Structural Identification of Products from the Chloromethylation of Salicylaldehyde

Article abstract of DOI:10.1055/s-0037-1610334

In the functionalization of salicylaldehyde to give 5-(chloromethyl)salicylaldehyde, two byproducts [5-(hydroxymethyl)salicylaldehyde and 5,5′-methylenebis(salicylaldehyde)] were also isolated. Detailed characterizations and structural analyses of all three products by single-crystal X-ray diffraction, multinuclear NMR spectroscopy, high-resolution mass spectrometry, and IR spectroscopic techniques are presented and discussed. A strategy is presented for the preferential isolation of the two byproducts through column chromatography.

Full text of DOI:10.1055/s-0037-1610334

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2018, 29, A–E
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E. Kadwa et al.
Letter
Structural Identification of Products from the Chloromethylation
of Salicylaldehyde
Ebrahim Kadwa
Holger B. Friedrich
Muhammad D. Bala*
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School of Chemistry and Physics, University of KwaZulu-Natal,
Private Bag X54001, Durban 4000, South Africa
bala@ukzn.ac.za
Received: 16.10.2018
Accepted after revision: 30.10.2018
Published online: 26.11.2018
variety of salen-type compounds through derivatization,
with the aim of expanding our ability to tune the properties
of Schiff-base-derived compounds sterically and electroni-
cally, and to widen their scope of application in coordina-
tion chemistry and catalysis as functionalized ligands or in
bioorganic chemistry as drug synthons. Towards achieving
this goal, chloromethylation at the 5-position of the salicyl-
aldehyde ring is well established, and is a fundamental
route to ring functionalization as a starting point in the
DOI: 10.1055/s-0037-1610334; Art ID: st-2018-k0673-l
Abstract In the functionalization of salicylaldehyde to give 5-(chloro-
methyl)salicylaldehyde, two byproducts [5-(hydroxymethyl)salicylalde-
hyde and 5,5′-methylenebis(salicylaldehyde)] were also isolated.
Detailed characterizations and structural analyses of all three products
by single-crystal X-ray diffraction, multinuclear NMR spectroscopy,
high-resolution mass spectrometry, and IR spectroscopic techniques
are presented and discussed. A strategy is presented for the preferential
isolation of the two byproducts through column chromatography.
production of new compounds, ligands, macrocycles, and
materials.1
2–17
Although the reaction is widely used and
common, there is a paucity of characterization data, espe-
cially on structural details of the products of the reaction.
We therefore present strategies for the synthesis and selec-
tive isolation of the products of chloromethylation of salicyl-
aldehyde, accompanied by detailed molecular and structur-
al analysis data.
Key words salicylaldehyde, chloromethylation, chloromethylsalicyl-
aldehyde, crystal structure, hydroxymethylsalicylaldehyde, methylene-
bissalicylaldehyde
The chloromethylation of benzene was first reported in
1
898,1 effectively leading to the functionalization of the
arene to give more reactive intermediates and value-added
products. The widely adopted Blanc reaction for the chloro-
methylation of arenes uses formaldehyde and concentrated
The method for the synthesis of compound 2 and its
associated byproducts is presented in Scheme 1. This is an
established method, in which salicylaldehyde (or its deriva-
tives) and (para)formaldehyde react in concentrated HCl,
2
HCl as sources of the chloromethyl functional group. Later
studies adopted paraformaldehyde, dichloromethyl ether,
which is then neutralized with NaHCO . Although this
3
HCl gas, acetic acid, SnCl , or other Lewis acids as reagents,
method for the Blanc reaction has been adopted by many
4
and they also investigated the effects of arene-ring substi-
tution on the products of the reaction.3–5 Utilization of the
products of the chloromethylation process has led to useful
products that include cross-linked resins and polymerizable
researchers,6
–8,12,13,18
it suffers from many, often overlooked,
shortcomings. For example, the reported yields of the pre-
ferred chloromethylated product 2 vary widely, and results
show poor reproducibility. Moreover, despite many
attempts, we found it impossible to drive the reaction selec-
tively to give the chloromethylated salicylaldehyde exclu-
sively. Although compounds 3 and 4 are often obtained by
this method, to the best of our knowledge, previous adapta-
tions of the Blanc reaction have not adequately accounted
for these potentially useful byproducts.
