Synthesis and spectroscopic properties of isomeric trideuterio- and tetradeuterio pyridines

Article abstract of DOI:10.1002/jhet.5570440637

(Chemical Equation Presented) The syntheses of the six possible isomeric trideuteriopyridines and the three possible isomeric tetradeuteriopyridines are described. These deuteriopyridines were characterized by their mass and NMR spectra.

Full text of DOI:10.1002/jhet.5570440637

Nov-Dec 2007
1485
Synthesis and Spectroscopic Properties of Isomeric
Trideuterio- and Tetradeuterio Pyridines
James W. Pavlik* and Somchoke Laohhasurayotin
Department of Chemistry and Biochemistry
Worcester Polytechnic Institute
Worcester, MA 01609
jwpavlik@wpi.edu
Received April 17, 2007
D
N
D
N
D
N
D
N
D
D
D
D
D
D
D
D
D
D
N
D
D
N
D
D
D
D
H
D
D
D
H
D
H
D
D
N
D
N
D
D
N
D
The syntheses of the six possible isomeric trideuteriopyridines and the three possible isomeric
tetradeuteriopyridines are described. These deuteriopyridines were characterized by their mass and NMR
spectra.
J. Heterocyclic Chem., 44, 1485 (2007).
INTRODUCTION
Scheme 1
D
As part of our interest in the vapor phase photo-
chemistry of pyridine, [1,2] we were interested in
obtaining pure samples of the six possible isomeric
trideuteriopyridines and of the three possible isomeric
tetradeuteriopyridines shown in Table 1. To our
knowledge, neither the synthesis nor spectroscopic
properties of either set of deuterated isomers have been
reported.
D
D
D
D2O / K2CO3
190°
H2O / K2CO3
reflux
N
O
D
N
O
2-2,3,4,5,6-d5
2
D
D
D
H
D
D
D
PCl3
CH2Cl2
N
O
H
N
RESULTS AND DISCUSSION
Trideuteriopyridines. 3,4,5-Trideuteriopyridine (1-3,4,5-
d3) was synthesized from pyridine N-oxide (2) as shown
2-,3,4,5,-d3
1,3,4,5,-d3
Table 1
D
D
D
N
D
D
D
D
D
D
D
D
D
D
D
N
N
N
D
N
D
D
D
N
1-2,3,4-d3
1-2,3,5-d3
1-2,3,6-d3
1-2,4,6-d3
1-3,4,5-d3
1-2,4,5-d3
D
D
H
N
D
D
D
H
D
D
H
D
D
D
D
N
N
D
1-2,3,4,5-d4
1-2,3,4,6-d4
1-2,3,5,6-d4
in Scheme 1. Base catalyzed deuterium exchange at 190°
[3,4] gave 2-2,3,4,5,6-d5 which exhibited a molecular ion
in the mass spectrum at m/z = 100, consistent with
perdeuteration.
exhibited triplets at ꢀ 139.4 (C2,6, J = 28.5 Hz), 126.1
(C4, J = 25.6 Hz), and 125.9 (C3,5, J = 26.3Hz) due to
In addition, the 13C-nmr spectrum

1486
J. W. Pavlik and S. Laohhasurayotin
Vol 44
13C-D coupling at each ring position. Selective exchange
of deuterium for hydrogen at ring positions 2 and 6 in
refluxing aqueous potassium carbonate led to 2-3,4,5-d3.
The mass spectrum of the product exhibited a molecular
ion at m/z = 98, confirming the exchange of two
deuterium atoms for protons while the 1H- and 13C-spectra
confirmed that the exchange occurred at ring positions 2
respectively. Although it was not possible to unambig-
uously assign the structures of these three dichloro-
pyridine isomers on the basis of their 13C-NMR spectra,
the resulting trideuteriopyridines could be unambiguously
distinguished by their 1H-NMR spectra.
The 1H-NMR spectrum of 1-2,3,4-d3, exhibited two
doublets with J = 4.8 Hz. The magnitude of this coupling
constant confirms that the two adjacent ring protons must
be ꢀ and ꢁ to the ring nitrogen as in the assigned structure
1
and 6. Thus, the H-NMR spectrum exhibited an intense
singlet at ꢀ 8.18, where H2 and H6 are known to absorb,
while the 13C-NMR spectrum showed a singlet at ꢀ 139.1
for the C2 and C6 ring atoms but triplets at ꢀ 126.1 (C4, J
= 25.6 Hz) and ꢀ 125.9 (C3,5, J = 26.3 Hz) confirming
that only C2 and C6 were bonded to protons. As shown
in Tables 1 and 2, the 1H and 13C-NMR spectra confirmed
that reduction of N-oxide 2-3,4,5-d3 to 1-3,4,5-d3 using
phosphorous trichloride [5] occurred without change of
the labeling pattern.
1-2,3,4-d3, 1-2,4,5-d3 and 1-2,3,6-d3 were synthesized
from commercially available 3-chloropyridine (3) as
shown in Scheme 2. N-oxidation [6] followed by perdeu-
teration [3,4] provided 2,4,5,6-tetradeuterio-3-chloro-
pyridine-N-oxide (4-2,4,5,6-d4), confirmed by the mass
spectrum which exhibited a molecular ion at m/z = 133
and the 13C-NMR spectrum which showed a singlet for
C3 and four triplets for the four non-equivalent ring
carbon atoms bonded to deuterium. Reaction of this
compound with phosphorous oxychloride [7] provided the
1
[9,10]. Alternatively, the H-NMR spectrum of 1-2,3,6-d3
exhibited two doublets with J = 7.6 Hz. This larger
coupling constant indicates that neither proton can be ꢀ to
the ring nitrogen and thus must be ꢁ and ꢂ to nitrogen as
1
in the assigned structure [9,10]. Finally, the H-NMR
spectrum of 1-2,4,5-d3 exhibits two singlets at ꢀ 7.36 and
8.59 where H 3(5) and H 2(6) of pyridine are known to
absorb. Unambiguous assignment of these structures thus
confirmed that the assigned structures for the
dichloropyridines are also correct.
