Design and preparation of polyphenyl distance markers for solid-state 19F NMR

Article abstract of DOI:10.1560/9T7N-K3L6-TTUF-359R

With ¹³C-labeled samples, it is possible to measure internuclear distances up to 7 A by solid-state NMR, thus providing a powerful tool for probing ligand-receptor interactions. However, limitations in measurable distances and appreciable natur

Full text of DOI:10.1560/9T7N-K3L6-TTUF-359R

Design and Preparation of Polyphenyl Distance Markers for Solid-State 19F NMR
KENJI MONDE,† YORK TOMITA,‡ M. LANE GILCHRIST JR.,¶ ANN E. MCDERMOTT, KOJI NAKANISHI*
Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
(Received 23 August 2000 and in revised form 11 October 11 2000)
Abstract. With 13C-labeled samples, it is possible to measure internuclear dis-
tances up to 7 Å by solid-state NMR, thus providing a powerful tool for probing
ligand–receptor interactions. However, limitations in measurable distances and
appreciable natural abundant 13C background signals present problems in solid-state
13C NMR. In order to overcome these disadvantages, a set of reference compounds
with known F–F distances, namely, quinolinol, p-biphenyl, and p-terphenyl-bearing
trifluoromethyl and trifluoromethylthio groups, have been synthesized. The prepara-
tion of these reference compounds and means for diluting these references in solid-
state NMR are described.
INTRODUCTION
systems, we have examined the magnetization exchange
Magnetization exchange mediated by dipolar coupling effects between two fluorine functional groups using
has been used for determining internuclear distances in distance marker compounds in the range of 5–16 Å. The
molecules in the solid state.1–3 In the case of 13C-labeled results have shown that distances up to ca. 12 Å can be
samples, it is possible to measure internuclear distances measured.7 In the following, we describe the design and
up to 7 Å by solid-state NMR.2,3 Various pulse se- preparation of polyphenyl compounds bearing two fluo-
quences have been developed for distance measure- rine functional groups that were used as distance mark-
ments; some of the widely used techniques based on ers. These series of molecules (nicknamed “shishkebabs”
homonuclear dipolar interactions being rotational reso- from the molecular shape) fulfilled the requirements for
nance4 and radio-frequency-driven dipolar recoupling.5 solid-state 19F NMR measurements.
Distance measurements of a doubly 13C-labeled retinal
bound to bacteriorhodopsin6 have demonstrated the util-
RESULTS AND DISCUSSION
ity of solid-state NMR as a powerful tool for probing
After examination of several fluorine functional groups,
ligand–receptor interactions. However, limitations in
e.g., ArOCF3, ArCD2F, and ArF, the trifluoromethyl and
measurable distances and appreciable natural abundant
trifluoromethylthio groups attached to rigid aromatic
13C background signals present problems in solid-state
ring systems were chosen. These two functionalities
13C NMR.
satisfy the criteria for solid-state NMR distance mea-
To overcome these disadvantages, we have recently
surements since their 19F NMR signals are well sepa-
conducted solid-state 19F NMR distance measurements.7
rated (∆δ = ca. 20 ppm) and since, compared to mono or
Since fluorine has a larger gyromagnetic ratio than that
*Author to whom correspondence should be addressed.
of 13C by a factor of 3.7, longer distance measurements
can be obtained with enhanced sensitivity. Moreover,
E-mail: kn5@columbia.edu
†
Present addresses: Institute for Chemical Reaction Science,
fluorine can be readily incorporated into ligand mol-
Tohoku University, Katahira 2-1-1, Sendai 980-8577, Japan.
ecules by synthesis or biosynthesis. Other attributes of
‡Lombardi Cancer Center, Georgetown University Medical
the fluorine nuclei are the large chemical shift anisot-
Center, 3970 Reservoir Road, NW, Washington, DC 20007,
USA. ¶Department of Chemical Engineering, City College of
New York, 140th St. and Convent Ave., New York, NY
10031, USA.