6–10
monomers for new functional materials.
Indeed, one of
the more recognizable and useful resins, the Merrifield res-
in, employs chloromethylated cross-linked polystyrene as
an anchoring point for the first amino acid used in peptide
11
synthesis.
Salicylaldehyde is a common starting material for the
synthesis of salen Schiff-base ligands, which are popular in
coordination chemistry and in homogeneous catalysis. Con-
sequently, there is an ever-increasing need to extend the
We have therefore developed unambiguous and repro-
ducible techniques for the selective isolation of the main
product 219 and each of the associated byproducts 3 and 4.
20
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Scheme 1 Synthetic route to products 2, 3, and 4, with carbon-atom numbering consistent with the NMR assignment and the single-crystal structural
analysis data
For the first time, detailed spectroscopic and analytical
methods were used to characterize fully and to compare
and contrast the three related compounds 2, 3, and 4.
To maximize the yield of 2, we tested long reaction
times (1–3 days at room temperature), reaction at the
reflux temperature, and the use of ZnCl as a catalyst and
2
H SO as a promoter. In all of these permutations, TLC and
2
4
NMR analyses of the reaction mixture showed multiple
products and, for the reactions at room temperature, the
presence of unreacted starting material 1 (~80% conversion
to all products). When the products were subjected to sepa-
ration by column chromatography (silica gel or alumina sta-
tionary phase, hexane–ethyl acetate mobile phase) com-
pounds 4 (11% isolated yield) and 3 (9% isolated yield) were
eluted in that order, but only a minuscule amount (<1%) of
the target compound was recoverable by column chroma-
tography as the third eluent (Scheme 1). However, we found
that the target compound 2 was most effectively isolated
from the reaction mixture by recrystallization from diethyl
ether (50% isolated yield). Hence, to maximize the yield of 2,
column chromatography should be avoided. We believe that
a base­-promoted hydroxylation of compound 2 occurs on
the surface of the silica in the column to give byproduct 3;
therefore, column chromatography is best avoided for the
isolation of the main product.
1
Figure 1 Stacked H NMR spectra, highlighting the formation of prod-
ucts 2–4 from 1
This was also observed in the 13C NMR spectra (Figure
2), where functionalization resulted in the appearance of
new (C8) signals at δ = 46, 62, and 39 ppm for 2–4, respec-
tively. The signal due to C5 (δ = 119 ppm) was shifted
downfield by 9, 14, and 13 ppm for 2–4, respectively, when
the C5–H bond was deprotonated, resulting in coupling
(C5–C8) products with –CH Cl, –CH OH, and –CH –salicyl-
We planned to use compound 2 as part of a broader ef-
fort to develop novel polyfunctional ligands bearing Schiff
base/N-heterocyclic carbene (SB/NHC) hybrid ligands, to-
gether with their transition-metal complexes, for applica-
2
2
2
aldehyde as substituents on the parent salicylaldehyde moi-
ety.
21,22
tions in homogeneous catalysis.
The three products of the chloromethylation reaction
were isolated as analytically pure compounds which were
1
analyzed spectroscopically. Stacked H NMR spectra high-
lighting the formation of products 2–4 from 1 are presented
in Figure 1, from which the region δ = 3.5 and 5 ppm pro-
vides a convenient handle for monitoring the products of
1
the reaction. Analysis of the H NMR spectra shows that
salicylaldehyde was functionalized at the C5 position, as
seen by the loss of the C5–H signal at δ = 6.94 ppm, with the
corresponding appearance of methylene (C8–H) signals at
δ = 4.75, 4.42 and 3.84 ppm for 2, 3 and 4 respectively.