Although 1-2,4,6-d3 could be prepared by hydro-
genolysis of 8-2,4,6-d3, the yield of this dichloro isomer
was too low for this approach. Instead, 1-2,4,6-d3 was
synthesized from pyridine N-oxide (2) as shown in
Scheme 3.
The sequence started with selective deuteration at ring
positions 2 and 6 to provide 2-2,6-d2 [3,4]. Nitration with
fuming nitric acid [11], replacement of nitro by chloro by
Scheme 2
D
Cl
D
D
Cl
D
Cl
CH3COOH
H2O2 , heat
K2CO3, D2O
190°
N
O
N
O
N
4-2,4,5,6-d4
3
4
D
Cl
D
D
D
D
Cl
Cl
D
D
Cl
D
Cl
D
Cl
Cl
D
POCl3
+
+
+
N
N
D
Cl
N
D
N
5-4,5,6-d3
6-2,5,6-d3
7-3,4,6-d3
8-2,4,6-d3
H2 / Pd-C
H2 / Pd-C
H2 / Pd-C
H
N
D
N
D
N
D
D
H
D
D
D
H
H
D
H
H
D
1-2,3,4-d3
1-2,3,6-d3
1-2,4,5-d3
four dichlorotrideuteriopyridine isomers 5-4,5,6-d3, 6-
2,5,6-d3, 7-3,4,6-d3, and 8-2,4,6-d3 which were separated
by flash column chromatography. Hydrogenolysis over
palladium on charcoal converted 5-4,5,6-d3, 6-2,5,6-d3,
and 7-3,4,6-d3 to 1-2,3,4-d3, 1-2,3,6-d3, and 1-2,4,5-d3
reaction with acetyl chloride [11] followed by reduction
with PCl3 in dichloromethane [5] gave 4-chloro-2,6-
dideuteriopyridine 11-2,6-d2. Mass spectral analyses
confirmed that each of these intermediate compounds
remained dideuterated while the 13C-NMR spectra

Nov-Dec 2007
Synthesis and Spectroscopic Properties of Isomeric Trideuterio- and Tetradeuterio Pyridines
1487
confirmed that the two deuterium atoms were bonded to
carbon atoms adjacent to the ring nitrogen. Reduction of
11-2,6-d2 with deuterium and palladium on charcoal [8]
gave the desired 1-2,4,6-d3. As shown in Tables 1 and 2,
the 1H-NMR spectrum exhibited a singlet at ꢀ 7.08 where
the C3 proton of pyridine is known to absorb while the
13C-NMR spectrum exhibited a singlet at ꢀ 123.9 where
the C3 is known to absorb and triplets at ꢀ 136.1 for C4
and at ꢀ 149.8 for C2(6) confirming that deuterium atoms
were bonded to C2(6) and C4 of the pyridine ring.
The mass spectrum of this compound exhibited a
molecular ion at m/z = 82, consistent with a trideuterated
1
pyridine. The H- and 13C-spectra, summarized in Tables
1 and 2 confirmed that the deuterium atoms were at ring
positions 2, 3 and 5. Thus, the 1H-NMR spectrum
exhibited singlets at ꢀ 7.75 and 8.60 where protons at ring
positions 4 and 2 are known to absorb whereas the 13C-
NMR spectrum exhibited triplets at ꢀ 150.2, 124.2, and
123.8 confirming that the carbon atoms at ring positions
6, 3, and 5 are all bonded to deuterium.
Tetradeuteriopyridines. 2,3,4,5-Tetradeuteriopyridine
(1-2,3,4,5-d4) was prepared from pyridine N-oxide (2) as
shown in Scheme 5. Treatment of pyridine N-oxide-d5
(2-2,3,4,5,6-d5) with phosphorus oxychloride [7] provided
a mixture of 4-chloropyridine-d4 and 2-chloropyridine-d4
(13-3,4,5,6-d4) from which the latter was obtained in pure
form by column chromatography. The 13C-NMR spectrum
of this compound exhibited four triples at ꢀ 149.4 (J =
28.1 Hz), 138.2 (J = 25.2 Hz), 124.1 (J = 26.6 Hz), and
121.7 (J = 25.4 Hz) for the C6, C4, C3 and C5 ring
carbons respectively and a singlet at ꢀ 151.5 for the C2
carbon, confirming that the chlorine is bonded to this ring
position. Reduction with hydrogen over palladium on
Scheme 3
NO2
H2SO4
HNO3
D2O / K2CO3
reflux
N
O
D
N
O
D
D
N
O
D
2
2-2,6-d2
9-2,6-d2
Cl
Cl
PCl3
CH3COCl
D
CH2Cl2
D
N
D
N
O
D
1
10-2,6-d2
11-2,6-d2
charcoal [8] gave the desired 1-2,3,4,5-d4. The H-NMR
spectrum of this product exhibited one singlet at ꢀ 8.60
where protons at C2 or C6 of pyridine are known to
absorb. In addition to triplets in the 13C-NMR spectrum
for C3, C4 and C5, the carbons at ring positions 2 and 6
appeared as a sharp singlet at ꢀ 148.6 overlapping with a
triplet (J = 27.2 Hz) at ꢀ 148.3 confirming that one of
these carbon atoms is bonded to a proton while the other
is bonded to deuterium.
D
N
D2 / Pd-C
D
D
1-2,4,6-d3
1-2,3,5-d3 was synthesized by a similar procedure
shown in Scheme 4. This involves synthesis of 2,4-
dichloropyridine-3,5,6-d3 (12-3,5,6-d3) by the sequence of
reactions shown. Hydrogenolysis using hydrogen gas and
palladium on charcoal [8] gave the desired 1-2,3,5-d3.
