An efficient method for the synthesis of heteroaryl C-O bonds in the absence of added transition metal catalysts

Article abstract of DOI:10.1039/c4ra04851b

Reaction of 2-chloropyrazine and 2-chloropyrimidine with phenols and alcohols in the presence of K₂CO₃ in DMSO results in high yielding S_NAr coupling. The reaction works particularly well with phenols and yields are compar

Full text of DOI:10.1039/c4ra04851b

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An efficient method for the synthesis of heteroaryl
C–O bonds in the absence of added transition
metal catalysts†
Cite this: RSC Adv., 2014, 4, 28072
a
b
a
*
Katie Walsh, Helen F. Sneddon and Christopher J. Moody
Received 17th October 2013
Accepted 18th June 2014
Reaction of 2-chloropyrazine and 2-chloropyrimidine with phenols and alcohols in the presence of K2CO3
in DMSO results in high yielding SNAr coupling. The reaction works particularly well with phenols and yields
are comparable or superior to the metal-catalysed couplings described in the literature.
DOI: 10.1039/c4ra04851b
www.rsc.org/advances
However, although the use of palladium and copper has
substantially promoted these aryl C–O bond forming processes,
Introduction
these precious metals are still being employed for couplings
involving more activated substrates where catalysis may be
unnecessary; for instance, 2-chloropyrimidine is 1014 times
more reactive than chlorobenzene towards SNAr reactions.10
Some recent examples of metal-catalysed couplings with these
more activated heteroaryl halide substrates are shown in
Scheme 1,11–14 with some examples demonstrating low loadings
of the transition metals.15,16 Whilst these catalysed reactions can
be carried out in good yield, the conditions remain quite
forcing, and oen require expensive ligands. In fact the use of
transition metals may not be necessary to carry out these
processes on such activated halides. As a consequence, we
sought to develop an optimised approach to these C–O bond
forming reactions that avoids the use of precious metals, which
others have noted.17,18 In continuation of our interest in alter-
natives to transition-metal catalysed C–O and C–N coupling
reactions, for example in amination chemistry,19 we now report
the results of this study.
The formation of aryl and heteroaryl C–O bonds in organic
chemistry is an important synthetic tool, with the aryl ether
products present in a variety of both natural and synthetic
bioactive molecules. Examples include purmorphamine, which
activates the Hedgehog-signalling pathway, an important
regulator of stem cell renewal and cancer growth,1 and bispyr-
ibac-sodium, which is used as a herbicide (Fig. 1).2
Traditionally the formation of these aryl C–O bonds was
performed using nucleophilic aromatic substitution (SNAr),
however poor substrate scope and reactivity has led to more
elaborate synthetic strategies. For instance, the palladium-cat-
alysed Buchwald–Hartwig reaction,3–5 or modern copper-cata-
lysed variants on the classical Ullmann reaction.6–9
Results and discussion
The reaction of 2-chloropyrimidine and p-cresol to give 2-(p-
tolyloxy)pyrimidine 1 was used as a typical example, in order to
carry out an initial investigation into the optimum choice of
solvent and base (Table 1). We limited our solvent selection only
to those that are generally accepted as ‘green’.20
Reactions in 2-methyltetrahydrofuran, 1-butanol and cyclo-
pentylmethylether (entries 1–3) gave poor recoveries, as did
reactions in water using potassium uoride as the base
(entry 4), although these could be improved when switching to
potassium carbonate and tribasic potassium phosphate (entries
6 and 7). Combinations of DMSO and water gave improved
yields (entries 9 and 10) whilst the highest yields were obtained
using DMSO, which also made the reaction mixtures much
cleaner and easier to extract and purify. For extractions,
Fig. 1 Structures of purmorphamine and bispyribac-sodium.
aSchool of Chemistry, University of Nottingham, University Park, Nottingham NG7
2RD, U.K. E-mail: c.j.moody@nottingham.ac.uk; Fax: +44 (0)115 951 3564
bGreen Chemistry Performance Unit, GlaxoSmithKline R&D Ltd, Medicines Research
Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K
† Electronic supplementary information (ESI) available: Copies of NMR spectra.