Figure 2 Stacked 13C NMR spectra of compounds 1–4
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The electronic influence of the –CH Cl, –CH OH, and
2
2
–
CH –salicylaldehyde substituents on salicylaldehyde was
2
1
also observed in the H NMR spectra as shifts in the posi-
tions of the aryl and phenolic proton signals (Figure 1). In
general, the signals of 2–4 were shifted downfield for 2 and
upfield for 3 and 4 with respect to those of 1 for the aryl
(δ = 7–8 ppm) and phenolic (δ > 10 ppm) proton regions,
respectively. These trends are due to the electron-with-
drawing nature of the –CH Cl group and the electron-
2
donating influences of the –CH OH group and the –CH –
salicylaldehyde moiety.
An analysis of the multiplicity patterns of the NMR sig-
nals in the aryl region is noteworthy. For compounds 2–4,
the C6–H signals were not the expected singlets, but in-
stead appeared as doublets with coupling constants of J =
2
2
Figure 4 ORTEP diagram of 3 with thermal ellipsoids drawn at the 50%
probability level (left) and the hydrogen-bonding networks binding
molecules of 3 (right)
2.1–2.3 Hz. COSY NMR spectra (see Supplementary Infor-
mation) revealed that the splitting is due to in-ring coupling
of C6–H with C4–H. Also, C4-H is simultaneously coupled to
the neighboring C3–H (J4,3 = 8.3–8.5 Hz) and through-ring
with C6–H (J4,6 = 2.2–2.3 Hz), resulting in a doublet of dou-
blets.
Single crystals of the products of suitable quality for
structural analysis by X-ray diffraction were grown from
ethyl acetate, and their structures were determined.23
ORTEP diagrams for 2–4 are shown in Figures 3–5, respec-
tively. Each of the three compounds shows an occupancy of
four molecules in the asymmetric unit cell, and there is
very little change in bond distances and angles between the
atoms making up the parent salicylaldehyde moiety. How-
ever, the C5–C8 bond does show slight variations; the pres-
ence of a chloride substituent at C8 results in a shorter
bond length, due to its electron-withdrawing nature.
Figure 5 ORTEP diagram of 4 with thermal ellipsoids drawn at the 50%
probability level (left upper), packing of 4 in the unit cell showing the
separation (3.284 Å) of planes formed by adjacent salicylaldehyde
moieties (right upper), and intermolecular (O2–H···O1) hydrogen bond-
ing in 4 (lower).
Compound 2 crystallized in the P2 /c space group of the
1
monoclinic system with four molecules in the asymmetric
unit cell. Intermolecular hydrogen bonds (2.404 Å) form
chains that bind neighboring molecules through the pheno-
lic hydrogen of one molecule and the carbonyl oxygen of a
neighboring molecule. This pattern is repeated in a chain-
like structure between molecules with alternating orienta-
tions. The chlorine atoms are not involved in any nonclassi-
cal hydrogen bonding, due to the head-to-head nature of
the packing in 2.
Figure 3 ORTEP diagram of 2 with thermal ellipsoids drawn at the 50%
probability level (left) and hydrogen-bonding (O2–H···O1) in 2 (right)
Differences in crystal packing and hydrogen bonding at
the molecular level explain the melting point ranges record-
ed for compounds 2–4. Salicylaldehyde is a liquid at room
temperature with a melting point of –7 °C; the introduction
of functional groups onto the ring results in solid products
of increasing melting point, i.e. 84, 102, and 135 °C for 2–4,
respectively, as a result of the increasing molecular size and
the significant contributions from intermolecular hydrogen
bonding and π–π stacking interactions (see below).