Scheme 5
D
D
D
D
D
POCl3
D2O / K2CO3
190°
Scheme 4
N
O
N
O
D
NO2
D
D
D
D
D
D
D
D
2-2,3,4,5,6-d5
H2SO4
HNO3
D2O / K2CO3
190°
2
D
N
D
N
O
N
O
N
O
D
D
H
D
D
D
H2 / Pd-C
2
9-2,3,5,6-d4
2-2,3,4,5,6-d5
D
N
Cl
Cl
Cl
D
D
D
D
POCl3
CH3COCl
D
D
D
13-3,4,5,6-d4
1-2,3,4,5,-d4
N
O
N
Cl
2,3,4-6-Tetradeuteriopyridine
(1-2,3,4,6-d4)
was
12-3,5,6-d3
synthesized as shown in Scheme 6. 3-Chloropyridine (3)
was oxidized [12] and perdeuterated as previously shown
in Scheme 2 to yield 3-chloropyridine N-oxide-d4 (4-
2,4,5,6-d4). Reduction with phosphorous trichloride [5]
provided 3-chloropyridine-d4 (3-2,4,5,6-d4). In contrast
to the 2-chloro-isomer, 13-3,4,5,6-d4, shown in Scheme 5,
the 13C-NMR spectrum of the 3-chloro-isomer exhibited
10-2,3,5,6-d4
H
N
H2 / Pd-C
D
D
D
H
1-2,3,5-d3

1488
J. W. Pavlik and S. Laohhasurayotin
Vol 44
triplets at ꢀ 148.8 (J = 28.0 Hz), 147.7 (J = 28.7 Hz),
136.0 (J = 26.1 Hz) and 124.3 (J = 25.8 Hz) for the C2,
C6, C4 and C5 ring atoms respectively and a singlet at ꢀ
132.4 confirming that the C3 ring carbon is bonded to the
chlorine atom. Further reduction with hydrogen over
palladium on charcoal [8] provided 1-2,3,4,6-d4. In this
case the 1H-NMR spectrum exhibited one singlet at ꢀ 7.36
where the H3 or H5 protons of pyridine are known to
absorb while the 13C-NMR exhibited three triplets and a
sharp singlet at ꢀ 126.1 confirming that only the C3 ring
carbon is bonded to a proton.
The mass spectrum of this compound exhibited a
molecular ion at m/z = 152, consistent with a tri-
deuterated-dichloropyridine. In addition, the 13C-NMR
spectrum exhibited triplets at ꢀ 146.7 (J = 29.1 Hz) for the
equivalent C2,6 carbon atoms, a triplet at ꢀ 135.8 (J =
26.5 Hz) for the C4 carbon atom, and a singlet at ꢀ 132.4
for the equivalent C3,5 carbons bonded to chlorine.
Treatment of this compound with sodium methoxide in
methanol at room temperature then allowed selective
exchange of the C4 deuterium with hydrogen to provide
14-2,6-d2 [13]. The mass spectrum of this compound
exhibited a molecular ion at m/z = 151 confirming the
exchange of one deuterium for hydrogen while the triplet
at ꢀ 135.8 for the C4 carbon in the 13C-NMR spectrum of
the reactant, 14-2,4,6-d3, was replaced with a singlet at ꢀ
136.0 for the C4 carbon in the 13C-NMR spectrum of the
product, 14-2,6-d3. This confirms that the exchange took
place selectively at the C4 ring position. Treatment of
this compound with deuterium over palladium on
charcoal [8] provided the final desired product, 1-2,3,5,6-
Scheme 6
Cl
Cl
CH3COOH
H2O2 , heat
D2O / K2CO3
190°
N
N
O
3
4
D
D
D
Cl
D
Cl
D
PCl3
CH2Cl2
1
d4. As required, the H-NMR spectrum exhibited one
D
N
D
singlet at ꢀ 7.75 where the proton at ring position 4 is
known to absorb while the 13C-NMR spectrum exhibited
triplets at ꢀ 150.3 and 124.2 for C2,6 and C,3,5
respectively, and a singlet at ꢀ 136.5 for the C4 ring
carbon atom.
D
N
O
3-2,4,5,6-d4
4-2,4,5,6-d4
D
N
D
H
D
H2 / Pd-C
Table 1
D
1H-NMR Chemical Shifts ( ꢀ ppm ) of Deuterated Pyridines *
1-2,3,4,6-d4
Compound
Ring Position
4
2
3
5
6
Scheme 7 shows the synthetic route used to prepare
2,3,5-6-tetradeuteriopyridine (1-2,3,5,6-d4). 3,5-Dichloro-
pyridine (14) was first oxidized with methyltrioxo-
rhenium (VII), [12] then perdeuterated to yield 15-2,4,6-
d3, and reduced with PCl3 [5] to provide 14-2,4,6-d3.
-----
-----
-----
7.34, d
J = 4.8 Hz J = 4.8 Hz
-----
7.34, d
J = 7.6 Hz
7.08, s
7.34, d
1-2,3,4-d3
-----
-----
-----
-----
1-2,3,5-d3
1-2,3,6-d3
7.75, s
7.76, d
J = 7.6 Hz
-----
8.60, s
-----
-----
-----
7.08, s
1-2,4,6-d3**
8.59, s
8.44, s
8.60, s
1-2,4,5-d3
1-3,4,5-d3
1-2,3,4,5-d4
----- 7.36, s
-----
-----
-----
-----
-----
-----
7.36, s
-----
Scheme 7
8.44, s
-----
-----
-----
-----
Cl
Cl
Cl
Cl
-----
-----
-----
CH3ReO3
K2CO3 , D2O
-----
-----
-----
1-2,3,4,6-d4**
1-2,3,5,6d4
N
7.75, s
H2O2 , MnO2
N
O
110°
* Spectra recorded in acetone-d6 unless otherwise noted. ** Spectra
recorded in deuteriochloroform
14
15
D
D
N
NaOCH3
Cl
Cl
D
Cl
Cl
D
PCl3
EXPERIMENTAL
CH3OH , rt
D
N
O
D
Synthesis of 3,4,5-Trideuteriopyridine (1-3,4,5-d3).