See DOI: 10.1039/c4ra04851b
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Table 1 Optimisation of conditions for coupling 2-chloropyrimidine
and p-cresola
Entry
Base
Solvent
Temp/ꢀC
Yield/%
1
2
3
4
5
6
7
8
KF
KF
KF
KF
2-Methyl THF
1-Butanol
Cyclopentylmethylether
H2O
DMSO
H2O
H2O
DMSO
DMSO/H2O
DMSO/H2O
DMSO
DMSO
DMSO
Propylene carbonate
2-Methyl THF
1-Butanol
80
80
80
80
80
100
100
100
100
100
100
100
100
100
80
—
19b
—
24b
KF
40b
K3PO4
K2CO3
DBU
60b
54b
33b
9
K3PO4
K2CO3
K3PO4
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
64 (72b)
66 (71b)
70 (78b)
73 (78b)
65 (69b)
60b
10
11
12
13
14
15
16
64b
80
59b
a
All reactions were performed using 2-chloropyrimidine (1.75 mmol)
and p-cresol (1.75 mmol), with the specied base (3.50 mmol) and
b
solvent (1 mL), at the given temperature for 17 h. Yield given as a
conversion% as measured from 1H NMR integration.
With the optimum conditions established, the reactivities of
2-chloropyrimidine and 2-chloropyrazine were tested against
various phenols and primary alcohols (Table 2) to judge how the
methodology compared to the metal-catalysed literature proto-
cols shown in Scheme 1. The results show that reactions
involving phenols (entries 1–6, 9–11) gave the highest yields. For
the reactions with 2-chloropyrimidine (entries 1, 4–7) the
products were obtained in directly comparable yields to those
repeated in the literature; p-cresol for instance gave a yield of
Scheme 1 Examples of palladium- and copper-catalysed formation of
heteroaryl ethers [NMP ¼ N-methylpyrrolidine].
isopropyl acetate was chosen since this is easier to recycle and 73% compared to 66% under copper catalysis (Scheme 1).13
recover on larger scale. Reactions with simple primary and secondary alkyl alcohols,
In terms of the base, inorganic reagents proved more effec- such as 2-(4-methoxyphenyl)ethanol, 3-octyn-1-ol or cyclo-
tive than an organic base such as DBU (entry 8). Potassium hexanol, were examined but without success. Changing the base
uoride (entries 1–5) gave poor recoveries whilst potassium and from potassium carbonate to potassium hydroxide or KHMDS
caesium carbonate bases and tribasic potassium phosphate (in THF) made no difference. Substitutions involving primary
gave good to excellent yields. Propylene carbonate (entry 14) was benzylic alcohols (entries 7 and 8) gave lower yields; 51% and
also tested as an alternative to DMSO, however not only was the 33% for furfuryl alcohol and benzyl alcohol respectively.
yield lowered but removal of the propylene carbonate at the end
Interestingly, substitution reactions with 2-chloropyrazine
of the process was difficult. On the other hand, 2-methyl-THF (entries 9–11) gave superior yields than those with 2-chlor-
and 1-butanol performed relatively well (entries 15 and 16), and opyrimidine (entries 1 and 2); for instance the coupling of 2-
in the latter case there was no sign of any butoxypyrimidine chloropyrazine with p-cresol gave an excellent yield of 93%.
showing the lack of reactivity of primary alcohols under these However in our previous amination chemistry,19 2-chloropyr-
conditions (see below). It was found that by using two equiva- imidine was found to generally give better yields as it is 102
lents of potassium carbonate in DMSO at 100 C for 17 h, the times more reactive to nucleophilic substitution.21 Again, the
ꢀ
highest yield of 73% of 2-(p-tolyloxy)pyrimidine 1 was achieved greater reactivity of phenols over primary alcohols under these
(entry 9). Indeed this result was superior to the literature yield of conditions is seen with the reaction of 2-(4-hydroxyphenyl)-
66% using copper catalysis under more forcing conditions.13
ethanol (entry 11).
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Table 2 Reactions of 2-chloropyrimidine and 2-chloropyrazine with alcohols and phenolsa
Entry
1
Heteroaryl halide
Alcohol/phenol
Product
Yield/%b
73 [66]
2
3
4
63
72
67 [71]
5
6
67 [76]
65 [65, 97, 99]
7
51
8
35
9
93
10
91 [87]
11
87 [83]
a
All reactions were performed using 2-chloropyrimidine or -pyrazine (1 eq.), alcohol (1 eq.) and K2CO3 (2 eq.) in DMSO at 100 ꢀC for 17 h. b Yields in
square brackets are for metal-catalysed literature couplings shown in Scheme 1.
