1H and 13C NMR spectral assignments of halogenated transformation products of pharmaceuticals and related environmental contaminants

Full text of DOI:10.1002/mrc.4056

Letter - spectral assignment
Received: 13 November 2013
Revised: 1 February 2014
Accepted: 7 February 2014
Published online in Wiley Online Library: 1 April 2014
(wileyonlinelibrary.com) DOI 10.1002/mrc.4056
1
13
H and C NMR spectral assignments of
halogenated transformation products of
pharmaceuticals and related environmental
contaminants
Kemal Solakyildirim, Daryl N. Bulloch and Cynthia K. Larive*
present. The availability of structurally defined standards will
facilitate the targeted analyses of these compounds in the
Introduction
Pharmaceuticals and personal care products (PPCPs) are an
emerging class of environmental pollutants frequently
encountered in wastewater at ng-μg/L levels.[1] Some PPCPs have
raised regulatory concern about their presence in the
environment because of their ability to elicit endocrine-
disrupting effects on nontarget aquatic biota.[2] Recent research
has shown the potential for PPCPs to be chlorinated during
wastewater treatment when the commonly used disinfectant
chlorine, usually introduced as sodium hypochlorite, is
applied prior to effluent discharge, creating halogenated
disinfection byproducts often termed as transformation products
(TPs).[3,4] These compounds can either be chlorinated or
brominated through the oxidation of bromide ion often
present in wastewaters.[5] Analytical standards of most
halogenated PPCP TPs are unavailable, necessitating their
synthesis and purification.
This study focuses on the NMR characterization of the major
chlorination products of a set of parent PPCPs selected because
of their documented presence in wastewater effluents, potential
for halogenation under conditions employed in wastewater
treatment, and, for several of the PPCPs, toxicological properties
of the parent PPCP or its TPs. Salicylic acid is a metabolite of
the analgesic acetylsalicylic acid, whose dichlorinated TP
has been identified as a potent inhibitor of the enzyme 20α-
hydroxysteroid dehydrogenase.[6] Naproxen and diclofenac are
non-steroidal anti-inflammatory drugs, and diclofenac has been
shown to affect endocrine function in Japanese medaka
(Oryzias latipes) at concentrations as low as 1 μg/L.[7] Gemfibrozil
is a lipid-lowering fibrate whose halogenated TPs have been
shown to be more potent antiandrogens than the parent in
Japanese medaka.[8] Bisphenol A is a plasticizer known
for its estrogenic potential. Halogenated analogs of bisphenol
A show enhanced endocrine disrupting properties in addition
to enhanced peroxisome proliferator-activated receptor γ
binding affinity compared with the parent compound.[9–11]
tert-Octylphenol was selected because of its in vitro and
in vivo potency as an endocrine disruptor and its widespread
occurrence in the environment.[12,13]
environment, which in turn may provide data useful for future
risk assessment and environmental regulation.
Experimental
Compounds
The chlorinated and brominated analogs of the PPCPs were
synthesized following the method of Bulloch et al.[8] Briefly, for
chlorination reactions, 10–20 mg of the parent PPCP was
dissolved in 50% methanol in water to which a fivefold to tenfold
molar excess of hypochlorite was added while stirring. For
bromination reactions, a molar excess of bromide : hypochlorite,
introduced as KBr, was first added to the hypochlorite solution
to produce hypobromite. 1,4-Dioxane was used in place of
methanol for reactions involving tert-octylphenol to avoid the
formation of methoxylated products.[14] Sample reaction
schemes for the chlorination and bromination of gemfibrozil
are given in Figs 1A and B, respectively. Reaction evolution was
monitored using a Waters Acquity ultra performance liquid chro-
matograph with a Waters Micromass quadrupole time-of-flight
mass spectrometric detector. After attenuation of the parent
PPCP into its halogenated analogs, the halogenation reaction
was quenched with a molar excess of sodium thiosulfate. The
crude reaction mixture was concentrated by C18 solid phase
extraction and the products purified by analytical scale reversed
phase HPLC with UV detection.