ropy and, unlike carbon and hydrogen, the absence of
NMR background signals in nature. In order to measure
long-range 19F–19F internuclear distances in biological
Israel Journal of Chemistry
Vol. 40
2000 pp. 301–306

302
Table 1
Perdeuteration of compounds 1 and 2
conditions
deuteration ratio (%)a
entry
substrate
reagents
concd D2SO4
time
methodb
yield
2
3
5
6
7
8
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2
2
2
2
2
11 h
4 h
15 min
5 min
10 min
9 min × 4c
5 h
15 min
25 min
20 min
10 min × 4c
A
A
B
B
B
B
A
B
B
B
17%
99%
85%
37%
24%
3%
45%
29%
decomp
33%
21%
0
0
0
0
0
0
27
99
0
0
0
0
33
45
51
99
0
0
0
0
71
78
83
0
3M D2SO4–D2O–DME
40% NaOD–D2O
10% NaOD–D2O
8% NaOD–D2O
8–10% NaOD–D2O
concd D2SO4
37% DCl–D2O
concd D2SO4
40% NaOD–D2O
10–40% NaOD–D2O
99
50
61
70
78
99
99
0
0
99
0
0
10
11
99
98
99
98
50
55
99
85
99
89
99
92
B
a Numbers denote deuteration sites on the quinoline ring system (see Scheme 1). b Method A: Mixture was heated in sealed tubes
at 150~200 °C. Method B: Mixture was heated in a Teflon bomb in the microwave oven. Mixture was submitted to four
microwave treatments.
c
R
R
OH
R
SH
Br
SR
5
4
R
R
3
R
a
b
6
+
2
7
N
R'
8
1
R'
B(OH)
Br
2
SR
1 R=H or D, R'=CF
2 R=R'=H or D
7 R=CF
8 R=CH
R=CF
3
3
3
R=CH
3
3
3 R=CF
3
4 R=CH
R
3
CF
R
3
R
Br
Br
b
c
b
+
+
7
B(OH)
2
R=CF
B(OH)
3
Br
2
R=CH
3
9 R=CF
10 R=CH
11
R'
5 R=CF , R'=SCF
3
3
3
3
6 R=R'=CH
3
Scheme 1. Synthesis of polyphenyl distance markers and dilutants. (a) CF3I, Et3N/DMF; (b) Pd(PPh3)4/20% Na2CO3–H2O–
toluene; (c) i) n-BuLi/THF, ii) B(O-i-Pr)3, iii) 10% HCl.
difluoro functional groups, the trifluoromethyl groups nyl 3, p-terphenyl 5, and p-quaterphenyl8 compounds
have moderate spin lattice relaxation times with strong bearing trifluoromethyl and trifluoromethylthio groups
intensity. The perdeuterated derivative of the commer- at terminal positions were employed. The interfluorine
cially available 2,8-bis(trifluoromethyl)-4-quinolinol 1 distances in these rigid molecules are 5.4 Å for 1, 11.5 Å
was used as the model with a short F–F distance. As for 3, 15.8 Å for 5, and 20.1 Å for the p-quaterphenyl
references for longer F–F distances, the series p-biphe- compound, as estimated by Macromolecule 5.0.
Israel Journal of Chemistry
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303
Biphenyl and terphenyl fluorinated compounds 3, 5 wave irradiation of both 1 and 2 (Table 1, entries 6 and
were synthesized mainly by sequential Suzuki coupling 11), while high temperature deuterium exchange reac-
reactions.9 Trifluoromethylation of 4-bromothiophenol tion of 1 (3M D2SO4, 200 °C) gave only 3-d-1 (Table1,
was performed by trifluoromethyl iodide in the presence entry 2).
of triethylamine.10 The resulting bromothioanisole 7
The present study describes the preparation of
was subjected to cross coupling reaction with 4- polyphenyl distance marker compounds, including the
trifluoromethylphenylboronic acid, with Pd(PPh3)4 as dilution methods best suited for solid-state 19F NMR.
catalyst, to give the biphenyl compound 3. Terphenyl Due to the synthetic ease of these compounds, they are
compound 5 was prepared by sequential coupling. suited for use as references for calibration of distance
Namely, coupling of trifluoromethylphenylboronic acid measurements in organic host–guest systems or in mac-
with excess 1,4-dibromobenzene gave mono coupling romolecular biological systems. Details of the solid-
compound 9, 74% yield. This was subjected to metal- state 19F NMR studies will be published elsewhere.7
halogen exchange followed by a triisopropyl borate-
hydrolysis protocol11 to afford 11, which, upon cross
coupling with 7, yielded the terphenyl compound 5,
82% yield.
