether group (–O–C–O–). Finally, results of the DFT
calculations probing the role of water in the reaction medium
are presented, attempting to shed light on our previously
reported experimental observation that deprotection yields
were higher in the binary MeCN/water system compared to
the neat solvent.12
6
4
78
7
2
3
2
6
85
85
75
82
8
9
10
2. Results and discussion
2.1. Cleavage of MOM-ether and ester derivatives
11
10
3
88
92
We explored the cleavage of a variety of alcohol protected MOM
ethers under the optimized BiCl3 mediated cleavage conditions
(30 mol% of BiCl3, 5 : 0.1 v/v MeCN/H2O, and 50 1C) developed
for phenolic ethers. However, we found that the deprotection of
1a was slow and proceeded in low yield (38% isolated yield).
Increasing the amount of BiCl3 to 50 mol% did not improve the
deprotection yield but when 100 mol% BiCl3 was used, com-
plete conversion of 1a, as monitored by TLC, was observed to
afford the desired alcohol 1b in 79% yield (Table 1, entry 1). The
deprotection of a series of alcoholic MOM ethers was next
examined using 100 mol% BiCl3 as depicted in Table 1.
Primary, secondary and tertiary alkanol MOM ethers were
cleaved in good yields (entries 1–7). The BiCl3 deprotection
protocol also worked well for alkenyl (entries 6 and 7), alkynyl
(entries 8–10), benzyl (entry 11) and anthracene (entry 12) MOM
ether derivatives to release the corresponding free alcohols in
good yields. The BiCl3 mediated cleavage protocol was extended
to MOM esters of both aliphatic and aromatic carboxylic acids
(Table 2) in order to further demonstrate the efficiency and
applicability of the method. MOM esters were found to depro-
tect smoothly to afford the corresponding carboxylic acid
derivatives in good yields. The acetate group remained unaf-
fected under the cleavage conditions (Table 2, entry 6).
12
a
Products were characterized using 1H NMR, 13C NMR, and FT-IR and
b
compared with authentic samples. Isolated yields after column
chromatography.
2.2. Computational studies
To study the MOM cleavage by BiCl3, quantum chemical
calculations were carried out for six MOM substrates, namely,
phenolic (19–22) and alcoholic (2a, 3a) MOM ethers.
Based on the Lewis acidity of BiCl3,13 we considered the first
step of the interaction to be the formation of a molecular complex
(MC) in which the substrate was coordinated to BiCl3 via the lone
pair of one of the oxygen atoms of the MOM ether. For each
substrate, two possible coordination pathways (1 and 2) were
investigated (Scheme 3). Pathway 1 corresponds to the coordina-
tion of BiCl3 by the phenolic or alcoholic oxygen (represented as
O1), whereas pathway 2 refers to the coordination of BiCl3 by the
MOM oxygen (represented as O2) of the MOM ether (Scheme 3).
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Table
2
Cleavage of carboxylic MOM esters (BiCl3 (100 mol%) in
MeCN–H2O (5 : 0.1 v/v) at 50 1C)
Entry Substrate
1
Producta
Time (h) Yieldb (%)
1
2
78
89
2
Scheme 3 Systematic representation of BiCl3 coordination with the
oxygens of MOM ether via either pathway 1 or pathway 2.
3
4
1
1
83
85
bond and one of the Bi–Cl bonds were lengthened irrespective
of the pathway (Fig. 1 and 2(a), (b)). The INs of all reactions and
pathways considered were characterized by the presence of two
distinct molecular species following the cleavage of the Bi–Cl
and O1–C (or O2–C) bonds. Depending on the pathway, the
leaving Cl atom was bonded to a C atom to generate either
MOMCl (pathway 1) or a chloromethoxy (or chloromethanoate)
derivative of the substrate (pathway 2). Comparable changes in
interatomic distances were observed for the five other sub-
strates shown in Scheme 2 (Tables S5.1, S5.2, S5.3, S5.4 and
S5.5, ESI†).
5
1
1
87
85
6
a
Products were characterized using 1H NMR, 13C NMR and FT-IR and
b
compared with authentic samples. Isolated yields after column
chromatography.