NMR spectroscopy
The parent, chlorinated and brominated analogs of the PPCPs
were dissolved in methanol-d4 and 600 μL introduced into a
5 mm NMR tube. The 1H (3.31 ppm) and 13C (49.2 ppm)
*
Correspondence to: Cynthia K. Larive, Department of Chemistry, University of
California – Riverside, Riverside, CA 92521, United States. E-mail: clarive@ucr.edu
The spectral assignments presented in this paper confirm the
structures of halogenated TP standards formed by the chlorina-
tion of aqueous pharmaceuticals with and without bromide
Department of Chemistry, University of California – Riverside, Riverside, CA,
92521, United States
Magn. Reson. Chem. 2014, 52, 310–317
Copyright © 2014 John Wiley & Sons, Ltd.

1H and 13C NMR spectral assignments of halogenated transformation products
1
window function. The H and 13C chemical shifts are given on
the δ scale (ppm), and coupling constants J are reported in hertz
(Hz). The abbreviations s, d, dd, t, and m were used for singlet,
doublet, doublet-doublet, triplet, and multiplet, respectively.
The (-) in the tables represents that coupling constant of the
peaks could not determined because of peak overlapping.
Results and Discussion
Chlorinated and brominated analogs of the PPCPs were obtained
following synthesis strategies similar to those shown in Fig. 1. Six
different groups of compounds and 27 different structures were
analyzed by a combination of 1H survey and 2D HMBC
experiments. The 1H and 13C chemical shifts and coupling
constants as well as the HMBC 13C–1H correlations were used to
elucidate the structures and unambiguously determine the
substitution locations. Although ultra performance liquid
chromatograph quadrupole time-of-flight measurements allowed
us to efficiently follow the course of the halogenation reaction
and easily identified the number and type (e.g. Cl or Br) of halogen
atoms added, mass spectra are not informative about the specific
substitution location. In some cases, it was possible to predict the
reaction site with confidence; however, for parent compounds
with multiple aromatic rings and for mixed chloro/bromo
products, experimental evidence provided by NMR was crucial in
determining the product structure.[16]
This approach is illustrated using the HMBC spectrum of
salicylic acid in Fig. 2. The horizontal axis shows the 1H spectrum,
whereas the vertical axis shows 13C projections. One bond 1H–13C
couplings are identified by circles surrounding the cross peaks.
All the peaks and their HMBC correlations in Fig. 2 were fully
assigned. For example, the H-6 signal at δ = 7.85 ppm disclosed
three long-range HMBC correlations with C-4, C-2, and C-7. A
similar strategy was used to make initial spectral assignments of
the seven halogenated salicylic acid TPs, summarized in Table 1.
Figure 1. Example of the synthetic strategies used for the chlorination
and bromination of Gemfibrozil.
resonances of methanol-d4 were used as the chemical shift
reference. NMR spectra were measured using a Bruker Avance
spectrometer operating at 599.69 MHz for 1H and 150.79 MHz
for 13C at 295 K using a broadband inverse probe with x, y, and
z gradients. 1H NMR spectra were acquired with 64 transients into
32 768 data points using a 7.2 kHz spectral window and a 1.5 s
relaxation delay. Prior to Fourier transformation, the free
induction decays were zero-filled to 65 536 points and apodized
by multiplication with an exponential function equivalent to
0.5 Hz line broadening. Proton-detected heteronuclear correla-
tions were measured using the ‘hmbcgplpndqf’ pulse sequence
optimized for an 8 Hz long-range coupling.[15] HMBC spectra
were acquired with 4 K × 256 data points and spectral widths of
5388 and 27 146 Hz in the F2 (1H) and F1 (13C) dimensions,
respectively, using a 2 s relaxation delay. The spectra were zero-
filled to 4096 × 1024 data points and apodized using a cosine2
Figure 2. 1H-13C HMBC spectrum of salicylic acid. The horizontal axis shows the 1H survey spectrum; the vertical axis shows 13C projection. Black circles
indicate single-bond HSQC peaks.