EXPERIMENTAL SECTION
General
To measure the distances correctly between the two
groups in these molecules, intermolecular dipolar cou-
plings from neighboring fluorine compounds should be
minimized. For this purpose, several methods were ex-
amined, including host–guest techniques using organic
or inorganic host molecules. Finally, it was found that
1
Melting points are uncorrected. H and 13C spectra were
measured on Bruker DRX 400 or DMX 300 spectrometers
with tetramethylsilane as internal standard. 19F NMR spectra
in solution were measured on a Varian VXR 200 spectrometer
with fluorobenzene as the external standard. IR spectra were
recorded on a Perkin-Elmer Paragon 1000FT IR spectropho-
dilution by co-crystallization with structurally similar tometer as CHCl3 solution or KBr pellets. Measurements of
low- and high-resolution mass spectra were performed on a
NERMAG R10-10 or a JEOL JMS-DX 303HF mass spec-
trometer. UV spectra were recorded on a Perkin-Elmer
Lambda 40 UV spectrometer. HPLC analysis was performed
with a Perkin-Elmer Model Series 4 liquid chromatograph
with YMC-Pack SIL (150 × 4.6 mm i.d., S-3 µm, 120 Å) with
hexane. Microwave reactions were conducted in a commer-
cially available Sanyo-EM729 microwave oven (900 W).
Analytical TLC was performed with precoated silica gel plates
(Merck Art 7754) and preparative TLC with Analtech
Uniplate silica gel GF preparative layers, 20 × 20 cm (1000
nonfluorinated compounds was the most effective
method. Since the nonfluorinated molecules, so-called
“dilutants”, should be structurally similar to the corre-
sponding fluorinated molecules, compounds 2, 4, and
612 were designed for 1, 3, and 5, respectively. Single
Suzuki coupling of 4-bromothioanisole 8 with 4-
methylphenylboronic acid gave the biphenyl dilutant 4.
Synthesis of terphenyl 6 was performed by stepwise
coupling reactions. Excess of 1,4-dibromobenzene was
reacted with 4-methylphenylboronic acid to give 4-
bromo-4′-methylbiphenyl 10 in 87% yield. The second microns). Silica gel used for flash column chromatography
was Selecto Scientific silica gel, 32–63 mesh (Art 162824).
coupling reaction of 10 with boronic acid gave
terphenyl dilutant 6 as a white solid. Careful crystalliza-
tion of the nonfluorinated compound with trace amounts
of the fluorinated sample from moderate solvents at
ambient temperature gave samples for solid-state NMR
measurements. In some cases, lyophilization of frozen
benzene containing the dilutant and a small amount of
Synthesis
Perdeuterio-2,8-bis(trifluoromethyl)-4-quinolinol (1).
Compound 1 (360 mg, 1.28 mmol) was dissolved in 12 mL of
10% NaOD–D2O, poured into Teflon bombs (2 mL × 6) which
were then placed in the center of the microwave oven. The
high energy setting was used three times for 3 min each time.
the fluorine sample was performed. The ratio of The combined aqueous reaction mixture was diluted with
water (200 mL) and acidified with 6 M HCl to pH ~1. To the
acidic aqueous solution, solid NaHCO3 was added gradually,
and the mixture was extracted twice with ethyl acetate (200 mL
× 2). The combined organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo to give first residue
(174 mg, 48%). The residue was submitted to a second heating
in the same manner and workup. Microwave heating was
performed a total of three times to obtain perdeuterated 1
(10 mg, total 3%). Further purification by PTLC (SiO2, ben-
zene/ethyl acetate) gave pure perdeuterated 1 (3.5 mg). Deu-
fluorinated compounds to nonfluorinated compounds,
which was <1%, was determined by HPLC.