In the initial step of the reaction of phenolic MOM ether 19
with BiCl3, the formation of the MC was accompanied by a
slight to moderate increase in the Gibbs free energy of the
system [Fig. 2(a) and (b)]. The subsequent conversion of the MC
to the IN occurred in a one-step process characterized by a
Gibbs free energy barrier at the TS. Although the exact magni-
tude of the Gibbs free energy barrier varied depending on the
level of theory used in the calculations, the activation energy for
the formation of the TS was consistently lower via pathway 1
than via pathway 2 by 8–12 kcal molÀ1, thus indicating that
coordination by the phenolic oxygen O1 (pathway 1) was
kinetically favoured over the MOM oxygen O2 when phenolic
MOM ether 19 reacted with BiCl3 (Tables 3 and Table S5.6 and
S5.7, ESI†).
Corresponding calculations were carried out for the three
other substituted phenolic substrates. Energies are provided in
the ESI† for substrates 20 (Table S5.8 and Fig. S5.1(a), (b), ESI†),
21 (Table S5.9 and Fig. S5.2(a), (b), ESI†) and 22 (Table S5.10
and Fig. S5.3(a), (b), ESI†), respectively. Results for all sub-
strates are in qualitative agreement with those of substrate 19
in support of a kinetically favoured coordination of the pheno-
lic oxygen to BiCl3 during the deprotection of phenolic MOM
ethers. These findings are in agreement with the Mulliken
charge on O1 being more negative than on O2 for all four
substrates [Table S5.11(a), ESI†]. We also observed that the
interaction energy, obtained from the natural bond order
analysis, of the MC is generally greater when BiCl3 is coordi-
nated by O1 than when it is coordinated by O2 [Table S5.11(b),
ESI†].
Each of the six MOM substrates in Scheme 2 was investi-
gated by considering its reaction with BiCl3 through pathways
1 and 2. As the reaction proceeded, the initially generated MC
was converted to a transition state (TS) which was subsequently
transformed into a reaction intermediate (IN). For each
reaction and pathway considered in the present work, we
determined electronic energies, enthalpies, Gibbs free energies
(at 25 1C and 50 1C) and entropies of the MCs, TSs and INs. All
reported energies were relative to that of the corresponding
total energy of the reactants. The results for phenolic MOM
ether 19 are tabulated in Table 3. Since energies computed in
the gas phase and using implicit solvent (MeCN or water) are
qualitatively similar, results are presented and discussed based
primarily on gas-phase calculations in the present work.
DFT-optimized structures of the TS of the reaction of phe-
nolic MOM ether 19 with BiCl3 indicated that the Bi and the O1
(or O2) atoms were bonded in the TS while the O1–C (or O2–C)
Relative Gibbs free energy profiles of the coordination of
BiCl3 by the alcoholic MOM substrate 2a are shown in Fig. 3(a)
Scheme 2 Chemical structures of phenolic and alcoholic MOM sub-
strates considered for computational studies.
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Table 3 Relative electronic energies (DE, in kcal molÀ1), enthalpies (DH, in kcal molÀ1), Gibbs free energies (DG, in kcal molÀ1) and entropies (DS, in cal
molÀ1 À1) including zero-point energy corrections computed using the M06-2X functional and LANL2DZ basis set for Bi and 6-31G(d) basis set for all
K
other atoms in the gas phase for the reaction of 19 with BiCl3 (19 = (methoxymethoxy)benzene). Values in parentheses and square brackets are for MeCN
and water, respectively
O1 (pathway 1)
DEa
O2 (pathway 2)
DEa
DHa
DGa
DGb
DSa
DHa
DGa
DGb
DSa
19MC1
19TS1
19IN1
À9.8
(À6.6)
[À7.0]
14.1
À11.8
[11.8]
À6.2
À0.6
[0.1]
À9.5
(À6.6)
[À6.8]
14.4
À12.2
[12.2]
À5.6
À1.1
[0.7]
3.3
4.4
À42.9
19MC2
19TS2
19IN2
À13.8
(À9.7)
[À10.1]
23.8
À13.8
(À9.9)
[À10.2]
24.2
0.4
1.6
À47.6
À7.8
[7.1]
27.4
À25.1
[25.1]
5.8
À8.1
[8.3]
28.6
À26.1
[26.2]
6.7
(À48.3)
[À46.7]
À43.8
À5.5
[4.8]
36.8
À33.8
[33.7]
5.4
À5.9
[6.0]
37.9
À34.9
[34.7]
6.3
(À51.4)
[À50.1]
À42.5
(À43.2)
[À43.3]
À38.2
À21
À21.4
[21.4]
À6.2
(À41.6)
[À41.1]
À38.8
[20.9]
À6.7
À13.6
À13.3
(À41.9)
[À39.9]
À1.4
À1.9
À14.1
À15.1
(À41.0)
[À40.9]
[12.6]
[13.6]
[1.7]
[2.1]
[14.3]
[15.3]
a
b
At 25 1C. At 50 1C.