Not only do the couplings have comparable and oen temperatures up to 120 ꢀC for 24 h (Scheme 1), compared to 100
superior yields to their metal-catalysed counterparts described ꢀC for 17 h. Hence these conditions are not only greener in
in the literature that generally require the use of use terms of solvent,20 cheaper in that potassium carbonate is less
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expensive than palladium or copper catalysts (plus complex
ligands in some cases), but also more energy efficient. The
potassium carbonate used was assayed by ICP-MS, and found to
contain less than 20 and 75 ppb of palladium and copper
respectively. Hence we are wary of claiming that our reactions
are palladium- or copper-free, mindful of previous “palladium-
free” Suzuki biaryl couplings, where the commercial sodium
carbonate that contained 50 ppb palladium was possibly
responsible for the biaryl formation,22 but nevertheless they
proceed well in the absence of added transition-metal or
ligands.
2-(4-Methylphenoxy)pyrimidine 1
Following the general procedure, 2-chloropyrimidine (200 mg,
1.75 mmol), p-cresol (184 mL, 1.75 mmol) and potassium
carbonate (483 mg, 3.50 mmol) in DMSO (1 mL) at 100 ꢀC for 17
h gave aer purication by chromatography (1 : 9 ethyl acetate/
light petroleum) the title compound as a yellow oil (237 mg,
73%); (lit.,13 mp 70–71 ꢀC); (found; M+, 187.0872. C11H11N2O
requires 187.0866); dH (400 MHz; CDCl3) 8.58 (2H, d, J 4.8, 4H,
6H), 7.25 (2H, d, J 8.3, ArH), 7.11 (2H, d, J 8.3, ArH), 7.03 (1H, t, J
4.8, 5H), 2.39 (3H, s, CH3); dC (100 MHz; CDCl3) 165.6 (C), 159.7
(CH), 150.6 (C), 135.2 (C), 130.3 (CH), 121.4 (CH), 116.0 (CH),
21.0 (CH3). Data recorded matches literature.13
Conclusions
2-(2-Methylphenoxy)pyrimidine 2
An efficient, green method to access aryl C–O bonds, without
the need for added transition-metal catalysis is described.
Results show that optimum yields were obtained using only
potassium carbonate in DMSO at 100 ꢀC. These conditions were
tested on several phenols and alcohols. The best results were
seen with phenols, which gave high yields comparable to those
seen in the literature involving palladium and copper catalysis.
Following the general procedure, 2-chloropyrimidine (200 mg,
1.75 mmol), o-cresol (180 mL, 1.75 mmol) and potassium
carbonate (483 mg, 3.50 mmol) in DMSO (1 mL) at 100 ꢀC for 17
h gave aer purication by chromatography (1 : 9 ethyl acetate/
light petroleum) the title compound as a yellow solid (238 mg,
+
67%); mp 76–78 C (lit.,13 mp 77–78 C); (found; M , 187.0875.
C
ꢀ
ꢀ
11H11N2O requires 187.0866); nmax (CHCl3)/cmꢁ1 3004, 1573,
1495, 1409, 1320, 1287; dH (400 MHz; CDCl3) 8.58 (2H, d, J 4.5,
4H, 6H), 7.32–7.27 (2H, m, ArH), 7.22–7.19 (1H, m, ArH), 7.15–
7.13 (1H, m, ArH), 7.05–7.02 (1H, m, ArH), 7.03 (1H, t, J 4.5, 5H),
2.21 (3H, s, CH3); dC (100 MHz; CDCl3) 165.2 (C), 159.8 (CH),
151.3 (C), 131.4 (CH), 130.6 (C), 127.1 (CH), 125.9 (CH), 121.9
(CH), 116.0 (CH), 16.3 (CH3). Data recorded matches
literature.13
Experimental
General experimental details
Commercially available reagents were used throughout without
purication unless otherwiꢀse stated. Light petroleum refers to
the fraction with bp 40–60 C.
Analytical thin layer chromatography was carried out on
aluminium backed plates coated with silica gel, and visualized
under UV light at 254 and/or 360 nm and/or by chemical
staining. Flash chromatography was carried out using silica gel,
with the eluent specied.
Infrared spectra were recorded using an FT-IR spectrometer
over the range 4000–600 cmꢁ1. NMR spectra were recorded at
400 or 500 MHz (1H frequency, 100 or 125 MHz 13C frequency).