15-2,4,6-d3
14-2,4,6-d3
Pyridine N-oxide-d5 (2-2,3,4,5,6-d5). A solution of pyridine
N-oxide (2) (2.0 g, 21 mmol) and potassium carbonate (2.0 g)
dissolved in deuterium oxide (20 mL) was heated in an
autoclave at 190˚C for 5 hours. The resulting solution was
concentrated by rotary evaporation and the liquid residue was
dissolved in deuterium oxide (10 mL) and heated again in an
H
H
D
D
D
D
D2 / Pd-C
Cl
Cl
D
N
D
N
14-2,6-d2
1-2,3,5,6-d4

Nov-Dec 2007
Synthesis and Spectroscopic Properties of Isomeric Trideuterio- and Tetradeuterio Pyridines
1489
Table 2
13C-NMR Chemical Shifts ( ꢀ ppm ) of Deuterated Pyridines *
Ring Position
4
Compound
2
3
5
6
150.2, t
J = 26.8 Hz
150.2, t
J = 27.6 Hz
150.3, t
J = 27.8 Hz
149.8, t
J = 27.1 Hz
150.3, t
J = 26.9 Hz
151.7, s
124.4, s
150.6, s
1-2,3,4-d3
1-2,3,5-d3
1-2,3,6-d3
1-2,4,6-d3**
124.0, s
J = 25.4 Hz
124.2, t
J = 24.6 Hz
124.1, t
J = 25.6 Hz
123.9,s
136.2, t
J = 25.3 Hz
136.3, s
123.8, t
J = 24.9 Hz
123.5, s
150.5, s
150.3, t
J = 27.8 Hz
149.8, t
136.4, s
136.1,t
J = 25.1 Hz
136.2,t
J = 25.3 Hz
137.2,t
J = 24.9 Hz
134.1,t
J = 24.6 Hz
138.0,t
J = 24.9 Hz
136.5,s
123.9, s
J = 27.8 Hz
1-2,4,5-d3
1-3,4,5-d3
124.1,t
J = 25.0 Hz
125.3,t
J = 25.3 Hz
122.0,t
J = 25.5 Hz
126.1,s
150.6,s
151.7,s
148.6,s
124.3,s
125.3,t
J = 25.3 Hz
122.1,t
J = 25.2 Hz
125.8,t
J = 25.8 Hz
124.2,t
1-2,3,4,5-d4
148.3,t
J = 27.2 Hz
152.1,t
J = 30.4 Hz
150.3,t
1-2,3,4,6-d4**
152.1,t
J =30.4 Hz
150.3,t
1-2,3,5,6d4
124.2,t
J = 25.5 Hz
J = 25.5 Hz
J =27.9 Hz
J = 27.9 Hz
* Spectra recorded in acetone-d6 unless otherwise noted. ** Spectra recorded in deuteriochloroform
autoclave at 190˚C for an additional 5 hours. The resulting
solution was extracted with chloroform (6 x 20 mL). The
organic extract was dried (sodium sulfate) and concentrated to
dryness to give 2-2,3,4,5,6-d5 as a highly hygroscopic white
solid: yield 2.0 g (20 mmol, 95%) mp 50˚C, 13C-NMR
(deuteriochloroform) ꢀ 139.4 (t, C2,6, J = 28.5Hz), 126.1 (t, C4,
J = 25.6Hz), 125.9 (t, C3,5, J = 26.3 Hz); MS m/z (%) 100
(100), 84 (81).
made basic with solid potassium carbonate and then shaken with
chloroform (50 mL). The solid material was removed by
filtration and the filtrate was dried (sodium sulfate) and
concentrated to give 4 as a light yellow solid: yield 1.69g (13.0
mmol, 74%); mp; 54-55˚C; 1H-NMR (deutriochloroform) ꢀ
(DEPT-135) 139.2(+), 138.2 (+), 133.8(0), 126.9(+), 126.3(+);
MS m/z (%) 131 (27), 129 (100), 115 (33), 113 (95).
3-Chloropyridine N-oxide-2,4,5,6-d4 (4-2,4,5,6-d4).
A
Pyridine N-oxide-3,4,5-d3 (2-3,4,5-d3). Pyridine N-oxide-d5
(2-2,3,4,5,6-d5) (0.96g, 9.6 mmol) was dissolved in 10%
aqueous sodium carbonate (120 mL) and heated at reflux for 12
hours. The resulting solution was extracted with dichloro-
methane (5 x 10 mL). The organic extract was dried (sodium
sulfate) and concentrated to dryness to give 2-3,4,5-d3 as a
liquid which solidified upon standing in a desiccator to provide
a white solid: yield 0.48 g (4.9 mmol, 51%); 13CNMR
(deuterium oxide) ꢀ 139.2 (s, C2,6), 132.5 (t, C4, J = 26.0 Hz),
127.3 (t, C3,5, J = 25.9 Hz).
3,4,5-Trideuteriopyridine (1-3,4,5-d3).A solution of pyridine
N-oxide-3,4,5-d3 (2-3,4,5-d3) (0.48g, 4.9 mmol) in dichloro-
methane (40 mL) was added dropwise to phosphorous trichloride
(1.0 mL) at 0˚C. The resulting solution was heated at reflux for 1
hour, poured onto ice (20 g), and made basic with 10N aqueous
sodium hydroxide. The aqueous phase was extracted with
dichloromethane (3 x 10 mL). The organic extract was dried
(sodium sulfate) and concentrated. The residual oil was purified
by distillation (Kugelrohr, 95˚C, water aspirator) to give 3,4,5-
trideuteriopyridine (1-3,4,5-d3) as a colorless liquid: yield 0.18g
(2.2 mmol, 45%); MS m/z (%) 82 (100), 55 (90). The 1H and 13C-
NMR data are given in Tables 1 and 2.
solution of 3-chloropyridine N-oxide (4), (1.69 g, 13.0 mmol)
and potassium carbonate (1.0 g) dissolved in deuterium oxide
(10 mL) was heated in an autoclave at 190˚C for 5 hours. The
resulting solution was concentrated, re-dissolved in deuterium
oxide (10 ml) and heated again in an autoclave for an additional
5
hours.
The resulting solution was extracted with
dichloromethane (5 x 20 mL). The organic extract was dried
(sodium sulfate) and concentrated to give 4-2,4,5,6-d4 as a
yellow solid: yield 0.8 g (6.0 mmol, 46%); mp 52-54˚C; 13C-
NMR (deuteriochloroform) ꢀ 138.9 (t, C2, J = 30.2 Hz), 137.9
(t, C6, J = 28.9 Hz), 133.6 (s, C3), 126.1 (t, C5, J = 26.9 Hz),
125,8 (t, C4, 25.8 Hz); MS m/z(%) 135(33), 133 (100), 119
(19), 117 (61).