Fig. 1 Selected interatomic distances (in Å) in the MCs, TSs and INs for the reactions of 19 with BiCl3 via pathway 1 (left) and pathway 2 (right) according
to the M06-2X/6-31G(d) calculations in the gas phase. Interatomic distances corresponding to the Bi–Cl cleavage are shown in blue font.
and (b), and corresponding energetics data are provided in the with respect to the MCs at the M06-2X/6-31G(d) level of theory.
ESI† (Table S5.12).
Similar results were obtained at other levels of theory with
The activation energies for the coordination of BiCl3 by the activation energies differing by only about 1 kcal molÀ1
alcoholic oxygen O1 (pathway 1) and by the MOM oxygen O2 between pathways 1 and 2 (Table S5.12, ESI†). Thus, in contrast
(pathway 2) of 2a are 32.9 and 31.7 kcal molÀ1, respectively, to our results for phenolic substrates, the two initial binding
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Fig. 3 (a) Relative Gibbs free energy profile computed using B3LYP and
M06-2X functionals and MP2 method in correlation with the 6-31G(d)
basis set for all atoms, excluding bismuth for which LANL2DZ was used as
the basis set for the reaction of 2a with BiCl3 via pathway 1, where BiCl3
was attached to O1 in the gas phase at 50 1C. (b) Relative Gibbs free energy
profile computed using B3LYP and M06-2X functionals and MP2 method
in correlation with the 6-31G(d) basis set for all atoms, excluding bismuth
for which LANL2DZ was used as the basis set for the reaction of 2a with
BiCl3 via pathway 2, where BiCl3 was attached to O2 in the gas phase
at 50 1C.
Fig. 2 (a) Relative Gibbs free energy profile computed using B3LYP and
M06-2X functionals and MP2 method in correlation with 6-31G(d) basis set
for all atoms, excluding bismuth where LANL2DZ was used as basis set for
the reaction of 19 with BiCl3 via pathway 1 where BiCl3 was attached to O1
in the gas phase at 50 1C. (b) Relative Gibbs free energy profile computed
using B3LYP and M06-2X functionals and MP2 method in correlation with
6-31G(d) basis set for all atoms, excluding bismuth where LANL2DZ was
used as a basis set for the reaction of 19 with BiCl3 via pathway 2, where
BiCl3 was attached to O2 in the gas phase at 50 1C.
pathways may be competitive for the alcoholic substrate. Simi-
larly, the coordination of alcoholic MOM substrate 3a to BiCl3 is
characterized by activation barriers of 29.2 and 29.9 kcal molÀ1
via pathways 1 and 2, respectively, relative to the corres-
ponding MCs according to the M06-2X/6-31G(d) calculations
(Table S5.13 and Fig. S5.4(a), (b), ESI†). The observation that
activation barriers were again nearly identical for both path-
ways further supports the existence of two competitive path-
ways in the initial binding step of BiCl3 mediated cleavage of
the MOM moiety from alcoholic MOM substrates. A compar-
ison of the coordination Gibbs free energies of phenolic MOM
ethers (19, 20, 21, 22) and the alcoholic MOM ethers (2a, 3a) via
pathway 1 with BiCl3 shows that activation barriers for the
formation of INs from the MCs were higher for alcoholic ethers
than for the phenolic MOM ethers by 4–8 kcal molÀ1. Together
with the presence of competitive pathways, higher activation
barriers might explain the significantly longer reaction times
(8–12 h) and the greater amount of BiCl3 (100 mol%) required
by alcoholic MOM ethers 2a and 3a compared to phenolic MOM
ethers 19, 20, 21 and 22 for which the cleavage of the MOM
group was completed in at most 3 h at 30 mol% BiCl3.12
The formation of INs from the substrate and BiCl3 was
endergonic for all substrates, irrespective of the pathway con-
sidered. We hypothesized that the subsequent hydrolysis of INs
to yield the desired phenol is sufficiently fast in the presence of
water to drive the reaction forward. To test our hypothesis,
we computed M06-2X/6-31G(d) Gibbs free energies for the
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alkyne and acetate. DFT studies revealed the differential initial
binding site preferences of the phenolic and alcoholic MOM
substrates to the Bi atom. In particular, coordination of BiCl3 by
the phenolic oxygen (O1) was favoured over coordination by the
MOM oxygen (O2) for the phenolic MOM ethers, 19, 20, 21 and
22, whereas, for the alcoholic MOM ethers 2a and 3a, coordina-
tion at the O1 and O2 positions was competitive. However,
when subsequent reactions of intermediates with water to yield
the desired deprotected alcohol were considered, coordination
by O1 was favoured overall for all MOM substrates investigated
in the present work. Based on the pathways considered in this
work, BiCl3 mediated cleavage of the MOM moiety is a multi-
step process characterized by initial binding of the phenolic or
alcoholic oxygen to BiCl3 and facilitated by water to afford the
deprotected alcohol.