Chemical shis are quoted in parts per million (ppm), and are
referenced to residual H in the deuterated solvent as the
internal standard. Coupling constants, J, are quoted in Hz. In
the 13C NMR spectra, signals corresponding to CH, CH2, or CH3
groups are assigned from DEPT. Mass spectra were recorded on
a time-of-ight mass spectrometer using electrospray ionization
(ESI), or an EI magnetic sector instrument.
2-(4-Methoxyphenoxy)pyrimidine 3
Following the general procedure, 2-chloropyrimidine (200 mg,
1.75 mmol), 4-methoxyphenol (217 mg, 1.75 mmol) and potas-
sium carbonate (483 mg, 3.50 mmol) in DMSO (1 mL) at 100 ꢀC
for 17 h gave aer purication by chromatography (1 : 4 ethyl
acetate/light petroleum) the title compound as a colourless solid
(253 mg, 72%); mp 57–59 ꢀC; (found; M+, 225.0640.
C
11H11N2O2Na+ requires 225.0640); nmax (CHCl3)/cmꢁ1 3006,
2838, 1612, 1571, 1507, 1465; dH (400 MHz; CDCl3) 8.58 (2H, d, J
4.7, 4H, 6H), 7.15 (2H, d, J 9.2, ArH), 7.03 (1H, t, J 4.7, 5H), 6.97
(2H, d, J 9.2, ArH), 3.84 (3H, s, CH3); dC (100 MHz; CDCl3) 165.7
(C), 159.7 (CH), 157.1 (C), 146.3 (C), 122.5 (CH), 116.0 (CH),
114.7 (CH), 55.6 (CH3).
General procedure
2-(2-Methoxyphenoxy)pyrimidine 4
To a Reacti-vial (Thermo Scientic) was added aryl halide (1 eq., Following the general procedure, 2-chloropyrimidine (200 mg,
1.75 mmol), alcohol (1 eq., 1.75 mmol), reagent grade potas- 1.75 mmol), 2-methoxyphenol (195 mL, 1.75 mmol) and potas-
sium carbonate (2 eq., 3.50 mmol) in dimethylsulfoxide (1 mL) sium carbonate (483 mg, 3.50 mmol) in DMSO (1 mL) at 100 ꢀC
and the resulting mixture heated to 100 ꢀC for 17 h on a heating for 17 h gave aer purication by chromatography (1 : 4 ethyl
block. Aer cooling, the mixture was quenched with water (20 acetate/light petroleum) the title compound as a yellow solid (238
+
mL) and saturated potassium carbonate solution (10 mL), and mg, 67%); mp 118–120 C (lit.,13 mp 121–122 C); (found; M ,
extracted with isopropyl acetate (2 ꢂ 20 mL). The combined 203.0822. C11H11N2O2 requires 203.0815); nmax (CHCl3)/cmꢁ1
organic layers were then washed with brine (30 mL), dried over 3009, 1607, 1573, 1501, 1465, 1439; dH (400 MHz; CDCl3) 8.57
sodium sulfate and the solvent evaporated under reduced (2H, d, J 4.7, 4H, 6H), 7.27–7.26 (1H, m, ArH), 7.25–7.24 (1H, m,
pressure. If necessary the residue was puried by chromatog- ArH), 7.23–7.22 (1H, m, ArH), 7.06–7.04 (1H, m, ArH), 7.03 (1H,
ꢀ
ꢀ
raphy on silica gel.
t, J 4.7, 5H), 3.77 (3H, s, OCH3); dC (100 MHz; CDCl3) 165.3 (C),
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159.6 (CH), 151.6 (C), 141.9 (C), 126.6 (CH), 122.8 (CH), 121.0 (2H, s, CH2); dC (100 MHz; CDCl3) 165.0 (C), 159.3 (CH), 136.5
(CH), 115.9 (CH), 112.8 (CH), 55.9 (CH3). Data recorded matches (C), 128.4 (CH), 127.9 (CH), 127.9 (CH), 115.1 (CH), 69.0 (CH2).