Magn. Reson. Chem. 2014, 52, 310–317
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K. Solakyildirim, D. N. Bulloch and C. K. Larive
Table 1. 1H and 13C chemical shifts (ppm), coupling constants (Hz), and multiplicities for halogenated salicylic acid analogs
Salicylic acid
3-chlorosalicylic acid
5-chlorosalicylic acid
3,5-dichlorosalicylic acid
1H
13C
1H
13C
1H
13C
1H
13C
1
2
3
4
5
6
7
—
—
113.9
163.2
118.1
136.4
120.0
131.5
173.5
—
115.4
158.9
122.7
136.5
120.3
130.1
173.1
—
114.9
161.8
119.8
136.2
124.5
130.5
172.3
—
nd
—
—
—
6.93 (d, 8.90)
7.45 (dd, 8.94, 2.68)
—
—
157.7
123.3
135.5
124.3
129.4
171.5
6.91 (dd, 8.37, 0.62)
7.45 (m)
—
7.61 (d, 2.54)
—
7.57 (dd, 7.90, 1.53)
6.88 (t, 7.88)
7.82 (dd, 7.93, 1.53)
—
6.88 (m)
7.85 (dd, 7.94, 1.59)
—
7.80 (d, 2.69)
—
7.79 (d, 2.54)
—
3-bromo,5-
chlorosalicylic acid
3-bromosalicylic acid
5-bromosalicylic acid
3,5-dibromosalicylic acid
1H
13C
1H
13C
1H
13C
1H
13C
1
2
3
4
5
6
7
—
114.4
159.7
111.5
139.6
nd
—
115.7
162.2
120.4
139.2
111.3
133.6
172.1
—
nd
—
nd
—
—
—
6.88 (d, 8.86)
7.57 (dd, 8.90, 2.49)
—
—
159.0
111.2
141.3
112.7
133.1
172.0
—
158.7
112.3
138.7
124.6
129.9
172.0
—
7.89 (d, 2.34)
—
—
7.78 (d, 2.51)
—
7.73 (dd, 7.90, 1.45)
6.83 (t, 7.88)
7.87 (dd, 7.87, 1.43)
—
130.7
173.2
7.95 (d, 2.49)
—
7.97 (d, 2.34)
—
7.84 (d, 2.51)
—
Especially for the compounds containing both chlorine and
bromine, the locations of the halogens were confirmed by
comparison of chemical shifts and HMBC couplings for the series
of halogenated analogs. Moreover, the chloro and bromo
substituents have different effects on the chemical shift of the
carbon atom to which they are directly attached. The signal
of C-3 and C-5 appeared at δ = 122.7 ppm and δ = 124.5 ppm for
3-chloro and 5-chloro salicylic acids, respectively, in comparison
to C-3 at δ = 118.1 and C-5 at δ = 120.0 in the parent salicylic acid.
Upon bromination, the signal of C-3 and C-5 appeared at
δ = 111.5 ppm and δ = 111.3 ppm for 3-bromo and 5-bromo
salicylic acids, respectively.
5-chlorosalicylic acid is shifted to lower frequency. In contrast,
when bromide substitution occurs at the C-5 position of salicylic
acid, both the H-4 and H-6 peaks shifted to higher frequency
(Fig. 3F). We observed a similar trend in the dihalogenated com-
pounds of 3,5-dichlorosalicylic acid and 3,5-dibromosalicylic
acid (Fig. 3D and G). In the 1H NMR spectrum of 3,
5-dichlorosalicylic acid, the H-4 and H-6 resonances shifted to
higher and lower fields, respectively, compared with their
positions in salicylic acid (Fig. 3D). In contrast, both the H-4
and H-6 signals of 3,5-dibromosalicylic acid shifted to higher
frequency (Fig. 3G). Figure 3H shows the1H NMR spectrum of
the mixed 3-bromo,5-chlorosalicylic acid. The H-4 resonance of
3-bromo,5-chlorosalicylic acid appears at δ = 7.78 ppm, which is
very close to the H-4 resonance in 3-bromosalicylic at δ = 7.73 ppm.
