A practical laboratory route to the synthesis of trideuteriomethyl-[13C] iodide

Article abstract of DOI:10.1002/jlcr.666

A practical synthetic laboratory route for the synthesis of trideuteriomethyl-[¹³C] iodide (¹³CD₃I) (from tetradeuterio-[¹³C]-methanol and hydriodic acid) is described. We comment on the experimental protocol, and the use of water as an 'additive' to improve the synthetic yield. Copyright

Full text of DOI:10.1002/jlcr.666

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 291–296.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.666
Research Article
A practical laboratory route to the synthesis
of trideuteriomethyl-[13C] iodide
Gregory S. Coumbarides, Jason Eames* and Neluka Weerasooriya
Department of Chemistry, Queen Mary, University of London, Mile End Road,
London E1 4NS, UK
Summary
A practical synthetic laboratory route for the synthesis of trideuteriomethyl-
[13C] iodide (13CD3I) (from tetradeuterio-[13C]-methanol and hydriodic acid) is
described. We comment on the experimental protocol, and the use of water as
an ‘additive’ to improve the synthetic yield. Copyright # 2003 John Wiley &
Sons, Ltd.
Key Words: Deuterium; Carbon-13 and Trideuterio-[13C]-methyl iodide
The incorporation of a multi-[D, 13C]-labelled methyl substituents
within an organic molecule is very well documented.1 The most
common strategy has relied on carbon–carbon bond forming processes
involving direct addition of the labelled methyl group motif.2 This
methodology has been conducted in two ways; through the use of a
nucleophilic labelled methyl source,3 such as a Grignard reagent4 (e.g.
13CH3MgI) or by using the complementary electrophilic source, such as
an alkyl halide (e.g. 13CH3I).5 In practise, both strategies can rely on the
use of the same alkyl halide starting precursor. A pivotal component of
this methodology is in the synthesis of the required labelled methyl
iodide, which is generally synthesized from the corresponding alcohol.6
*Correspondence to: J. Eames, Department of Chemistry, Queen Mary, University of London,
Mile End Road, London E1 4NS, UK. E-mail: J. Eames@amw.ac.uk
Copyright # 2003 John Wiley & Sons, Ltd.
Received 17 July 2002
Revised 13 September 2002
Accepted 16 September 2002