4. Experimental methods
4.1. General considerations
Scheme 4 The pathways considered in the present work for DFT inves-
tigations of the initial binding of BiCl3 to oxygen atoms of MOM substrates
and subsequent reactions with water to form the deprotected alcohol.
All reagents and solvents were purchased from commercial
sources and were used as received without further purification.
Thin layer chromatography (TLC) was conducted on glass-
backed plates coated with a 0.2 mm thickness of silica gel 60
F254; chromatograms were visualized using UV radiation
(254 nm) or by staining with KMnO4 or phosphomolybdic acid.
Flash column chromatography was performed on 300–400
mesh silica gel using mixtures of ethyl acetate and hexane as
the eluent system. NMR (1H NMR and 13C NMR) experiments
were recorded using an Agilent/Varian VNMRS 400 MHz instru-
ment using deuterated chloroform (CDCl3). Chemical shifts (d)
are referenced to the residual proton in the NMR solvent
(CDCl3, 7.26 ppm). Data are reported as follows: chemical shift,
multiplicity, coupling constants (J) reported in Hertz (Hz)
and integration and the following abbreviations are used:
s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet
of doublets, br = broad, and m = multiplet. IR spectra were
recorded using a PerkinElmer FT-IR spectrophotometer (Spec-
trum two) and only the more significant peaks are reported.
4.1.1 General experimental procedure for MOM ethers and
esters. MOMCl (1.5 mmol) was added to a stirred solution of
alcohol or carboxylic acid substrate (1 mmol) in CH2Cl2 (15 mL)
at 0 1C. DIPEA (2 mmol) was slowly added to the reaction
mixture. The ice-bath was removed and the mixture was stirred
overnight at room temperature. Distilled water (15 mL) was
added to the reaction mixture and the organic phase was
separated, and washed with 0.5 M of HCl, distilled water, 1 M
of NaOH, and brine. The organic phase was dried using
anhydrous sodium sulphate, filtered and concentrated. Flash
column chromatography of the residue over silica gel (hexane :
formation of the alcohol by the reaction of INs with a water
molecule. For pathway 1, we considered the reaction of the
intermediate R–O–BiCl2 with a water molecule while for path-
way 2, the reaction of the intermediate chloromethoxy deriva-
tive with water was studied. (Scheme 4). Results are tabulated in
Table S5.14 in the ESI.† We found that the formation of alcohol
by the reaction of INs with water was consistently exergonic via
pathway 1 for all phenolic substrates (DG = À4.1 to À6.1 kcal
molÀ1) as well as for both alcoholic substrates (DG = À1.8 to
À2.3 kcal molÀ1) at 50 1C in the gas phase. Interestingly,
the formation of the alcohol via pathway 2 was ergoneutral
(DG = À0.2 kcal molÀ1) for substrate 20 and endergonic for all
the other five substrates (DG = 1.0 to 6.1 kcal molÀ1). Therefore,
although pathways 1 and 2 may be competitive for the for-
mation of INs from the alcoholic substrate, pathway 1 is favored
over pathway 2 in the subsequent steps of the deprotection to
form the alcohol.
Furthermore, our results suggest that in the absence of
water, the equilibrium likely lies further to the left and a
complete conversion to the IN is not achieved. This might
explain our experimental observation that the cleavage of
phenolic MOM ether 19 proceeded with lower yield in neat
MeCN compared to a mixture of MeCN : water (5 : 0.1 v/v).12
3. Conclusions
To conclude, bismuth trichloride was shown to be an effective, EtOAc mixture) yielded the desired MOM protected alcohol
mild and eco-friendly cleavage reagent for MOM ether and or ester.