Also, the H-6 resonance of 3-bromo,5-chlorosalicylic acid
appears at δ = 7.84 ppm, which is very close to the H-6 resonance
in 5-chlorosalicylic at δ = 7.80 ppm.
Figure 3 shows the 1H NMR survey spectra of salicylic acid and
its halogenated analogs. Although four distinct resonances were
observed for the aromatic protons of salicylic acid (Fig. 3A), only
three main resonances were located in the aromatic region of
the 1H NMR spectrum of monochlorinated and monobrominated
products (Fig. 3B, C, E, and F). The chloride and bromide substit-
Figure 3 also allows the quantitative evaluation of the purity of
the isolated standards by integration of the aromatic resonances.
Multiple halogenation products were observed for salicylic acid,
and because of their similar structures, resolving them by
reverse-phase chromatography to obtain standards with high
purity (i.e. > 95%) proved challenging. For example, while
1
uents have different effects on the H chemical shifts of neigh-
boring proton resonances. For instance, while the H-4
resonance of 3-chlorosalicylic acid appears at δ = 7.57 ppm, in
3-bromosalicylic acid it is shifted to higher frequency at δ = 7.73
ppm. When chlorination occurs at the C-5 position of salicylic
acid, the chemical shift of the H-4 peak (Fig. 3C) is unaffected
compared with the parent compound (Fig. 3A) although the
coupling pattern is clearly impacted, whereas the H-6 signal of
1
5-chlorosalicylic acid was isolated in pure form (Fig. 3C), the H
NMR spectrum of 3-chlorosalicylic acid also contains resonances
of 5-chlorosalicylic acid as a minor impurity (Fig, 3B). Similarly
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Magn. Reson. Chem. 2014, 52, 310–317

1H and 13C NMR spectral assignments of halogenated transformation products
H3
H5
H5
H4
H6
A
B
H6
H4
5Cl-H3
H3
5Cl-H4
H6
C
H4
D
E
H6
H4
H6
H5
H4
5Cl-H6
3Cl-H6
3Cl-H5
5Cl-H3
3Cl-H4
5Cl-H4
H5
H6
5Cl-H6
3Br-H4
F
G
H
H4
3Br-H5
5Cl-H4
5Cl-H3
3Br-H6
H6
H4
H6
H4
3Cl,5Br-H6
3Cl,5Br-H4
8.5
8.0
7.5
7.0
6.5
ppm
1H
Figure 3. 1H NMR spectra of halogenated salicylic acid compounds.
while 3,5-chlorosalicylic acid (Fig. 3D) and 3,5-bromosalicylic
acid (Fig. 3G) were isolated in pure form, the purities of the iso-
lated 3-bromosalicylic acid (Fig. 3E) and 5-bromosalicylic acid
(Fig. 3F) were 75.6% and 87%, respectively. For the isolated
3-bromosalicylic acid (Fig. 3E), we observed the resonances of
3-chloro- and 5-chlorosalicylic acids as impurities. Similarly, we
found 3-bromo- and 5-chlorosalicylic acids as impurities
with the isolated 5-bromosalicylic acid (Fig. 3F). The mixed
3-bromo,5-chlorosalicylic acid was isolated as the main product
(78%) in Fig. 3H, with 3-chloro,5-bromosalicylic acid present as an
impurity. Although we did not isolate 3-chloro,5-bromosalicylic
acid as a primary product in which it was the most abundant
compound, because its 1H resonances are well resolved in Fig. 3H,
we were able to complete its resonance assignments using the
HMBC correlations of this impure sample.