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G. S. COUMBARIDES ET AL.
Methyl iodide is one of the more challenging alkyl halides to
synthesise due to its volatile and electrophilic nature. Unlabelled methyl
iodide is relatively inexpensive and is available in multi-kilogram
quantities. Many of these available protocols are understandably large
scale due to readily available cheap starting precursors. However, when
dealing with high value isotopically labelled systems, such as
tetradeuterio-[13C]-methanol (13CD3OD), the situation is different; the
reactions are generally performed on a smaller scale, and must be
reproducible.
We now report a reliable and experimentally simple synthetic
protocol for the synthesis of [13C]-methyl iodide (13CH3I) 2 and
trideuterio-[13C]-methyl iodide (13CD3I) 5 derived from [13C]-methanol
1 and tetradeuterio-[13C]-methanol 4, respectively, by simple addition of
hydriodic acid (HI). We had initially attempted to synthesize the slightly
cheaper variant, [13C]-methyl iodide 2 using Ott’s previously reported
protocol;8 by addition of a solution of [13C]-methanol 1 containing
11.9% water to a cooled hydriodic acid solution (57% solution in
water), followed by heating for 4 h (by raising the temperature to
initially 70oC), then up to 85oC (for several hours) and collecting the
distillate, [13C]-methyl iodide 2 in 94% yield using a dry ice cooled trap
(Scheme 1). However, we found following this protocol with spectro-
scopically pure [13C]-labelled methanol 1 (99.9% purity) and hydriodic
acid (99.99% purity, 57 wt % in water) gave very little [13C]-methyl
iodide 2 (yield 55% – Scheme 2: Entry 1) and no recovered
Hl
13CH3OH*
13CH3l
94%
1
2
* containing 11.9% water
Scheme 1.
Hl
13CH3OH
13CH3l
13CH3O13CH3
H2O
H2O
1
2
3
Entry
1
Yield
0 wt %
<5%
70%
74%
76%
2
3
50 wt %
60 wt %
80 wt %
4
5
100 wt % 85%
Scheme 2.
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A PRACTICAL LABORATORY ROUTE
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[13C]-methanol 1 (determined by 1H and 13C NMR spectroscopy)
(Scheme 2). We believe this suggests that under our slightly modified
conditions, the reaction must evidently proceed via formation of the
unwanted and much more volatile dimethyl-[13C] ether 3 (b.p. À258C).
Formation of dimethyl ether under related acidic conditions is well
documented.8 It is particularly interesting to note that Ott’s specified9
the use of a solution of [13C]-methanol which contained 11.9% water.
We were unsure about the reason why the water content in the solution
of [13C]-methanol 1 was specified so accurately (approximately
16 mol%), when considering the amount of water present within the
aqueous solution of hydriodic acid (57 wt % in water).
We were surprised to find that the success of this reaction did hinge
on an additional amount of water being added. We probed this
procedure by pre-adding water to a fresh solution of [13C]-labelled
methanol 1 (50–100 wt% – Scheme 2: entries 2–5) and repeating Ott’s
original procedure. The additional water is crucial for the outcome of
this reaction; in short, the more present, the better the overall yield of
[13C]-methyl iodide 2 (Scheme 2). The unaccounted loss of [13C]-
methanol is presumably due to competitive formation of volatile
dimethyl-[13C] ether 3. We next investigated the synthesis of the more
valuable trideuterio-[13C]-methyl iodide 5 using our optimized proce-
dure; addition of tetradeuteriomethyl-[13C]-methanol 4 (Scheme 3) to a
solution of 100 wt% of water, followed by the addition of a solution of
hydriodic acid (57% in water) gave the required trideuterio-[13C]-methyl
iodide 5 in 73% yield (after distillation). The product was pure–
determined by 13C NMR spectroscopy, and was subsequently stored in
a sealed ampoule over a copper shot. This sample was shown to be
stable and the purity remained constant over the course of a year.9
In conclusion, we have probed the synthesis of [13C]-methyl iodide 2
(derived from [13C]-methanol 1 and hydriodic acid) and have shown
that the reaction is dependent on the additional presence of water within
the reaction mixture. We have extended this protocol by synthesizing
the more valuable trideuterio-[13C]-methyl iodide 5 in 73% yield from
tetradeuterio-[13C]-methanol 4. The effect of adding water to the
reaction mixture to promote formation of labelled methyl iodide is
Hl
13CD3OD
13CD3l
73%
H2O
4
5
Scheme 3.
Copyright # 2003 John Wiley & Sons, Ltd.
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G. S. COUMBARIDES ET AL.
complex. We presume the presence of water lowers the relative rate of
formation of dimethyl ether 3, by a combination of lowering the relative
concentration of methanol and by making the hydriodic acid solution
less dehydrating.
Previous attempts at synthesizing [13C]-methyl iodide using related
procedures have shown a variety of yields, ranging from 62% to 94%.10
This variation in yield may be due to the volatility of dimethyl-[13C]-
iodide,7 but more than likely is a result of competitive dimethyl-[13C]-
ether formation due to the quality of hydriodic acid used. This side
reaction appears to have been kept to a minimum within the synthesis of
short-lived [11C]-methyl iodide11 by continuous removal using a carrier
gas (typically N2)12 or by conducting the reaction on a pre-adsorbed
Al2O3-hydriodic acid column.13 Alternatively, preparation using a
phosphorus/iodine method has been documented, but the apparatus
and procedure have been shown to be more complex.14
Procedure for the synthesis of trideuterio-[13C]-methyl iodide 5: Water
(5.0 g, 5.0 ml, 0.27 mol) was added to a stirred solution of tetradeuterio-
[13C]-methanol 4 (5 g, 4.2 ml, 0.135 mol) in a 100 ml single neck round
bottom flask. Hydriodic acid (50 ml, 99.99% purity, 57 wt% in water)
was slowly added, and a micro-distillation apparatus fitted. The
resulting solution was heated to 40oC and stirred for 2 h. The
temperature of the reaction mixture was increased gradually by 5oC
every 30 min until the temperature of the oil bath reached 80oC. At this
point trideuterio-[13C]-methyl iodide was collected using a 50 ml round
bottom flask which was permanently cooled to À848C using an ethyl
acetate–liquid nitrogen bath. The temperature of the reaction mixture
(inside the vessel) remained at 408C. This distillation procedure was
carried out (over 6–8 h) under a sealed nitrogen atmosphere using a
balloon of nitrogen to give the trideuterio-[13C]-methyl iodide 5 (14.3 g,
73%) as a colourless liquid.
Procedure for the synthesis of [13C]-methyl iodide 2: In the same way
as above, [13C]-methanol 1 (5 g, 4.8 ml, 0.151 mol), water (5 g, 5 ml,
0.27 mol) and hydriodic acid (50 ml, 99.99% purity, 57 wt% in water) gave,
after distillation [13C]-methyl iodide 2 (18.4 g, 85%) as a colourless liquid.
Acknowledgements
We thank Queen Mary, University of London for a college studentship
(to N.W.), the London University Central Research Fund, The Nuffield
Copyright # 2003 John Wiley & Sons, Ltd.
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A PRACTICAL LABORATORY ROUTE
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Foundation (NUF-NAF 99), GOSS Scientific Instruments Ltd and The
Royal Society for their generous financial assistance.
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