Each molecule of 3 is involved in twice as many inter-
molecular hydrogen bonds as those in 2 (Figure 4). These
contribute to its higher melting temperature of 102–103 °C,
compared with 84–85 °C for compound 2, by increasing the
threshold of energy input required to disrupt the efficiently
packed crystal system of 3. Although compound 3 crystal-
lized in the orthorhombic crystal system, it also showed
similar intramolecular hydrogen bonding between the phe-
nolic hydrogen and the carbonyl oxygen atoms of neighbor-
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ing molecules (O2–H···O1 = 2.452 Å) to that observed in 2.
In addition, each of the C8-bound hydroxy (O3–H) protons
is involved in a twofold intermolecular hydrogen bonding,
resulting in a zigzagging network of hydrogen bonds (O3–
H···O3–H···O3) running along the b-axis, with each hydro-
gen bond separated by 2.307 Å. The additional bonding
between the hydroxy groups of 3 effectively forms cross-
links that efficiently bind the structure together.
basis of new, highly efficient, homogeneous, transfer-
hydrogenation catalysts bearing polyfunctional hybrid
SB/NHC ligands.
Funding Information
This project is generously supported by the c* change PAR program,
the National Research Foundation, and the University of KwaZulu-
Natal, for which we are grateful.()
The bis(salicylaldehyde) molecule 4 crystallizes in the
P2 /n space group of the monoclinic crystal system and, in-
1
terestingly, the molecular packing (Figure 5) in compound 4
possesses the longest (weakest) hydrogen bond (2.557 Å)
amongst the three products examined. Also, the interplanar
spacing between neighboring planes of aryl (C1–C6) atoms
is responsible for enhanced π–π interactions with a separa-
tion of 3.284 . No such π–π stacking interactions were ob-
served in the crystal structures of 2 and 3, due to the stag-
gered nature of their crystal packing.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610334.
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References and Notes
(1) Grassi-Christaldi, G.; Maselli, M. Gazz. Chim. Ital. 1898, 28, 477.
(2) Comprehensive Organic Name Reactions and Reagents; Wang, Z.,
Ed.; Wiley: Hoboken, 2010, 429.
Intermolecular hydrogen bonding was also detected in
the infrared spectra of 2 and 3, but not 4 (see Supporting
Information, Figure S3a). Analysis of the region 3000–3400
(
(
3) Rabjohn, N. J. Am. Chem. Soc. 1954, 76, 5479.
4) Fuson, R. C.; McKeever, C. H. In Organic Reactions;
Ed.; Wiley: New York, 1942.
V
o
l.
1
,
C
h
a
p
.
3
Adams, R.,
–
1
–1
cm revealed one broad band for 2 (3225 cm ) and two
–1
broad, more-intense, bands for 3 (3315 and 3218 cm ). The
bands at 3225 and 3218 cm were assigned to stretching of
the phenolic O2–H groups, which participate in the inter-
(
(
5) Olah, G. A.; Beal, D. A.; Olah, J. A. J. Org. Chem. 1976, 41, 1627.
6) Dalla Cort, A.; Mandolini, L.; Pasquini, C.; Schiaffino, L. Org.
Biomol. Chem. 2006, 4, 4543.
–1
24
–1
molecular O2–H···O1 bonding. The band at 3315 cm for 3
(7) El-Hendawy, A. M.; El-Sonbati, A. Z.; Diab, M. A. Acta Polym.
989, 40, 710.
1
was assigned to stretching of the primary hydroxy group
(8) El-Sonbati, A. Z.; El-Bindary, A. A.; Rashed, I. G. A. Spectrochim.
Acta, Part A 2002, 58, 1411.
(
O3–H), which participates in the formation of the intermo-
–1
lecular O3–H···O3–H···O3 chains. The band at 1019 cm was
present in the spectrum of 3 only, and is characteristic of
the C–O stretch of a primary alcohol; hence, it was assigned
to the C8–O3 bond. The characteristic aldehyde C=O stretch
(
9) Samuels, W. D.; LaFemina, N. H.; Sukwarotwat, V.; Yantasee,
W.; Li, X. S.; Fryxell, G. E. Sep. Sci. Technol. (Philadelphia. PA, U. S.)