The resonance assignments of the monochlorinated and
brominated naproxen analogs were similarly achieved by analysis
of the 1H and 13C chemical shifts, coupling constants, and HMBC
Table 2. 1H and 13C chemical shifts (ppm), coupling constants (Hz), and multiplicities for halogenated naproxen analogs
Naproxen
5-chloronaproxen
5-bromonaproxen
1H
13C
1H
13C
1H
13C
a
—
178.3
46.5
—
178.0
46.4
—
178.0
46.3
b
c
3.83 (q, 7.17)
1.53 (d, 7.13)
3.89 (s)
3.88 (q, 7.17)
3.89 (q, 7.17)
19.2
1.54 (d, 7.17)
19.1
1.55 (d, 7.15)
19.0
d
1
55.6
4.00 (s)
57.3
4.00 (s)
57.3
7.67 (—)
—
127.0
137.3
127.0
130.1
135.0
106.6
158.0
120.0
128.1
130.3
7.75 (—)
127.4
138.3
128.9
124.3
132.1
117.3
153.9
115.2
128.8
130.9
7.75 (—)
127.4
138.2
128.5
127.2
133.3
108.8
155.2
115.0
129.9
131.1
2
—
—
3
7.40 (dd, 8.40,1.97)
7.70 (-)
7.55 (dd, 8.84,1.58)
7.55 (dd, 8.90, 1.64)
4
8.11 (d, 8.80)
8.13 (d, 8.80)
4a
5
—
—
—
7.19 (d, 2.16)
—
—
—
—
—
6
7
7.11 (dd, 8.90,2.60)
7.72 (—)
—
7.42 (d, 9.10)
7.81 (d, 9.00)
—
7.41 (d, 9.00)
7.87 (d, 9.00)
—
8
8a
Magn. Reson. Chem. 2014, 52, 310–317
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K. Solakyildirim, D. N. Bulloch and C. K. Larive
13C–1H correlations (Table 2). A single enantiomer of naproxen
((S)-(+)-6-methoxy-α-methyl-2-naphthaleneacetic acid) was used
in this study. On the basis of the coupling patterns in the 1H
survey spectrum, we discerned that halogenation must have
occurred either at the C-1 or C-5 positions. The H-1 resonances in
the HMBC spectra of chloro- and bromo-naproxen (structures
shown in Table 2) both showed strong long-range correlations
with C-b, C-8, and C-4a suggesting halogenation at C-5. The
three-bond correlations between the H-1 and C-b at δ = 46.4
ppm provided conclusive evidence of the proposed structures,
as this correlation would not be observed if halogenation had
occurred at C-1. Furthermore, as previously discussed for salicylic
acid, the chloro and bromo substituents differently affect the
chemical shift of the carbon atom to which they are directly
attached. Upon chlorination, the 13C frequency of C-5 shifts from
106.6 ppm in the parent to 117.3 ppm, whereas a smaller shift to
108.8 ppm is observed upon bromination.
attached C-4 carbon, which shifted from 120.5 ppm to 113.6 ppm.
Moreover, the chemical shifts of protons (H-3 and H-6) on the aro-
matic rings of both chlorinated and brominated analogs shifted
downfield compared with the parent gemfibrozil compound.
The structures of the chlorinated and brominated analogs of
diclofenac were also determined (Table 4). Diclofenac is an
interesting compound because the parent compound is itself
chlorinated. The location of the chloro and bromo substituents
of the TPs was discerned from the analysis of the coupling
patterns observed in their 1H NMR spectra. The H-3 and H-6
aromatic resonances have a doublet of doublets coupling pattern
in diclofenac reflecting both their 3-bond couplings to the
adjacent proton as well as weaker long-range couplings.
However, in both the chlorinated and brominated diclofenac
analogs, H-6 shows only a pattern of long-range doublet
couplings (J = 2.30 Hz and 2.20 Hz), and H-3 gives rise to a doublet
reflecting its coupling to the H-4 proton (J = 8.61 Hz and 8.58 Hz).