MOM ester derivatives in good yield. Attractive features of the
4.1.2 General experimental procedure for the cleavage of
cleavage method are the use of an inexpensive and easily MOM ethers and esters. BiCl3 (100 mol%) was added to a
handled solid reagent, simple experimental procedure and stirred solution of MOM protected alcohol or MOM esters
compatibility with other functional groups, such as alkene, (1 mmol) in MeCN/H2O (5 mL/0.1 mL; 5 : 0.1 v/v) and the
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mixture was stirred at 50 1C until the reaction was complete 1160 cmÀ1
Paper
;
1H NMR (400 MHz, CDCl3) d 7.45–7.49 (m, 2H),
(TLC control). The reaction mixture was filtered over a pad of 7.59–7.64 (m, 1H), 8.10–8.13 (m, 2H). 13C NMR (100 MHz, CDCl3)
Celite followed by washing of the Celite pad with CH2Cl2 d 128.5, 129.2, 130.2, 133.8, 172.0 ppm; the spectral data were
(10 mL). The resulting filtrate was dried over anhydrous sodium found to be consistent on comparison with the authentic sample.
sulphate, filtered and concentrated under reduced pressure.
Flash column chromatography of the residue over silica gel
(hexane: EtOAc mixture) afforded the desired pure alcohol or 5. Computational methods
carboxylic acids.
All the quantum chemical computations were carried out using the
4.2. Analysis data of the selected products
Gaussian 09/16 software suite17,18 running on SEAGrid,19–23 whereas
the processing of input and output files was done with
ExcelAutomat.24 Full optimisation of molecular complexes (MCs),
transition states (TSs) and intermediates (INs) of MOM ethers and
esters was performed in the gas phase using the popular B3LYP
functional25,26 as well as the M06-2X27 functional and MP228
method.29–31 The 6-31G(d)32 basis set was used for all atoms except
for bismuth for which the LANL2DZ33,34 basis set was employed.
Calculations carried out using M06-2X/6-31G(d) and more advanced
M06-2X/6-31+ G(d) and M06-2X/6-311G(d) methods yielded qualita-
tively comparable results for reactions of 19 with BiCl3 (Table S5.6,
ESI†). Consequently, 6-31G was selected as the basis set for all
subsequent calculations. To mimic experimental conditions, the
effects of MeCN and water were considered implicitly during
optimisation and energy calculations using the polarisable conti-
nuum model (PCM)35,36 for reactions of 19 with BiCl3 at 25 1C and
50 1C (Table 3 and Table S5.2, ESI†). Results agree qualitatively with
the gas-phase results. Stationary points were characterised using
frequency computation to verify that TSs have only one imaginary
frequency. Relative electronic energies were corrected based on zero-
point energies (ZPE). Intrinsic reaction coordinate (IRC)37,38 compu-
tations were performed to confirm that the TSs connect the MCs and
INs. Standard enthalpies and entropies were determined at 25 1C
and 1 atm. Gibbs free energies at 50 1C were estimated using
DG = DH À TDS by assuming that the constant pressure molar heat
capacity Cp is nearly constant over the temperature range of
25–50 1C.
4.2.1 1-Bromo-4-((methoxymethoxy)methyl)benzene (11a).
Following the general procedure for MOM protection, 11a was
obtained as a clear oil in 82% yield. FTIR (neat) 2934, 2884,
1
1594, 1487, 1208, 1148, 1042 cmÀ1; H NMR (400 MHz, CDCl3)
d 3.38 (s, 3H), 4.53 (s, 2H), 4.68 (s, 2H), 7.22 (d, J = 8.8 Hz, 2H),
7.46 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 55.4, 68.4,
95.7, 121.5, 129.4, 131.5, 136.9 ppm; the spectral data were
consistent with the previous literature report.14
4.2.2 (4-Bromophenyl)methanol (11b). Following the gen-
eral procedure for BiCl3 mediated MOM deprotection, 11b was
obtained as an oil in 88% yield. FTIR (neat) 3353, 2921, 1591,
1486, 1403, 1009 cmÀ1 1H NMR (400 MHz, CDCl3) d 1.98
;
(s, 1H), 4.60 (s, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.4
Hz, 2H). 13C NMR (100 MHz, CDCl3) d 64.5, 121.4, 128.6, 131.6,
136.7 ppm; the spectral data were found to be consistent on
comparison with the authentic sample.