2010, 45, 228.
(10) Uche, F. I.; McCullagh, J.; Claridge, T. W. D.; Richardson, A.; Li,
appeared at approximately 1650 cm–1 for all three com-
W.-W. Bioorg. Med. Chem. Lett. 2018, 28, 1652.
(
(
11) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
12) Neamţu, M.; Macaev, F.; Boldescu, V.; Hodoroaba, V.-D.;
Nădejde, C.; Schneider, R. J.; Paul, A.; Ababei, G.; Panne, U. Appl.
Catal., B 2016, 183, 335.
pounds, implying little effect of the C8 substituent on the
stretching frequency of the aldehyde carbonyl group. The
–1
set of bands between 1230 and 1300 cm were assigned to
the phenolic C–O stretch. Compound 2 showed a stretch at
(13) Wulff, G.; Akelah, A. Makromol. Chem. 1978, 179, 2647.
–
1
1
1
283 cm , which appeared at a higher frequency than the
(14) Sonar, S.; Ambrose, K.; Hendsbee, A. D.; Masuda, J. D.; Singer, R.
275 and 1273 cm–1 bands for 3 and 4, respectively, a strong
D. Can. J. Chem. 2012, 90, 60.
(
(
(
15) Minutolo, F.; Pini, D.; Petri, A.; Salvadori, P. Tetrahedron: Asym-
indication of the electronic effects of the substituent at C8
on the para phenolic group.
metry 1996, 7, 2293.
16) Haikarainen, A.; Sipilä, J.; Pietikäinen, P.; Pajunen, A.;
Mutikainen, I. J. Chem. Soc., Dalton Trans. 2001, 991.
17) Abbasi, V.; Hosseini-Monfared, H.; Hosseini, S. M. Appl.
Organomet. Chem. 2017, 31, e3554.
In conclusion, chloromethylation of salicylaldehyde re-
sulted in the product 5-(chloromethyl)salicylaldehyde and
the byproduct 5,5′-methylenebis(salicylaldehyde). The by-
product 5-(hydroxymethyl)salicylaldehyde resulted from
subsequent hydroxylation of the chloro group of 5-(chloro-
methyl)salicylaldehyde during column chromatography. All
products were isolated and unambiguously characterized.
These reported methods and full characterization data
serve as reference points for the synthesis, isolation, and
utilization of these useful compounds. These ideas form the
(18) Angyal, S. J.; Morris, P. J.; Tetaz, J. R.; Wilson, J. G. J. Chem. Soc.
1950, 2141.
(19) 5-(Chloromethyl)salicylaldehyde [2; 5-(Chloromethyl)-2-
hydroxybenzaldehyde]
Salicylaldehyde (15 g, 0.1228 mol) and 30% aq formaldehyde
(5 mL) were added to a stirred solution of concd HCl (100 mL) at
0
°C in an ice bath, and the mixture was allowed to warm to r.t.
After 24 h, the mixture was again cooled to 0 °C, and the solid
that precipitated out was washed with 5% aq NaHCO (30 mL),
3
collected by filtration, and dried in air. The resulting mixture
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(
12 g) was dissolved in Et O (50 mL), and 2 was recovered by
δ = 62.08, 116.99, 121.75, 127.09, 133.60, 135.00, 159.63,
191.84. HRMS (ESI ): m/z [M – H] calcd: 151.0395; found:
2
–
evaporation of the solvent from an open beaker in a fume hood.
Further purification was achieved by washing with hexane and
151.0375. Anal. Calcd for C H O : C, 63.15; H, 5.30. Found: C,
8
8
3
crystallization from Et O to give a white powder; yield: 10.8 g
63.46; H, 6.28.
2
18
(
1
0.0619 mol, 50%); mp 84–86 °C (lit. 85–86 °C). IR (ATR, air):
Single crystals suitable for studies by X-ray diffraction were
grown from EtOAc layered with hexane.