1
1
The H and 13C chemical shift assignments of gemfibrozil and
The structures proposed on the basis of the H NMR spectra of
its chlorinated and brominated analogs, summarized in Table 3,
are in good agreement with prior literature assignments.[8] The
doublet coupling observed between the adjacent H-3 and H-4
protons in gemfibrozil disappears in the 1H-NMR spectra of both
the chlorinated and brominated gemfibrozil analogs, indicating
that halogenation occurred at either C-3 or C-4. In the HMBC
spectrum of chlorogemfibrozil, the H-3 resonance at 7.05 ppm
disclosed long-range correlations with C-8 (CH3), C-1, and C-5,
proving that chlorination did not occur at the H-3 position. Also,
the location of chlorine at the C-4 position, para to an oxygen
substituent, is in a good agreement with the directing effect
of oxygen in the electrophoretic aromatic substitution reaction.[16,17]
Bromination also occurred at the C-4 position; however, the bromide
substituent has a different effect on the frequency of the directly
the halogenation products are also consistent with changes
observed in the 13C chemical shifts. The signal of C-5 appears at
δ = 121.9 ppm, 127.3 ppm, and 114.4 ppm for the parent
diclofenac, chlorinated diclofenac, and brominated diclofenac,
respectively, consistent with the trends observed for the
halogenated salicylic acid analogs. Moreover, the H-3 signal of
diclofenac compounds appears at a very low frequency (around
6.35 ppm), which is explained by the shielding effect of the
8,12-dichlorinated ring.
The full structural elucidation of chlorinated and brominated
1
analogs of tert-octylphenol, including H and 13C chemical shifts
and coupling constants was accomplished using the 1H NMR
survey and HMBC spectra (Table 5). In the parent tert-
octylphenol, the H-3 and H-6 aromatic resonances have a doublet
Table 3. 1H and 13C chemical shifts (ppm), coupling constants (Hz), and multiplicities for halogenated gemfibrozil analogs
Gemfibrozil
4-chlorogemfibrozil
13C
4-bromogemfibrozil
13C
1H
13C
1H
1H
a
—
—
181.9
43.0
—
—
181.6
42.8
—
—
181.7
42.7
b
c,d
e
f
1.21 (s)
1.71 (m)
1.75 (m)
3.91 (t, 5.92)
—
25.4
1.21 (s)
1.71 (m)
1.76 (m)
3.93 (t, 6.03)
—
25.6
1.21 (s)
1.72 (m)
1.76 (m)
3.93 (t, 5.97)
—
25.6
38.2
38.1
38.1
38.2
38.1
38.1
g
1
2
3
4
5
6
7
8
68.8
69.3
69.4
158.4
124.6
131.0
121.9
137.6
113.2
21.4
156.9
127.0
131.3
125.6
134.7
114.5
20.1
157.6
127.3
134.4
115.0
136.7
114.5
22.8
—
—
—
6.94 (d, 7.45)
7.05 (s)
—
7.23 (s)
—
6.61 (dd, 7.63, —)
—
—
—
6.66 (s)
6.76 (s)
2.29 (s)
2.13 (s)
6.78 (s)
2.31 (s)
2.13 (s)
2.27 (s)
2.13 (s)
16.0
15.9
15.7
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1H and 13C NMR spectral assignments of halogenated transformation products
Table 4. 1H and 13C chemical shifts (ppm), coupling constants (Hz), and multiplicities for halogenated diclofenac analogs
Diclofenac
5-chlorodiclofenac
1H
5-bromodiclofenac
1H
1H
13C
13C
13C
a
—
3.63 (s)
—
180.5
43.9
—
175.0
38.7
—
175.1
38.7
b
3.75 (s)
3.74 (s)
1
129.2
144.3
117.9
127.4
121.9
131.2
139.7
130.6
130.0
131.4
—
127.8
143.0
119.8
nd
—
128.1
143.3
120.0
nd
2
—
—