2,3-Dichloropyridine-4,5,6-d3(5-4,5,6-d3), 3,4-dichloro-
pyridine-2,5,6-d3 (6-2,5,6-d3), 2,5-dichloropyridine-3,4,6-d3
(7-3,4,6-d3), and 3,5-dichloropyridine-2,4,6-d3 (8-2,4,6-d3). A
mixture of 3-chloropyridine N-oxide-2,4,5,6-d4 (4-2,4,5,6-d4)
(2.20g, 16.5 mmol) and phosphorus oxychloride (16.5 mL) was
heated at 120˚ C for 2 hours. The resulting solution was
concentrated by distillation to give a brown liquid which was
mixed with ice (10 g) and made basic with saturated aqueous
potassium carbonate and extracted with dichloromethane (10 x
20 mL). The organic extract was dried (sodium sulfate) and
concentrated. The resulting brown liquid residue (1.90 g) was
subjected to column chromatography (silica gel). Elution with
hexane (10%) – dichloromethane (90%) gave four fractions.
Fraction one gave 2,5-dichloropyridine – 3,4,6-d3 (7-3,4,6-d3)
as a white solid: yield 0.34 g (2.3 mmol, 13.7%); 13C-NMR
(deuteriochloroform) ꢀ 149.7 (s, C2), 148.5 (t, C6, J = 28.8 Hz),
138.5 (t, C4, J = 26.1 Hz), 131.1 (s, C5), 125.2 (t, C3, J = 26.4
Synthesis of 2,3,4-Trideuteriopyridine (1-2,3,4-d3), 2,3,6-
Trideuteriopyridine (1-2,3,6-d3) and 2,4,5-Trideuterio-
pyridine (1-2,4,5-d3).
3-Chloropyridine N-oxide (4). 3-Chloropyridine (3) (2.0 g,
17.6 mmol), glacial acetic acid (10.8 mL) and hydrogen
peroxide (3.6 mL, 30%) were heated at 80˚C for 10 hours. The
resulting solution was concentrated and the liquid residue was

1490
J. W. Pavlik and S. Laohhasurayotin
Vol 44
Hz); MS m/z (%) 154(10), 152 (54), 150 (100), 117 (25), 115
(79).
(t, C2, 6, J = 29.8 Hz), 121.2 (t, C3, 5, J = 26.7 Hz); MS m/z
(%) 144 (53), 128 (40), 114 (43).
Fraction two gave 2,3-dichloropyridine – 4,5,6-d3 (5-4,5,6-d3)
as a white solid: yield 0.62 g (4.1 mmol, 25%); 13C-NMR
(deuteriochloroform) ꢀ 149.6 (s, C2), 147.3 (t, C6, J = 28.1 Hz),
138.8 (t, C4, J = 25.9 Hz), 131.0 (s, C3), 123.1 (t, C5, J = 25.5
Hz); MS m/z (%) 154 (11), 152 (59), 150 (96), 117 (31), 115
(100).
Fraction three gave 3,5-dichloropyridine-2,4,6-d3 (8-2,4,6-d3)
as a white solid: yield 0.07g (0.5 mmol, 2.8 %); 13C-NMR
(deuteriochloroform) ꢀ 146.8 (t, C2, 6, J = 29.2Hz), 135.7 (t, C4,
J = 26.3 Hz), 132.4 (s, C3, 5); MS m/z (%) 154 (10), 152 (66),
150 (100), 117 (19), 115 (61).
Fraction four gave 3,4-dichloropyridine-2,5,6-d2 (6-2,5,6-d3)
as a yellow liquid: yield 0.20 g (1.3 mmol, 8%; 13C-NMR
(deuteriocloroform) ꢀ 150.4 (t, C2, J = 29.2 Hz), 148.2 (t, C6, J
= 28.0 Hz), 142.3 (s, C4), 131.3 (s, C3), 125.2 (t, C5, J = 26.5
Hz); MS m/z (%) 150 (10), 152 (64), 150 (100), 117 (20), 115
(67).
4-Chloropyridine N-oxide-2,3,5,6-d4 (10-2,3,5,6-d4). Acetyl
chloride (11.0 mL) was added to 4-nitropyridine N-oxide-2,3,5,6-
d4 (10-2,3,5,6-d4) (2.12 g, 14.7 mmol) which was warmed to 50˚C
in a water bath. The resulting mixture was refluxed for
approximately 30 minutes until a white solid formed. The excess
acetyl chloride was removed under reduced pressure and the white
solid residue was mixed with crushed ice (50 g), made basic with
saturated aqueous sodium carbonate, and extracted with
dichloromethane (8 x 20 mL). The extract was dried (sodium
sulfate) and concentrated to give 10-2,3,5-6-d4 as a white solid
which was recrystallized from acetone to yield white crystals:
yield 1.84 g (13.7 mmol, 93.2%); 13C-NMR (acetone-d6) ꢀ 1.40.1
(t, C2,6, J = 28.8 Hz), 132.0 (s, C4), 126.7 (t, C3,5, J = 26.2 Hz);
MS m/z (%) 135 (30), 133 (100), 117 (64), 82 (59).
2,4-Dichloropyridine-3,5,6-d3 (12-3,5,6-d3). A mixture of 4-
chloropyridine N-oxide-d4 (10-2,3,5,6-d4) (1.7g, 12.7 mmol) and
phosphorous oxychloride (13 mL) was heated at 110˚ for 2
hours. The excess phosphorous oxychloride was removed under
reduced pressure and the yellow residue was mixed with crushed
ice (3 g), made basic with saturated aqueous sodium carbonate,
and extracted with dichloromethane (8 x 20 ml). The extract
was dried (sodium sulfate) and concentrated to give a red liquid
which was subjected to preparative layer chromatography (silica
gel), 9:1 dichloromethane-hexane to give 12-3,5,6-d3 as a
colorless liquid: yield 0.90 g (6.0 mmol, 47.2%); 13C-NMR
(deuteriochloroform) ꢀ 152.6 (s, C6), 150.2 (t, C2, J = 28.2 Hz),
146.1 (s, C4), 124.6 (t, C3, J = 26.8 Hz), 123.0 (t, C5, J = 26.2
Hz); MS m/z (%) 154 (8), 152 (59), 150 (59), 150 (91), 117
(33), 115 (100), 78 (41).