4
White powder; yield: 3.31 g (11%); mp 135–138 °C. IR (ATR,
air): 3057, 2859, 1648, 1588, 1480, 1273 cm . H NMR (600
–1
1
649, 1581, 1476, 1283 cm . H NMR (400 MHz, DMSO-d ):
6
δ = 4.75 (s, 2 H), 7.01 (d, J = 8.66 Hz, 1 H), 7.58 (dd, J = 8.51/2.30
Hz, 1 H), 7.72 (d, J = 2.29 Hz, 1 H), 10.26 (s, 1 H), 10.90 (s, 1 H).
13
–1
1
C NMR (100 MHz, DMSO-d ): δ = 45.71, 117.75, 122.17,
6
128.80, 129.12, 136.95, 160.73, 190.72. Anal. Calcd for
MHz, DMSO-d ): δ = 3.84 (s, 2 H), 6.93 (d, J = 8.45 Hz, 2 H), 7.37
6
C H ClO ·⅛H O: C, 55.59; H, 4.23; Found: C, 55.29; H, 3.9.
(dd, J = 8.28/2.24 Hz, 2 H), 7.47 (d, J = 2.28 Hz, 2 H), 10.21 (s, 2
8
7
2
2
13
(
20) 5-(Hydroxymethyl)salicylaldehyde [3; 2-Hydroxy-5-(hydroxy-
methyl)benzaldehyde] and 5,5′-Methylenebis(salicylalde-
hyde) [4; 3,3′-Methylenebis(6-hydroxybenzaldehyde)]
H), 10.58 (s, 2 H). C NMR (150 MHz, DMSO-d ): δ = 38.62,
6
117.49, 122.10, 128.45, 132.29, 136.89, 159.24, 191.50. Anal.
Calcd for C15H12O : C, 70.07; H 4.72. Found: C, 70.31; H 4.36.
4
The same procedure as used in the preparation of 2 was fol-
lowed. For the isolation of 3 and 4 in pure form, 12 g of the
mixture was added to the top of a column packed with silica gel.
Elution was started with pure hexane, and the solvent polarity
was slowly increased to 30% EtOAc–hexane. Compound 4 eluted
out first (R = 0.86), followed by 3 (R = 0.46) (EtOAc–hexane,
Single crystals suitable for studies by X-ray diffraction were
grown from EtOAc layered with hexane.
(21) Abubakar, S.; Ibrahim, H.; Bala, M. D. Inorg. Chim Acta 2019, 484,
276.
(22) Abubakar, S.; Bala, M. D. J. Coord. Chem. 2018, DOI:
10.1080/00958972.2018.1493199.
f
f
1
:1). Each product was recovered by solvent evaporation from
(23) CCDC 1862047, 1862048, and 1862049 contain the supplemen-
tary crystallographic data for compounds 2–4, respectively. The
data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/getstruc-
tures. Tables of selected data collection and refinement infor-
mation, bond lengths and angles, and hydrogen-bonding
interactions are also available in the Supporting Information.
(24) Coulson, C. A.; Robertson, G. N. Proc. R. Soc. London, Ser. A 1975,
342, 289.
open beakers placed in a fume hood.
3
White powder; yield: 1.64 g (9%); mp 102–103 °C. IR (ATR, air):
–1 1
3315, 3218, 2876, 1650, 1582, 1482, 1275, 1019 cm . H NMR
(400 MHz, DMSO-d ): δ = 4.42 [d, J = 4.02 Hz (s after D
6
exchange), 2 H], 5.13 (s, exchangeable, 1 H), 6.95 (d, J = 8.58 Hz,
1
1
H), 7.46 (dd, J = 8.49, 2.25 Hz, 1 H), 7.60 (d, J = 2.10 Hz, 1 H),
13
0.24 (s, 1 H), 10.59 (s, 1 H). C NMR (100 MHz, DMSO-d ):
6
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Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E