Loss of isotope labeling in the conversion of [18O2]benzoic acid into [18O]benzoyl chloride with oxalyl chloride

Article abstract of DOI:10.1002/anie.200390101

Tell me where the ¹⁸O atoms are, where are they to be found? This question was raised when a large amount of the ¹⁸O labeling was lost in the course of the conversion of [¹⁸O₂]benzoic acid into [¹⁸O]b

Full text of DOI:10.1002/anie.200390101

Angewandte
Chemie
[
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Oxygen Labeling and Exchange
[
4] C. A. Barson, J. C. Bevington, J. Polym. Sci. Part A 1997, 35,
Loss of Isotope Labeling in the Conversion of
2955.
18
18
[
O ]Benzoic Acid into [ O]Benzoyl Chloride
2
[
5] M. Buback, J. Sandmann, Z. Phys. Chem. 2000, 214, 583.
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with Oxalyl Chloride**
[
[
[
[
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In the course of a study on reaction mechanisms, we needed
1
8
[
O]2-phenyl-2-oxodiazoethane (4*), which was prepared
110, 2877.
1
8
following the reactions given in Scheme 1. [ O]Water with an
enrichment of 95% 18O was used as labeling source in the
reactions. Based on this, benzoic acid (2*) formed by the
hydrolysis of benzotrichloride (1) should have a composition
[
10] S. Yamauchi, N. Hirota, S. Takahara, H. Misama, K. Sawabe, H.
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ers, J. Am. Chem. Soc. 1991, 113, 3599.
[
[
18
16 18
16
of 90.25% O , 9.5% O O, and 0.25% O . The exper-
2
2
[
13] T. M. Brockman, S. M. Hubig, J. K. Kochi, J. Org. Chem. 1997,
imental verification with the help of EI- (positive mode) and
ESI-mass spectrometry (negative mode) confirms this isotope
62, 2210.
[
14] T. Tateno, H. Sakuragi, K. Tokumaru, Chem. Lett. 1992, 20, 1883.
15] A. Charvat, J. A˚mann, B. Abel, D. Schwarzer, J. Phys. Chem. A
distribution (90% 18O , 10% O O, < 1% O ). Dissolution
16
18
16
[
2
2
2
001, 105, 5071.
of the labeled benzoic acid in water/acetonitrile does not
result in any decrease in the 18O content.
[
[
[
16] A. Charvat, J. A˚mann, B. Abel, D. Schwarzer, K. Henning, K.
Luther, J. Troe, Phys. Chem. Chem. Phys. 2001, 3, 2230.
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Rev. Phys. Chem. 1994, 45, 519.
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12981.
[
[
19] C. Maul, K.-H. Gericke, Int. Rev. Phys. Chem. 1997, 16, 1.
20] Gaussian98 (RevisionA.7), M. J. Frisch, G. W. Trucks,
H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheese-
man, V. G. Zakrzewski, J. A. Montgomery, R. E. Strat-
mann, J. C. Burant, S. Dapprich, J. M. Millam, A. D.
Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi, V.
Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C.
Adamo, S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q.
Cui, K. Morokuma, D. K. Malick, A. D. Rabuck, K. Raghava-
chari, J. B. Foresman, J. Cioslowski, J. V. Ortiz, A. G. Baboul,
B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.
Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham,
C. Y. Peng, A. Nanayakkara, C. Gonzalez, M. Challacombe,
P. M. W. Gill, B. G. Johnson, W. Chen, M. W. Wong, J. L. Andres,
M. Head-Gordon, E. S. Replogle, J. A. Pople, Gaussian, Inc.,
Pittsburgh, PA, 1998.
Scheme 1. Synthesis of a-diazoketone 4*, *¼18O: a) H218O/1108C/48 h, ampoule;
b) 3 equivalents of (COCl) /778C/1 h; c) CH N /Et O/08C.
2
2
2
2
For the derivatization of the marked benzoic acid (2*) to
1
8
[ O]benzoyl chloride (3*), we chose oxalyl chloride on
account of its preparative advantage, a decision which led to
unexpected consequences. The reaction of benzoyl chloride
(3*) with diazomethane gives the diazoketone 4*, the
carbonyl group of which unexpectedly shows two resonance
signals with marginally different shifts (Dd ¼ 0.03 ppm) in the
1
3
C NMR spectrum (Figure 1a).
[
[
[
[
21] M. Kieninger, O. N. Ventura, S. Suhai, Int. J. Quantum Chem.
Risley and Van Etten have also reported a similar isotope
effect for the 13C resonances of [ O]- and [ O]-carbonyl
16
18
1
998, 70, 253.
22] D. Schwarzer, J. Troe, M. Zerezke, J. Chem. Phys. 1997, 107,
380.
[2]
groups, in approximately the same range as ours, in which
8
the signal at a somewhat higher field strength can be assigned
23] B. Abel, J. A˚mann, P. Botschwina, M. Buback, M. Kling, R.
Oswald, S. Schmatz, J. Schroeder, T. Witte, unpublished results.
24] J. Aschenbr¸cker, M. Buback, N. P. Ernsting, J. Jasny, J.
Schroeder, U. Stegm¸ller, Appl. Phys. B 1997, 65, 441.
to the 18O isotopomer. It can be seen from the intensities of
1
8
the resonance signals of 4* that the required O-isotopomer
is formed in only 40%.
At first we thought that a hydration±dehydration se-
quence involving the formed a diazoketone 4*, because of
adventitious moisture present in ethereal diazomethane,
could be responsible for the drastic loss of 18O. This inference
[
*] Prof. Dr. K.-P. Zeller, Dipl.-Chem. P. Haiss
Institut f¸r Organische Chemie
Universit‰t T¸bingen
Auf der Morgenstelle 18, 72076 T¸bingen (Germany)
Fax: (þ49)7071-29-5076
E-mail: kpz@uni-tuebingen.de
[
**] We thank Prof. Dr. H.-J. Machulla, Sektion f¸r Radiopharmazie,
1
8
Universit‰tsklinikum T¸bingen, for a generous gift of [ O]water.
Angew. Chem. Int. Ed. 2003, 42, No. 3
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303