literature.13
2-(4-Methylphenoxy)pyrazine 9
2-(3,4-Dimethylphenoxy)pyrimidine 5
Following the general procedure, 2-chloropyrazine (156 mL, 1.75
Following the general procedure, 2-chloropyrimidine (200 mg,
mmol), p-cresol (184 mL, 1.75 mmol) and potassium carbonate
1.75 mmol), 3,4-dimethylphenol (214 mg, 1.75 mmol) and
(483 mg, 3.50 mmol) in DMSO (1 mL) at 100 ꢀC for 17 h gave the
potassium carbonate (483 mg, 3.50 mmol) in DMSO (1 mL) at
title compound as a beige crystalline solid (302 mg, 93%); mp 38–
100 ꢀC for 17 h gave aer purication by chromatography (1 : 4
40 ꢀC; (found; M+, 187.0875. C11H10N2O requires 187.0866); nmax
ethyl acetate/light petroleum) the title compound as a yellow oil
(CHCl3)/cmꢁ1 3061, 1580, 1532, 1504, 1465, 1401; dH (400 MHz;
(235 mg, 67%); (lit.,13 mp 49–51 ꢀC); (found; M+, 201.1028.
CDCl3) 8.43 (1H, d, J 1.1, 3H), 8.25 (1H, d, J 2.7, 6H), 8.11 (1H,
C
12H13N2O requires 201.1022); nmax (CHCl3)/cmꢁ1 3004, 1614,
dd, J 2.7, 1.1, 5H), 7.24 (2H, d, J 8.5, ArH), 7.07 (2H, d, J 8.5, ArH),
2.39 (3H, s, CH3); dC (100 MHz; CDCl3) 160.5 (C), 150.7 (C), 141.1
(CH), 138.3 (CH), 135.8 (CH), 135.1 (C), 130.3 (CH), 121.1 (CH),
20.9 (CH3).
1571, 1500, 1450, 1410; dH (400 MHz; CDCl3) 8.58 (2H, m, ArH,
4H, 6H), 7.20 (1H, d, J 7.8, ArH), 7.04–7.00 (2H, m, ArH), 6.98
(1H, d, J 7.8, ArH), 2.30 (3H, s, CH3), 2.29 (3H, s, CH3); dC (100
MHz; CDCl3) 165.7 (C), 159.7 (CH), 150.8 (C), 138.2 (C), 133.9
(C), 130.7 (CH), 122.6 (CH), 118.8 (CH), 115.9 (CH), 20.0 (CH3),
19.3 (CH3). Data recorded matches literature.13
2-(2-Methylphenoxy)pyrazine 10
Following the general procedure, 2-chloropyrazine (156 mL, 1.75
mmol), o-cresol (180 mL, 1.75 mmol) and potassium carbonate
2-Phenoxypyrimidine 6
Following the general procedure, 2-chloropyrimidine (200 mg, (483 mg, 3.50 mmol) in DMSO (1 mL) at 100 ꢀC for 17 h gave the
ꢀ
1.75 mmol), phenol (165 mg, 1.75 mmol) and potassium title compound as a yellow solid (295 mg, 91%); mp 40–42 C;
carbonate (483 mg, 3.50 mmol) in DMSO (1 mL) at 100 ꢀC for 17 (found; M+, 187.0868. C11H10N2O requires 187.0866); nmax
h gave aer purication by chromatography (1 : 9 ethyl acetate/ (CHCl3)/cmꢁ1 2915, 1578, 1531, 1485, 1466, 1397; dH (400 MHz;
light petroleum) the title compound as a yellow crystalline solid CDCl3) 8.45 (1H, d, J 1.2, 3H), 8.27 (1H, d, J 2.8, 6H), 8.11 (1H,
(195 mg, 65%); mp 84–86 ꢀC (lit.,13 mp 85–86 ꢀC); nmax (CHCl3)/ dd, J 2.8, 1.2, 5H), 7.34–7.27 (2H, m, ArH), 7.22 (1H, dt, J 7.5, 1.5,
cmꢁ1 3062, 1592, 1568, 1489, 1453, 1401; dH (400 MHz; CDCl3) ArH), 7.09 (1H, dd, J 7.8, 1.5, CH3); dC (100 MHz; CDCl3) 160.2
8.58 (2H, d, J 4.8, 4H, 6H), 7.46 (1H, t, J 7.7, ArH), 7.28 (1H, t, J (C), 151.3 (C), 141.3 (CH), 138.1 (CH), 135.3 (CH), 131.6 (CH),
7.8, ArH), 7.25–7.21 (2H, m, ArH), 7.05 (1H, t, J 4.8, 5H), 6.89 130.7 (C), 127.3 (CH), 125.9 (CH), 121.7 (CH), 16.3 (CH3). Data
(1H, d, J 7.8, ArH); dC (100 MHz; CDCl3) 165.3 (C), 159.8 (CH), recorded matches literature.11
152.3 (C), 129.8 (CH), 125.7 (CH), 121.7 (CH), 155.6 (CH), 111.6
(CH). Data recorded matches literature.13
2-(4-(Pyrazin-2-yloxy)phenyl)ethanol 11
Following the general procedure, 2-chloropyrazine (156 mL, 1.75
mmol), 2-(4-hydroxyphenyl)ethanol (242 mg, 1.75 mmol) and
potassium carbonate (483 mg, 3.50 mmol) in DMSO (1 mL) at
100 ꢀC for 17 h gave aer purication by chromatography (ethyl
acetate) the title compound as a colourless crystalline solid (311
mg, 87%); mp 65–67 ꢀC (lit.,14 mp 75 ꢀC); (found; M+, 239.0779.