6.38 (d, 8.61)
7.07 (dd, 8.72, 2.46)
—
—
6.32 (d, 8.58)
7.20 (dd, 8.71, 2.27)
—
3
6.37 (dd, 8.10, —)
6.97 (m)
4
5
6.83 (m)
127.3
131.4
138.7
131.1
130.1
131.2
114.4
134.3
138.5
131.1
130.1
131.3
6
7.20 (dd, 7.58, —)
—
7.25 (d, 2.30)
—
7.38 (d, 2.20)
—
7
8,12
9,11
10
—
—
—
7.37 (dd, 7.83, —)
7.01 (t, 8.08)
7.42 (dd, 8.09, —)
7.10 (t, 8.08)
7.43 (dd, 8.11, —)
7.11 (t, 8.15)
Table 5. 1H and 13C chemical shifts (ppm), coupling constants (Hz), and multiplicities for halogenated tertiary octylphenol analogs
4,6-dichloro-tert-
4,6-dibromo-tert-
tert-Octylphenol
4-chloro-tert-octylphenol
octylphenol
4-bromo-tert-octylphenol
octylphenol
1H
13C
1H
13C
1H
13C
1H
13C
1H
13C
a,b,c
d
0.71 (s)
—
32.5
nd
0.73 (s)
—
32.3 0.75 (s)
32.2
nd
0.73 (s)
—
32.4 0.74 (s)
32.4
nd
nd
57.7 1.72 (s)
38.7
—
nd
57.6 1.71 (s)
38.7
—
e
1.72 (s)
—
58
1.72 (s)
—
57.7
39.0
32.2
1.71 (s)
—
57.6
38.8
32.2
131.0
145.5
131.0
nd
f
38.8
32.2
—
—
g,h
1
1.32 (s)
1.32 (s)
32.2 1.32 (s)
126.6 7.25 (s)
1.32 (s)
32.1 1.32 (s)
127.4 7.45 (s)
7.18 (dd, 8.68,—)
128.1 7.13 (dd, 8.52, 2.31)
127.5 7.17 (dd, 8.55, 2.34)
2
—
141.6
128.1
115.3
155.8
115.3
—
7.26 (d, 2.35)
—
143.4
—
143.9
127.5
122.8
148.3
122.8
—
7.42 (d, 2.31)
—
143.7
—
3
7.18 (dd, 8.68, —)
6.69( dd, 8.70, —)
—
128.6 7.25 (s)
131.9 7.45 (s)
4
120.9
151.6
116.9
—
—
—
110.2
152.8
116.4
—
—
—
5
—
—
149.8
nd
6
6.69 (dd, 8.70, —)
6.82 (d, 8.53)
6.81 (d, 8.46)
of doublets coupling pattern reflecting both their 3-bond
couplings to the adjacent proton as well as weaker long-range
couplings. However, in both the 4-chloro tert-octylphenol and
4-bromo tert-octylphenol analogs, H-3 shows only a pattern of
long-range doublet couplings (J = 2.35 Hz and 2.31 Hz), and H-6
gives rise to a doublet reflecting its coupling to the H-1 proton
(J = 8.53 Hz and 8.46 Hz). The position of the second chloro and
bromo substituents was identified by using the coupling patterns
of the H-1 and H-3 protons. Both the H-1 and H-3 aromatic
resonances have a doublet of doublets coupling pattern in the
parent tert-octylphenol but after halogenation at the C-4 and
C-6 positions, both the H-1 and H-3 resonances appeared as
singlets indicating that the second halogenation takes place in
the C-6 position in the dichloro and dibromo tert-octylphenol
analogs. Also, the 13C chemical shifts of C-4 and C-6 at δ = 115.3 ppm
in parent tert-octylphenol analog shifted to δ = 120.9 ppm (C-4) and
δ = 122.8 ppm (C-6) in the 4-chloro tert-octylphenol and 6-chloro
tert-octylphenol analogs, respectively.
Magn. Reson. Chem. 2014, 52, 310–317
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

K. Solakyildirim, D. N. Bulloch and C. K. Larive
wileyonlinelibrary.com/journal/mrc
Copyright © 2014 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2014, 52, 310–317

1H and 13C NMR spectral assignments of halogenated transformation products
The structures of the chlorinated analogs of bisphenol A
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di-, tri- and tetrachlorinated analogs of bisphenol A.
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wileyonlinelibrary.com/journal/mrc