2,3,4-Trideuteriopyridine (1-2,3,4-d3). 2,3-Dichloropyridine –
4,5,6-d3 (5-4,5,6-d3) (0.37 g, 2.5 mmol), Pd-C (10%, 0.2 g),
potassium carbonate (0.6 g ), and methanol (15 ml) were sealed
with a septum in a Büchner flask equipped with a magnetic
stirring bar and a balloon secured on the sidearm. The flask was
purged with nitrogen and charged with sufficient hydrogen gas
to inflate the balloon. After stirring at room temperature for 4
hours the flask was unsealed and the catalyst was removed by
filtration. The filtrate was acidified with conc hydrochloric acid
and then concentrated to give a wet solid. This was made
alkaline with saturated aqueous potassium carbonate, extracted
with dichloromethane (5 x 20 ml), and the organic extract dried
(sodium sulfate). The solvent was removed by fractional
distillation (Vigreux column) and the residue purified by
distillation (Kugelrohr) to give 2,3,4-trideuteriopyridine (1-
2,3,4-d3) as a colorless liquid; yield 0.11g (1.3 mmol, 52%); MS
2,3,5-Trideuteriopyridine (1-2,3,5-d3). 2,4-Dichloropy-
ridine-3,5,6-d3, (12-3,5,6-d3), (0.40 g, 2.6 mmol) was subjected
to catalytic hydrogenolysis as described for 2,3-dichloro-
pyridine-4,5,6-d3 (5-4,5,6-d3) to give 2,3,5-trideuteriopyridine
(1-2,3,5-d3) as a colorless liquid: yield 0.16 g (2.1 mmol, 77%);
1
m/z (%) 82 (100), 55 (45), 54 (59). The H and 13C-NMR data
1
MS m/z (%) 82 (100), 55 (48), 54 (66). The H and 13C-NMR
are given in Tables 1 and 2.
2,4,5-Trideuteriopyridine (1-2,4,5-d3). 2,5-Dichloropy-
ridine-3,4,6-d3 (7-3,4,6-d3) (0.41 g, 2.7 mmol) was treated as
above to give 2,4,5-trideuteriopyridine (1-2,4,5-d3) as a colorless
liquid: yield 0.12g (1.5 mmol, 55.5%); MS m/z (%) 82 (100), 55
data are given in Tables 1 and 2.
Synthesis of 2,4,6-Trideuteriopyridine (1-2,4,6-d3).
Pyridine N-oxide-2,6-d2 (2-2,6-d2). A solution of pyridine N-
oxide (2) (2.0 g, 21 mmol) in deuterium oxide (20 ml)
containing sodium carbonate (3.0 g) was heated at reflux for 12
hours, cooled to room temperature, and extracted with
dichloromethane (10 x 20 mL). The extract was dried (sodium
sulfate) and concentrated and the white solid was dried in a
vacuum desiccator to yield 2-2,6-d2) as a white solid: 1.65 g (17
1
(43), 54 (59). The H and 13C-NMR data are given in Tables 1
and 2.
2,3,6-Trideuteriopyridine (1-2,3,6-d3). 3,4-Dichloropyridine
-2,5,6-d3 (6-2,5,6-d3) (0.27 g, 1.8 mmol) was treated as above to
give 2,3,6-trideuteriopyridine (1-2,3,6-d3) as a colorless liquid:
yield 0.08 g (1.0 mmol, 54.2 %); MS m/z (%) 82 (100), 55 (33),
54 (70). The 1H and 13C-NMR data are given in Tables 1 and 2.
1
mol, 81.0%); H-NMR (deuterium oxide) ꢀ 7.41 (m, 1H), 7.22
(m, 2H); 13C-NMR (deuterium oxide) (DEPT-135) ꢀ135.9 (0)
(t, C2, 6, J = 28.3), 132.9 (+) (s, C4), 127.5 (+) (s, C3, 5); MS
m/z (%) 98 (64), 97 (100), 82 (73), 81 (100).
Synthesis of 2,3,5-Trideuteriopyridine (1-2, 3, 5-d3).
4-Nitropyridine N-oxide-2,3,5,6-d4 (9-2,3,5,6-d4). A mixture
of pyridine N-oxide-d5 (2-2,3,4,5,6-d5) (2.74 g, 27.4 mmol),
conc sulfuric acid (10.0 mL), and fuming nitric acid (5.0 mL)
was heated at 130˚ C for 5 hours. The resulting mixture was
poured onto ice (100 g) and made basic with saturated aqueous
sodium carbonate solution. The precipitate was removed by
filtration and the filtrate was extracted with dichloromethane (8
x 20 mL). The extract was dried (sodium sulfate) and
evaporated to give 4-nitropyridine N-oxide-2,3,5,6-d4 (9-2,3,5,6-
d4) as a yellow solid that was recrystallized from acetone to
yield a yellow crystalline solid: yield 2.47 g (17.1 mmol,
62.4%); 13C-NMR (deuteriochloroform) ꢀ 142.7 (s, C4), 140.5
4-Nitropyridine N-oxide-2,6-d2 (9-2,6-d2). A mixture of
pyridine N-oxide-2,6-d2 (2-2,6-d2) (1.80 g, 18 mmol), conc
sulfuric acid (4 mL), and fuming nitric acid (2 mL) was heated
at 130˚C for 5 hours. The resulting mixture was poured onto ice
(20 g), made basic with saturated aqueous sodium carbonate
solution, and extracted with dichloromethane (5 x 20 mL). The
extract was dried (sodium sulfate) and evaporated to give 4-
nitropyridine N-oxide- 2,6-d2 (9-2,6-d2) which was recrystallized
from acetone to give lustrous yellow crystals: yield 1.58 g (11
1
mmol, 61.1 %); H-NMR (deuteriochloroform) ꢀ 8.41 (S, 2H);
13C-NMR (deuteriochloroform) (DEPT-135) ꢀ 142.2 (0)) (s,

Nov-Dec 2007
Synthesis and Spectroscopic Properties of Isomeric Trideuterio- and Tetradeuterio Pyridines
1491
C4), 139.9 (0) (t, C2,6, J = 29.0 Hz), 120.8 (+) (s, C3,5); MS
m/z (%) 142 (34), 126 (78).