2-(2-Furylmethoxy)pyrimidine 7
Following the general procedure, 2-chloropyrimidine (200 mg,
1.75 mmol), furfuryl alcohol (156 mL, 1.75 mmol) and potassium
carbonate (483 mg, 3.50 mmol) in DMSO (1 mL) at 100 ꢀC for 17
h gave the title compound as a brown oil (156 mg, 51%); (found;
M+, 199.0987. C9H9N2O2Na+ requires 199.0483); nmax (CHCl3)/
cmꢁ1 3009, 1578, 1568, 1502, 1449, 1425; dH (400 MHz; CDCl3)
8.55 (2H, d, J 4.8, 4H, 6H), 7.44 (1H, m, ArH), 6.97 (1H, t, J 4.8,
5H), 6.50–6.49 (1H, m, ArH), 6.38 (1H, m, ArH), 5.41 (2H, s,
CH2); dC (100 MHz; CDCl3) 165.5 (C), 159.3 (CH), 149.9 (C), 143.0
(CH), 115.3 (CH), 110.5 (CH), 107.4 (CH), 61.1 (CH2).
C
12H12N2O2 requires 239.0797); nmax (CHCl3)/cmꢁ1 3619, 3441,
3066, 3008, 2951, 1581; dH (400 MHz; CDCl3) 8.42 (1H, d, J 1.2,
3H), 8.25 (1H, d, J 2.6, 5H), 8.09 (1H, dd, J 2.6, 1.2, 6H), 7.30 (2H,
d, J 8.5, ArH), 7.12 (2H, d, J 8.5, ArH), 3.88 (2H, t, J 6.5, CH2), 2.90
(2H, t, J 6.5, CH2); dC (100 MHz; CDCl3) 160.3 (C), 151.5 (C),
141.1 (CH), 138.4 (CH), 135.9 (CH), 135.9 (CH), 130.4 (CH), 121.3
(CH), 63.5 (CH2), 38.6 (CH2). Data recorded matches literature.14
2-Benzyloxypyrimidine 8
Following the general procedure, 2-chloropyrazine (156 mL, 1.75
mmol), benzyl alcohol (181 mL, 1.75 mmol) and potassium
ICP-MS analysis
carbonate (483 mg, 3.50 mmol) in DMSO (1 mL) at 100 ꢀC for 17 Approximately 100 mg of potassium carbonate sample material
h gave evaporation of the remaining benzyl alcohol the title was dissolved and diluted to 50 mL of sample matrix solution
compound as a colourless oil (115 mg, 35%); (found; M+, (5% hydrochloric acid, 1% hydrogen peroxide aqueous solu-
187.0882. C11H10N2O requires 187.0866); nmax (CHCl3)/cmꢁ1 tion), and analysed by ICP-MS (ICP-MS X-SERIES 2 Thermo
3010, 1579, 1567, 1497, 1458, 1424; dH (400 MHz; CDCl3) 8.56 analyser). The instrument limit of quantitation was determined
(2H, d, J 4.8, 4H, 6H), 7.52 (1H, dd, J 7.2, 1.5, ArH), 7.39 (2H, dt, J by 10 times injection of blank matrix solution as 21 ppb and 7
7.2, 1.5, ArH), 7.35–7.31 (1H, m, ArH), 6.97 (1H, t, J 4.8, 5H), 5.48 ppb for Cu and Pd respectively.
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59.9
74
21.9
16.7
19
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Acknowledgements
We thank the Engineering and Physical Sciences Research
Council and GlaxoSmithKline for an Industrial CASE award
(to K. W) and Ben Pointer-Gleadhill for the ICP-MS data.
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