4.2.3 9-((Methoxymethoxy)methyl)anthracene (12a). Fol-
lowing the general procedure for MOM protection, 12a was
obtained as a pale yellow solid in 85% yield; m.p. = 81–82 1C;
FTIR (neat) 3003, 2962, 2885, 1526, 1446, 1146, 1037 cmÀ1
;
1H NMR (400 MHz, CDCl3) d 3.51 (s, 3H), 4.79 (s, 2H), 5.60 (s, 2H),
7.45–7.49 (m, 2H), 7.53–7.57 (m, 2H), 8.01 (d, J = 8.8 Hz, 2H),
8.42 (d, J = 9.2 Hz, 2H), 8.47 (s, 1H). 13C NMR (100 MHz, CDCl3)
d 55.7, 61.0, 95.6, 124.2, 125.0, 126.3, 128.2, 128.5, 129.0, 131.1,
131.4 ppm; the spectral data were consistent with the previous
literature report.15
4.2.4 9-Anthracenemethanol (12b). Following the general
procedure for BiCl3 mediated MOM deprotection, 12b was
obtained as a solid in 92% yield. FTIR (neat) 3417, 2927,
Author contributions
2861, 1475 cmÀ1 1H NMR (400 MHz, CDCl3) d 5.68 (s, 2H),
;
AP: investigation, data curation, and formal analysis; BZ: inves-
tigation, data curation, and formal analysis; DH: investigation,
data curation, and formal analysis; IR: investigation and valida-
tion; MV: investigation and validation; BI: conceptualization,
supervision, formal analysis, funding acquisition, writing-
original draft, and writing-review & editing; LR: supervision,
formal analysis, methodology, and writing-review & editing; PR:
conceptualization, supervision, funding acquisition, project
administration, resources, writing-original draft, and writing-
review & editing; RS: conceptualization, supervision, funding
acquisition, project administration, methodology, resources,
writing-original draft, and writing-review & editing.
5.98 (s, 1H), 7.45–7.49 (m, 2H), 7.52–7.56 (m, 2H), 8.02 (d, J = 8.8
Hz, 2H), 8.42 (d, J = 8.8 Hz, 2H), 8.47 (s, 1H). 13C NMR (100
MHz, CDCl3) d 55.4, 121.8, 123.6, 123.8, 125.1, 126.5, 128.4,
129.1, 131.5 ppm; the spectral data were found to be consistent
on comparison with the authentic sample.
4.2.5 Methoxymethyl benzoate (14a). Following the general
procedure for MOM protection, 14a was obtained as a clear oil
in 88% yield. FTIR (neat) 2930, 2860, 1719, 1636, 1455, 1260,
1163, 1055 cmÀ1; 1H NMR (400 MHz, CDCl3) d 3.54 (s, 3H), 5.48
(s, 2H), 7.42–7.46 (m, 2H), 7.55-7.58 (m, 1H), 8.06–8.08 (m, 2H).
13C NMR (100 MHz, CDCl3) d 57.7, 90.9, 128.4, 129.7, 129.8,
133.2, 166.0 ppm; the spectral data were consistent with the
previous literature report.16
4.2.6 Benzoic acid (14b). Following the general procedure
for BiCl3 mediated MOM deprotection, 14b was obtained as
Conflicts of interest
a solid in 89% yield. FTIR (neat) 3071, 2927, 2849, 1678, 1481, There are no conflicts to declare.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 7109–7116
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Paper
NJC
9 J. A. R. Salvador, S. A. C. Figueiredo, R. M. A. Pinto and
S. M. Silvestre, Future Med. Chem., 2012, 4, 1495–1523.
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14 W. W. L. Cheng, Z. W. Chen and J. R. Bracamontes, et al.,
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Acknowledgements
The authors gratefully acknowledge funding from the Depart-
ment of Chemistry, SUNY Plattsburgh to RS and from the
Programme de subventions de recherche de l’Universite de
´
Saint-Boniface (Canada) to BBI and RS. This work was also
supported in part by funding from the Higher Education
Commission (HEC) of Mauritius. RS acknowledges a travel
grant from Mauritius Research and Innovation Council. The
authors thank J. Jones for NMR measurements and S. Mattson
is acknowledged for the preparation of MOM esters 14a and
15a. SEAGrid (http:www.seagrid.org) is acknowledged for com-
putational resources and services for the selected results pre-
sented in this publication.
18 M. J. Frisch, et al., Gaussian 16, Revision B.01, Gaussian, Inc.,
Wallingford CT, 2016.
19 S. Pamidighantama, S. Nakandala, E. Abeysinghe,
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