Perdeuterio-1 and -2 were prepared in order to mini-
mize the effects of proton coupling and to compare with
magnetization exchange experiments obtained from the
fully protonated samples. Perdeuteration of 1 and 2 was
achieved by base-catalyzed deuterium–hydrogen ex-
change reaction in a microwave oven.13 Microwave irra-
diation accelerated the deuterium exchange rate of 1 and
2, especially under basic conditions (Table 1). Almost
1
teration ratio was determined by H NMR comparison to a
complete exchange was observed by sequential micro- phenolic signal as an internal standard. Non-labeled com-
Monde et al. / F–F Distance Markers for NMR

304
1
pound: H NMR (400 MHz, acetone-d6) δ 7.37 (s, 1H, 3-H), reaction mixture was then diluted with water and extracted
7.83 (dd, J = 8.4, 7.3 Hz, 1H, 6-H), 8.28 (d, J = 7.3 Hz, 1H, twice with ether. The combined ether solution was washed
7-H), 8.59 (d, J = 8.4 Hz, 1H, 5-H), 11.40 (brs, 1H, OH). with water and dried over Na2SO4. The residue obtained after
1
Labeled compound: H NMR (400 MHz, acetone-d6) δ 7.37 solvent removal in vacuo was submitted to flash chromatogra-
(0.22H), 7.83 (0.49H), 8.28 (0.17H), 8.59 (0.73H), 11.20 (brs, phy on silica gel (pentane) to give a white solid (272 mg,
1
1H, OH).
74%): mp 117–118 °C; H NMR (400 MHz, CDCl3) δ 7.46
(brd, J = 8.4 0.3 Hz, 2H), 7.60 (brd, J = 8.4 0.3 Hz, 2H),
7.65 (brd, J 8.4 0.3 Hz, 2H), 7.70 (brd, J = 8.4 0.3 Hz, 2H);
Perdeuterio-4-hydroxyquinoline (2). Compound 2
(550 mg, 3.79 mmol) was dissolved in 18 mL of 10% NaOD–
D2O, poured into Teflon bombs (2 mL × 9), and placed in the
center of the microwave oven. The high energy setting was
used twice for 5 min each time. The combined aqueous reac-
tion mixture was diluted with water (300 mL) and acidified
with 6 M HCl to pH ~1. To the acidic aqueous solution, solid
NaHCO3 was added gradually, and the mixture was extracted
twice with ethyl acetate (300 mL × 2). The combined organic
layers were dried over Na2SO4, filtered, and concentrated in
vacuo to give the first residue (416 mg, 76%). The residue was
submitted to a second heating in the same manner and workup.
A total of four microwave heatings were performed to give
perdeuterio-2 (117 mg, total 21%). Deuteration ratio was de-
13C NMR (75 MHz, CDCl3) δ 122.6 (C), 124.2 (q, JCF
=
271 Hz, C), 125.8 (brs, CH), 127.2 (CH), 128.8 (CH), 129.7
(q, JCF = 32 Hz, C), 132.1 (CH), 138.6 (C), 143.4 (C); 19F NMR
(188 MHz, CDCl3) δ –62.4; IR (CHCl3) 1389, 1326, 1169,
1130, 1072, 1020, 1005, 854, 819 cm–1; UV (CH3CN) λmax 260
(ε 22,900), 206 (31,800) nm; MS (EI) m/z 302 (M+), 300 (M+),
201, 152; HRMS (EI) calcd for C13H8BrF3: 299.9762, found:
299.9766.
4′-Trifluoromethyl-4-biphenylboronic acid (11). To a solu-
tion of bromide 9 (112 mg, 0.372 mmol) in dry THF (4 mL) in
argon at –78 °C, was added 1.6 M n-BuLi hexane solution
(256 µL, 0.410 mmol). The pale yellow reaction mixture was
kept at –78 °C for 20 min and treated with (i-PrO)3B (172 µL,
0.744 mmol) at –78 °C, and gradually warmed to rt. After 1 h,
water (1 mL) and then 10% aqueous HCl (5 mL) was added
and stirred vigorously for 1 h at rt. The THF was evaporated,
and the residual mixture was diluted with water and extracted
twice with ether. The combined ether solution was washed
with water and dried over Na2SO4. The residue was filtered,
and the solid was washed with hexane to give almost pure
borate (79 mg, 80%). The borate was used for the next cou-
pling without further purification: mp 266–268 °C (dec.);
1H NMR (400 MHz, acetone-d6) δ 7.72 (brd, J = 8.1 0.3 Hz,
2H), 7.80 (brd, J = 8.1 0.3 Hz, 2H) 7.92 (brd, J = 8.1
0.3 Hz, 2H), 8.00 (brd, J = 8.1 0.3 Hz, 2H); 13C NMR
(75 MHz, acetone-d6) δ 116.8 (C), 125.3 (q, JCF = 271 Hz, C),
126.5 (brs, CH), 127.1 (CH), 128.4 (CH), 130.4 (q, JCF = 34
Hz, C), 135.7 (CH), 141.7 (C), 145.7 (C); 19F-NMR (188
MHz, acetone-d6) δ –61.2; IR (CHCl3) 3659, 3367, 3019,
1608, 1421, 1409, 1377, 1344, 1324, 1219, 1169, 1129, 1112,
1071, 1006, 825 cm–1; UV (CH3CN) λmax 261 (ε 22,700), 207
(sh, 28,500) nm; MS (EI) m/z 266 (M+), 265 (M+–H), 248 (M+–
H2O), 222 (M+–BO2H), 201, 152; HRMS (EI) calcd for
C13H10BF3O2: 266.0726, found: 266.0732.