Synthesis of 2,3,4,6-Tetradeuteriopyridine (1-2,3,4,6-d4).
3-Chloropyridine-2,4,5,6-d4 (14-2,4,5,6-d4). A solution of 3-
chloropyridine N-oxide-2,4,5,6-d4 (4-2,4,5,6-d4) (0.76 g. 5.7
mmol) in dichloromethane (30 mL) was added dropwise to
phosphorous trichloride (0.82 mL) at 0˚C. The resulting solution
was heated at reflux for 2 hours, poured onto ice (20 g), and
made basic with saturated aqueous potassium carbonate. The
aqueous phase was extracted with dichloromethane (3 x 10 mL).
The organic extract was dried (sodium sulfate) and evaporated
to give 14-2,4,5,6-d4 as a pale yellow liquid: yield 0.60 g (5.1
mmol, 89.5%); 13C-NMR (deuteriochloroform) ꢀ 148.8 (t, C2, J
= 28.0 Hz), 147.7 (t, C6, J = 28.7 Hz), 136.0 (t, C4, J = 26.1
Hz), 132.4 (s, C3), 124.3 (t, C5, J = 26.8 Hz); MS m/z (%) 117
(100), 82 (66.3).
4-Chloropyridine N-oxide-2,6-d2 (10-2,6-d2). Acetyl chloride
(5.0 mL) was added to 4-nitropyridine N-oxide-2,6-d2 (9-2,6-d2)
(1.0 g, 7.0 mmol) which was warmed to 50˚C in a water bath.
The resulting mixture was refluxed for approximately 30
minutes until a yellow solid appeared. The resulting solid was
cooled in an ice bath and mixed with cold water. After the
vigorous reaction stopped, the solution was made basic with
saturated aqueous sodium bicarbonate and extracted with
dichloromethane (7 x 20 mL). The extract was dried (sodium
sulfate) and concentrated to give 10-2,6-d2 as a white solid:
1
yield 0.75 g (5.7 mmol, 81%) H-NMR (deuteriochloroform) ꢀ
7.21 (s, 2H; 13C-NMR (deuteriochloroform) (DEPT 135) ꢀ 140.2
(0) (t, C2, 6, J = 28, 5 Hz), 132.3 (0) (s, C4), 126.7 (+) (s, C3,
5); MS m/z (%) 131 (26), 115 (100).
2,3,4,6-Tetradeuteriopyridine (1-2,3,4,6-d4). 3-Chloropy-
ridine-2,4,5,6-d4 (14-2,4,5,6-d4) (0.30 g, 2.6 mmol), Pd-C (10 %,
0.08 g), potassium carbonate (0.6 g), and methanol (10 mL)
were sealed with a septum in a Büchner flask equipped with a
magnetic stirring bar and a balloon secured on the sidearm. The
flask was purged with nitrogen and then charged with sufficient
hydrogen gas to inflate the balloon. After stirring at room
temperature for 4 hours the flask was unsealed and the catalyst
2,4,6-Trideuteriopyridine (1-2,4,6-d3). 4-Chloropyridine-
2,6-d2 (10-2,6-d2) (0.12 g, 1.1 mmol) dissolved in ether (20 mL),
Pd-C (10%, 0.07 g), potassium carbonate (0.3 g) and a magnetic
stirring bar were sealed with a septum in a 50 mL Büchner flask
fitted with a balloon secured on the sidearm. The flask was
purged with nitrogen and charged with sufficient deuterium gas
to inflate the balloon. After stirring at room temperature for 4
hours the flask was unsealed and the catalyst was removed by
filtration. The filtrate was concentrated and the residue was
purified by distillation (Kugelrohr, 100˚C, waster aspirator) to
give 2, 4, 6-trideuteriopyridine (1-2,4,6-d3) as a colorless liquid:
yield 0.042 g (0.51 mmol, 46.8%), MS m/z (%) 82 (100), 54
(56). The 1H and 13C-NMR data are given in Tables 1 and 2.
removed by filtration.
The filtrate was acidified with
concentrated hydrochloric acid (2 mL) and the methanol was
removed by rotary evaporation. The residue was made basic
saturated aqueous potassium carbonate and extracted with
dichloromethane (3 x 15 mL). The organic extract was dried
(sodium sulfate) and concentrated by distillation through a
Vigreux column. The residue was distilled (Kugelrohr, 100˚ C)
at reduced pressure (water aspirator) to give 1-2,3,4,6-d4 as a
colorless liquid: yield 0.068g (0.82 mmol, 32%); MS m/z (%) 83
Synthesis of 2,3,4,5-Tetradeuteriopyridine (1-2,3,4,5-d4).
2-Chloropyridine-3,4,5,6-d4 (13-3,4,5,6,-d4). A mixture of
pyridine N-oxide-d5 (2-2,3,4,5,6-d5) (1.33 g, 13.0 mmol) and
phosphorous oxychloride (11.0 mL) was heated at 120˚ for 3
hours. The resulting solution was concentrated by distillation.
The viscous residue was dissolved in ice water, made strongly
alkaline with aqueous ammonia and the resulting red solution
extracted with dichloromethane (5 x 20 mL). The organic extract
was dried (sodium sulfate) and concentrated. The resulting red
liquid was subjected to column chromatography (silica gel).
Elution with dichloromethane gave 13-3,4,5,6-d4 as a colorless
liquid: yield 0.44 g (3.7 mmol, 28%); 13C-NMR (deuterio-
chloroform) ꢀ 151.5 (s, C2), 149.4 (t, C6, J = 28.1 Hz), 138.2 (t,
C4, J = 25.2 Hz), 124.1 (t, C3, J = 26.6 Hz), 121.7 (t, C5, J = 25.4
Hz); MS m/z (%) 119 (25), 117 (79), 116 (7), 82 (100).