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proved to be unfounded as reexamination revealed that 3*
exchange indicates that this view presents only an incomplete
picture of the actual processes involved in the formation of
benzoyl chloride.
had also been affected by loss of isotope labeling.
The 13C carbonyl resonance of 3* is split into two signals,
exactly as in the subsequent product (Figure 1b). Mass
spectrometry shows the hydrolysis of the intermediate 3*
An intramolecular Friedel±Crafts attack at the ipso
position of the intermediate 7* parallel to the collapse of 7*
to 3* (following the mechanism postulated by Adams and
(
ca. 1 mg 3*, few drops of water, ultrasound bath) affords
1
8
[3]
18
benzoic acid containing an O content of 39.8%, and not
expected 95%. Oxalyl chloride, used as a reagent in the step
Ulich ) is a plausible explanation for the loss of O labeling
in 3*. Thus, unlabeled 3 could be formed via a spiro-type s-
complex (either 10 or 11) with concomitant elimination of CO
2
*!3*, is thus the source for the considerable incorporation
16
of O observed.
and labeled CO (Scheme 3). This explanation would demand
2
that all the benzoic acid undergoing a loss of isotope labeling
should in fact loose the whole carbonyl group. Thus, a
1
3
corresponding loss of the C isotope labeling should take
1
3
13
place when using [carboxy- C]benzoic acid ( C-7).
1
3
18
Figure 1. Carbonyl region of the C NMR spectra of a) [ O]2-phenyl-2-
1
8
oxodiazoethane (4*) and b) [ O]benzoyl chloride (3*).
Scheme 3. Intramolecular ipso attack in the intermediate 7* or 13C-7; de-
1
8
13
13
mands the loss of O from 7* and the loss of C from C-7 (not observed),
*¼ O, * ¼ C.
1
8
13
The use of oxalyl chloride (6) for the preparation of
carboxylic acid chlorides dates back to the classical work of
[
3]
Adams and Ulich. Depending on the amount of 6 used in
the reaction with carboxylic acids, either carboxylic acid
anhydrides 9 (< 1 equiv) or acid chlorides (> 2 equiv) are
formed. Mixed anhydride 7 and in some cases isolable
diacyloxalates 8 have been shown to exist as intermediates
in the reaction (Scheme 2).
The carbonyl group of benzoic acid should, in principle, be
found intact in benzoyl chloride irrespective of the course of
the reaction. Our observation, that the oxygen atom of the
carbonyl group undergoes an appreciable oxygen-atom
Young and Robinson[4] have converted sodium [carboxy-
1
3
13
C]benzoate into [carbonyl- C]benzoyl chloride with com-
1
3
plete retention of C marking, by reaction with oxalyl
1
3
chloride in the presence of pyridine. In this reaction, C-7
as an isotopomer of 7* should be formed in the first partial
step by elimination of NaCl. The absence of loss of 13C label-
ing consequently excludes the intramolecular ipso attack.
However, this could be a result of the presence of pyridine,
1
3
which catalyzes the collapse to labeled [carbonyl- C]benzoyl
1
3
chloride ( C-3) and restrains the competing intramolecular
1
3
Friedel±Crafts acylation ( C-7!3; Scheme 4).
This consideration made it necessary to treat [carboxy-
1
3
C]benzoic acid with oxalyl chloride under the same con-
ditions as for 2* and to conduct an isotope analysis of the
benzoyl chloride thus formed. The hydrolysis of the resulting
benzoyl chloride obtained to benzoic acid and the mass
spectrometric analysis of the latter shows the complete
retention of the 13C enrichment (89.5% C).
13
Our studies lead to the surprising result that in the
reaction of benzoic acid with an excess of oxalyl chloride to
give benzoyl chloride, the carbonyl oxygen atom is exchanged
to an extent of 60%, while at the same time the carbon atom
of the carbonyl group retains its identity.
To explain these results, we propose the reversible
[
5]
formation of the 1,3-dioxetanes 12 or alternatively the