1
termined by H NMR comparison to a phenolic signal as
internal standard. Non-labeled compound: 1H NMR
(400 MHz, acetone-d6) δ 6.06 (d, J = 7.5 Hz, 1H,
H-3), 7.30 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H, 6-H), 7.55 (d, J = 7.8
Hz, 1H, 8-H), 7.61 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H , 7-H), 7.85
(d, J = 7.5 Hz, 1H, 2-H), 8.20 (dd, J = 8.1, 1.1 Hz, 1H, 5-H),
10.75 (brs, 1H, OH). Labeled compound: 1H NMR (400 MHz,
acetone-d6) δ 6.06 (0.02H), 7.30 (0.15H), 7.55 (0.08H), 7.61
(0.11H), 7.85 (0.02H), 8.20 (0.45H), 10.65 (brs, 1H, OH).
4-Trifluoromethyl-4′-trifluoromethylthiobiphenyl (3). To a
solution of 7 (56 mg, 0.22 mmol) and Pd(PPh3)4 (76 mg, 0.066
mmol) in a 20% Na2CO3 aqueous solution (4 mL) and toluene
(4 mL) under argon atmosphere and with stirring at room
temperature, was added 4-trifluromomethylphenylboronic
acid (52 mg, 0.27 mmol). The mixture was refluxed for 2 h
under vigorous stirring. The reaction mixture was then diluted
with water and extracted with ether. The combined ether solu-
tion was washed with water, then dried over Na2SO4. The
residue obtained after solvent removal in vacuo was submitted
to silica gel flash column chromatography (pentane) to give a
white solid (65 mg, 92%): mp 38–39 °C; 1H NMR (400 MHz,
CDCl3) δ 7.72 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 124.1 (q,
JCF = 270 Hz, C), 124.4 (brs, C), 126.0 (CH), 127.6 (CH),
128.3 (CH), 129.6 (q, JCF = 307 Hz, C), 130.3 (q, JCF = 33 Hz,
C), 136.8 (CH), 142.3 (C), 143.2 (C); 19F NMR (188 MHz,
CDCl3) δ –43.0, –63.0; IR (CHCl3) 1392, 1326, 1167, 1130,
1090, 1071, 1007, 825 cm–1; UV (CH3CN) λmax 262 (ε 22,100),
201 (31,100) nm; MS (EI) m/z 322 (M+), 253 (M+–CF3);
HRMS (EI) calcd for C14H8F6S: 322.0251, found: 322.0259.
4-Trifluoromethyl-4′-trifluoromethylthio-p-terphenyl (5).