2,3,4,5-Tetradeuteriopyridine (1-2,3,4,5-d4). 2-Chloropy-
ridine (13-3,4,5,6-d4) (0.44 g, 3.7 mmol), Pd-C (10%, 0.1 g),
potassium carbonate (0.6 g) and methanol (10 mL) were sealed
with a septum in a Büchner flask equipped with a magnetic
stirring bar and a balloon secured in the sidearm. The flask was
purged with nitrogen and charged with sufficient hydrogen gas
to inflate the balloon. After stirring at room temperature for 4
hours it was unsealed and the catalyst removed by filtration.
The filtrate was acidified with concentrated hydrochloric acid
and the solvent was removed by rotary evaporation. The residue
was made basic with aqueous potassium carbonate and extracted
with dichloromethane (3 x 10 mL). The organic extract was
dried (sodium sulfate) and the solvent removed by distillation.
The residue was distilled (Kugelrohr) at reduced pressure (water
aspirator) to give 1-2,3,4,5-d4 as a colorless liquid; yield 0.10 g
(1.2 mmol, 32.4%); MS m/z (%) 83 (100), 82 (11), 55 (57).
The 1H and 13C-NMR data are given in Tables 1 and 2.
1
(100), 55 (67). The H and 13C NMR data are given in Tables 1
and 2.
Synthesis of 2,3,5,6-Tetradeuteriopyridine (1-2,3,5,6-d4).
3,5-Dichloropyridine N-oxide (15). Hydrogen peroxide
(30%, 17.0 mL) was added to a mixture of 3,5-dichlorpyridine
(14) (14.8 g, 100 mmol) and methyltrioxorhenium (VII) (0.050
g, 0.2 mmol) in dichloromethane (40 mL) and allowed to stir for
17 hours. Manganese dioxide (0.025 g) was added to the
resulting biphasic mixture and stirring was continued until
oxygen evolution stopped (~ 1 hour). The aqueous phase was
separated and extracted with dichloromethane (3 x 20 mL). The
combined organic layers were dried (sodium sulfate) and
concentrated to give a white solid which was subjected to
column chromatography (silica gel). Elution with ethylacetate:
dichloromethane (1:1) gave 15 as a white solid, mp 109.110.5˚
1
C (lit. [12], 111˚ C: yield 11.5 g (70 mmol, 70%); H-NMR
(deuteriochloroform) ꢀ 8.15 (s, 2H), 7.27 (s, 1H); 13C-NMR
(deuteriochloroform) ꢀ 137.8 (C2, 6), 133.7 (C3,5), 126.5 (C4);
MS m/z % 165 (67), 163 (100), 147 (54).
3,5-Dichloropyridine N-oxide-2,4,6-d3 (15-2,4,6-d3).
A
solution of 3,5-dichloropyridine N-oxide (15) (1.0 g, 6.1 mmol)
and potassium carbonate (1.0 g) in deuterium oxide (10 mL) was
heated at 100˚ C for 8 hours. Cooling of the resulting solution
gave 15-2,4,6-d3 as white needles that were collected by
filtration. The filtrate was extracted with dichloromethane (3 x
10 mL). The organic extract was dried (sodium sulfate) and
concentrated to additional 15-2, 4, 6, d3 as white crystals. The
total yield, 0.84 g (5.0 mmol, 82%); 13C-NMR (deuterio-
chloroform) ꢀ 137.6 (t, C26, J = 29.6 Hz), 133.5 (s, C3,5), 126.4

1492
J. W. Pavlik and S. Laohhasurayotin
Vol 44
(t, C4, J = 27.2 Hz); MS m/z (%) 168 (47), 166 (74), 152 (68),
150 (100), 115 (62).
chloric acid (2.0 mL) concentrated, and made basic with
saturated aqueous potassium carbonate. The aqueous solution
was extracted with dichloromethane (5 x 20 mL), the organic
extract was dried (sodium sulfate), and concentrated by
fractional distillation (Vigreux column). The liquid residue was
distilled (Kugelrohr, 100˚ C, water aspirator) to give 1-2,3,5-6 as
3,5-Dichloropyridine-2,4,6-d3 (14-2,4,6-d3). A solution of
3,5-dichloropyridine N-oxide-2,4,6-d3 (15-2,4,6-d3) (0.83 g, 5.0
mmol) in dichloromethane (30 mL) was added dropwise to
phosphorous trichloride (0.64 mL) at 0˚ C. The resulting
solution was heated at reflux for one hour, poured onto ice (15
g), and made basic with saturated aqueous potassium carbonate
and extracted with dichloromethane (3 x 10 mL). The organic
extract was dried (sodium sulfate) and concentrated to give 14-
2,4,6-d3 as a white solid: yield 0.69 g (4.6 mmol, 92%); 13C-
NMR (deuteriochloroform) ꢀ 146.7 (t, C2,6, J = 29.1 Hz), 135.8
(t, C4, J = 26.5 Hz), 132.4 (s, C3,5); MS m/z (%) 152 (64), 150
(100), 117 (17), 115 (53).
3,5-Dichloropyridine-2,6-d2 (14-2,6-d2). A solution of 3,5-
dichloropyridine-2,4,6-d3 (14-2,4,6-d3) (0.59 g, 3.9 mmol) in
methanol (17 mL) containing sodium methoxide (1.5 M) was
stirred for 24 hours in a water bath maintained at room
temperature. The resulting solution was concentrated, mixed
with water (10 mL), and extracted with dichloromethane (5 x 10
mL). The organic extract was dried (sodium sulfate) and the
solvent removed to give 14-2,6-d2 as a white solid: yield 0.33 g
(2.2 mmol, 56%); 1H-NMR (deuteriochloroform) ꢀ 7.71 (s); 13C-
NMR 146.8 (t, C2,6 J = 29.3 Hz); 136.0 (s, C4), 132.5 (s,
C3,5); MS m/z (%) 151 (63), 149 (100), 114 (58).
1
a olorless liquid: yield 0.079 g (1.0 mmol, 50%). The H and
13C-NMR data are given in Tables 1 and 2.
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sealed with a septum in a Büchner flask equipped with a
magnetic stirrer and a balloon secured on the sidearm. The flask
was purged with nitrogen and charged with sufficient deuterium
gas to inflate the balloon. After stirring at room temperature for
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filtration. The filtrate was acidified with concentrated hydro
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