,3,5-trioxanes 13 or 14 from benzoyl chloride and oxalyl
chloride (Scheme 5). Such processes and intermediates ex-
1
Scheme 2. General reaction of carboxylic acids with oxalyl chloride, with
benzoic acid given as a specific example.
3
04
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Chemie
oxalyl chloride remain after formation of benzoyl
chloride (3) to set up the equilibrium with 12, or 13 and
4 as intermediates. Thus, for the distribution of the
1
1
6
18
oxygen atoms the ratio O: O is 4:1. Therefore under
complete equilibration, the benzoyl chloride (3*)
1
8
Scheme 4. Catalytic acceleration of the breakdown of 13C-7 to 13C-3 by pyridine.
resulting from 2* should contain 20% of the
O
labeling. After a total reaction time of 1 hour, we find
an enrichment of 39.8% 18O, which shows that the
oxygen-exchange process has not yet reached the
equilibration stage. A further loss of 18O marking is to
be expected for longer reaction times.
Received: June 28, 2002 [Z19636]
[
1] R. Salmon in Encyclopedia of Reagents for Organic
Synthesis, Vol. 6 (Ed.: L. A. Paquette), Wiley, Chichester,
1
995, pp. 3814 ± 3817.
2] J. M. Risley, R. L. Van Etten, J. Am. Chem. Soc. 1980, 102,
609 ± 4614.
3] R. Adams, L. H. Ulich, J. Am. Chem. Soc. 1920, 42, 599 ±
611.
[
[
[
[
4
1
8
Scheme 5. Oxygen exchange between [ O]benzoyl chloride (3*) and oxalyl
chloride (6) via 1,3-dioxetane 12 or the 1,3,5-trioxanes 13 and 14.
4] D. J. Young, M. J. T. Robinson, J. Labelled Compd. Radio-
pharm. 2000, 43, 121 ± 126.
5] The chemistry of 1,3-dioxetanes is less known although,
according to the MO calculations,[ they should be more
6]
plain the equilibration of the oxygen atoms of benzoyl
chloride and oxalyl chloride without an intermolecular
exchange of carbonyl carbon atoms in accordance with our
experimental observations.
[7]
stable than the intensively studied 1,2-isomers. A literature
survey up to 1995 excludes the existence of authentic 1,3-
dioxetanes.[ Our literature search revealed that 1,3-dioxetanes
are sporadically described as reactions products, for example,
Ref. [8].
7]
In principle, the same outcome would result from similar
equilibria between the starting material benzoic acid (2) and
the intermediates 7, 8, and 9 on one side, and oxalyl chloride
[
6] a) P. N. V. P. Kumar, X. D. Wang, B. Lam, T. A. Albright, E. D.
Jemmis, J. Mol. Struct. 1989, 194, 183 ± 190; b) T. H. Lay, T.
Yamada, P.-L. Tsai, J. W. Bozzelli, J. Phys. Chem. A 1997, 101,
(6) on the other side, these equilibria would be established
2471 ± 2477.
simultaneously on the formation of benzoyl chloride (3).
Because 3 possesses the highest carbonyl reactivity of all the
benzoic acid derivatives present in the reaction mixture, we
consider it as the most suitable candidate for this role.
Finally, as an especially reactive carbonyl compound, the
[7] C. R. Saha-Mˆller, W. Adam in Comprehensive Heterocyclic
Chemistry II, Vol. 1B (Eds.: A. R. Katritzky, C. W. Rees, E. F. V.
Scriven, A. Padwa), 1996, pp. 1041 ± 1082.
[
8] a) L. S. Boulos, I. T. Hennawy, Phosphorus Sulfur Silicon Relat.
Elem. 1993, 84, 173 ± 179; b) D. Bankston, J. Org. Chem. 1989, 54,
2003 ± 2006.
[
9]
formation of intermediate cyclohexadienylideneketene 15
[
9] We thank one of the referees for pointing out the possible
participation of a ketene intermediate.
through isomerization of benzoyl chloride (3*) or the decay of
the ion pair 10 can be considered (Scheme 6). The inter-
mediate 15 could undergo an oxygen-atom replacement with
oxalyl chloride (6), for example, via 16 in an analogous
manner.
We used exactly three equivalents of oxalyl chloride for
the reaction with benzoic acid. Two equivalents from the
Scheme 6. Oxygen Exchange via ketene intermediate 15.
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