To a solution of bromide 7 (64 mg, 0.25 mmol) and Pd(PPh3)4
(57 mg, 0.050 mmol) in 20% Na2CO3 aqueous solution (2
mL), toluene (3 mL) and DME (2 mL), was added boronic
acid 11 (44 mg, 0.17 mmol) under argon with stirring at rt. The
mixture was refluxed for 3 h under vigorous stirring, diluted
with water, and extracted twice with ether. The combined
4-Bromo-4′-trifluoromethylbiphenyl (9). To a solution of ether solution was washed with water, dried over Na2SO4,
1,4-dibromobenzene (1480 mg, 6.25 mmol) and Pd(PPh3)4 filtered, and concentrated in vacuo. Flash chromatography on
(423 mg, 0.366 mmol) in 20% Na2CO3 aqueous solution silica gel (hexane) of the residue gave a white solid (54 mg,
(8 mL), toluene (15 mL), and dimethoxyethane (DME, 10 mL) 82%): mp 147–148 °C; 1H NMR (400 MHz, CDCl3) δ 7.72 (m,
was added 4-trifluoromethylphenylboronic acid (232 mg, 12H); 13C NMR (75 MHz, CDCl3) δ 123.5 (brs, C), 124.3 (q,
1.22 mmol) under argon with stirring at rt. The mixture was JCF = 270 Hz, C), 125.8 (d, JCF = 4.1 Hz, CH), 127.3 (CH),
refluxed for 6 h under vigorous stirring. The residual boronic 127.8 (CH), 127.8 (CH), 128.0 (CH), 129.6 (q, JCF = 306 Hz,
acid was oxidized by 30% H2O2 (0.5 mL) at rt for 3 h. The C), 129.7 (q, JCF = 32 Hz, C), 136.8 (CH), 139.5 (C), 143.0 (C),
Israel Journal of Chemistry
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305
143.9 (C); 19F NMR (188 MHz, CDCl3) δ –42.6, dissolved in dichloromethane with ultrasonication. The
–62.4; IR (CHCl3) 1388, 1326, 1166, 1120, 1088, 1071, 1006, dichloromethane solution was washed with water and dried
819 cm–1; UV (CH3CN) λmax 289 (ε 40,700), 204 (50,000) nm; over Na2SO4. The residue obtained after solvent removal in
MS (EI) m/z 398 (M+), 329 (M+–CF3); HRMS (EI) calcd for vacuo was reprecipitated in chloroform to give a white solid
C20H12F6S: 398.0564, found: 398.0553.
(265 mg, 49%): mp 225–227 °C; 1H NMR (400 MHz, CDCl3)
δ 2.41 (s, 6H), 7.27 (d, J = 8.0 Hz, 4H), 7.54 (d, J = 8.0 Hz,
4H), 7.65 (brs, 4H); 13C NMR (100 MHz, CDCl3) δ 21.1
(CH3), 126.8 (CH), 127.2 (CH), 129.5 (CH), 137.1 (C), 137.9
(C), 139.7 (C); IR (CHCl3) 3030, 2919, 1492, 1391, 1187,
1115, 1004, 971, 858, 826, 809, 739 cm–1; UV (CH3CN) λmax
284 (ε 41,000), 207 (60,900) nm; MS (EI) m/z 258 (M+), 257,
241, 215, 165, 152, 129, 128.
4-Methyl-4′-methylthiobiphenyl (4). To a solution of 4-
bromothioanisole (503 mg, 2.48 mmol) and Pd(PPh3)4
(860 mg, 0.744 mmol) in 20% Na2CO3 aqueous solution
(20 mL) and toluene (20 mL), was added 4-methylphenyl-
boronic acid (388 mg, 2.85 mmol) under argon with stirring at
rt. The mixture was refluxed for 12 h with vigorous stirring,
diluted with water, and extracted twice with ether. The com-
bined ether solution was washed with water, and dried over
Na2SO4. The residue obtained after solvent removal in vacuo
Dilution Method of Fluorine Compounds
2,8-Bis(trifluoromethyl)-4-quinolinol (1)/4-Hydroxy-
was submitted to flash chromatography on silica gel (hexane/ quinoline (2). (i) Compound 1 was diluted with 2 more than
i-PrOH) to give a white solid (324 mg, 61%): mp 123–124 °C; ten times and dissolved in ether or hexane. The solution was
1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 2.51 (brs, 3H), warmed in a water bath with stirring to dissolve the com-
7.23 (brd, J = 8.1 0.3 Hz, 2H), 7.31 (brd, J = 8.1 0.3 Hz, pounds completely. The solution was cooled to rt to yield
2H) 7.46 (brd, J = 8.1 0.3 Hz, 2H), 7.50 (brd, J = 8.1
white crystals, which were analyzed by NMR or HPLC to
0.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 126.6 (CH), 127.0 determine the ratio. (ii) Perdeuterated 1 (10 mg) was dissolved
(CH), 127.2 (CH), 129.5 (CH), 136.9 (C), 137.1 (C), 137.6 into 4 mL of D2O and heated to 65 °C. The undissolved
(C), 138.0 (C); IR (CHCl3): 3007, 2925, 2864, 1490, 1483, crystals were solubilized by adding a small amount of acetone.
1440, 1396, 1099, 1004, 968, 840, 807 cm–1; UV (CH3CN) The solution was mixed with 100 mg of perdeuterated 2 and
λ
max 283 (ε 24,900), 202 (39,000) nm; MS (EI) m/z 214 (M+), then treated with 10 mL of acetone. After filtration of the small
199 (M+–CH3); HRMS (EI) calcd for C14H14S: 214.0816, amount of undissolved material, slow removal of solvent gave
found: 214.0807.
a white powder.
4-Bromo-4′-methylbiphenyl (10).14 To a solution of 1,4-
dibromobenzene (11440 mg, 48.5 mmol) and Pd(PPh3)4 (230
mg, 0.200 mmol) in 20% Na2CO3 aqueous solution (20 mL)
and DME (30 mL), was added 4-methylphenylboronic acid
(2196 mg, 16.2 mmol) under argon atmosphere with stirring at
rt. The mixture was refluxed for 8 h under vigorous stirring.
The reaction mixture was then diluted with water and ex-
tracted twice with ether. The combined ether solution was
washed with water and dried over Na2SO4. The residue ob-
tained after solvent removal in vacuo was submitted to flash
chromatography on silica gel (pentane) to give a white solid
(3488 mg, 87%): mp 130–132 °C; 1H NMR (400 MHz,
CDCl3) δ 2.38 (s, 3H), 7.23 (brd, J = 7.8 Hz, 2H), 7.42 (d, J =
8.5 Hz, 2H), 7.43 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 21.1 (CH3), 121.1 (C), 126.7
(CH), 128.5 (CH), 129.6 (CH), 131.8 (CH), 137.1 (C), 137.5
(C), 140.0 (C); IR (KBr) 3026, 2919, 1481, 1391, 1312, 1188,
1103, 1072, 1003, 843, 808, 723 cm–1; UV (CH3CN) λmax 260
(ε 24,700), 200 (47,600) nm; MS (EI) m/z 248 (M+), 246 (M+),
167, 165, 152; HRMS (EI) calcd for C13H11Br: 246.0044,
found: 246.0047.
4-Trifluoromethyl-4′-trifluoromethylthiobiphenyl (3)/
4-Methyl-4′-methylthiobiphenyl (4). Approximately 0.6% of 3
was added to 4 in hot ether. The ether solution was flashed by
argon to remove part of ether and the solution was chilled until
appearance of first crystals. The resulting crystals were fil-
tered and washed with cold hexane and ether. The sample
crystals were analyzed by HPLC to determine the ratio of 3/4
as 0.23%.
4-Trifluoromethyl-4′-trifluoromethylthio-p-terphenyl (5)/
4,4′′-dimethyl-p-terphenyl (6). Compound 5 (0.3 mg) and 6
(104 mg) were dissolved in hot benzene (15 mL). The benzene
solution was frozen instantaneously by liquid nitrogen and
was lyophilized gradually to give a white powder. HPLC
analysis showed 6 contained 0.32% of 5.
Acknowledgments. This contribution is dedicated in fond
memory of our dear friend, Professor Ray Lemieux. The authors
gratefully acknowledge the support from the Kanagawa Acad-
emy of Science and Technology (KAST) and NIH AI 10187.
REFERENCES AND NOTES
4,4′′-Dimethyl-p-terphenyl (6).15 The following protocol
differs somewhat from the published method. To a solution of
10 (523 mg, 2.11 mmol) and Pd(PPh3)4 (227 mg, 0.197 mmol)
in 20% Na2CO3 aqueous solution (20 mL) and benzene
(30 mL), was added 4-methylphenylboronic acid (321 mg,
2.36 mmol) under argon atmosphere with stirring at room
temperature. The mixture was refluxed for 18 h under vigor-
ous stirring, diluted with water, and washed with hexane and
dichloromethane. The insoluble white solid was filtered and
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