Recently reported crystalline isothiazole carbenes: Myth or reality

Article abstract of DOI:10.1002/anie.200702272

(Chemical Equation Presented) Singlet carbenes are not always stable: Isothiazole carbenes, recently reported as crystalline solids, cannot even be observed at room temperature; they rearrange into their 2-imino-2H-thiete isomers with an energy barrier of

Full text of DOI:10.1002/anie.200702272

Communications
DOI: 10.1002/anie.200702272
Singlet Carbenes
Recently Reported Crystalline Isothiazole Carbenes: Myth or
Reality**
Alan DeHope, Vincent Lavallo, Bruno Donnadieu, Wolfgang W. Schoeller, and Guy Bertrand*
Following the discovery of the first stable acyclic A and cyclic
carbenes B (Ad = adamantyl) by our group,[1] and Arduengoꢀs
group,[2] respectively, several types of singlet[3] carbenes have
been isolated.[4] For a long time, it was believed that these
electron-deficient species could only be stable when two
heteroatoms were directly linked to the carbene center. Even
in 2007, it has been written: “To date, all theoretical and
experimental evidence indicates that, in order to form a stable
carbene, the carbenic carbon needs to be bonded to strong p-
donor atoms”.[5] Such a statement is misleading since in recent
years, our group has reported the synthesis and X-ray crystal
structure of carbenes C–F (Dipp = 2,6-diisopropylphenyl),[6–9]
Scheme 1. Synthesis of isothiazole carbenes as reported in refer-
ence [12].
ever, despite their crystalline nature, single crystal diffraction
studies were not performed. It was mentioned that the
observed 13C NMR signal for the carbene carbon atom of 2S
(d = 194.3–195.7 ppm) corresponds to the shifts
observed for imidazol-2-ylidenes. This statement is
correct; however, since the 13C NMR signal for
carbenes featuring a nitrogen and a carbon sub-
stituent (such as D–F) appears usually at much
lower field,[7–9] these values were somewhat surpris-
ing.
The reported stability of carbenes 2S was even
more unexpected since, four decades ago, Wood-
ward[13a] and Woodman[13b] reported the formation
of ketoketenimines 4O in the deprotonation of 3-
unsubstituted isoxazolium salts 1O, the oxygen
analogues of heterocycles 1S. Indeed, considering the ylidic
structure of the putative carbene 2O (and of course 2S), one
can readily imagine a very simple ring-opening process
(Scheme 2).
which feature only one heteroatom substituent. Last year, we
even isolated carbene G, which has no heteroatom substituent
directly linked to the carbene center.[10] Nevertheless, singlet
carbenes are not always “bottle-able”![11]
Recently, in a paper entitled “Synthesis of
Stable Isothiazole Carbenes”,[12] it was claimed
that deprotonation of 2-aryl-4,5-diphenylisothiazo-
lium perchlorates 1S by potassium tert-butylate in
absolute THF at room temperature (08C according
to the Supporting Information) provides the stable
Scheme 2. Deprotonation of isoxazolium salts 1O leads to ketoketenimines 4O by
ring opening of transient carbenes 2O (reference [13]).
isothiazol-3-ylidenes 2S, which can be isolated as
yellow crystalline solids (Scheme 1). The authors
wrote: “the carbenes are stable in solution and in
the crystal”. The stability of derivatives 2S allowed
their characterization by 1H and 13C NMR spectroscopy, mass
spectrometry, and even melting points were reported. How-
We performed calculations at B3LYP/6-311 g** level plus
zero-point vibrational-energy correction within the harmonic
approximation[14] for the reported carbene 2S (Ar= Ph) and
its possible thioketoketenimine isomer 4S(s-cis) (Figure 1).
The latter did not appear to be an energy minimum; it
undergoes a ring closure into its 2-imino-2H-thiete isomer 3S,
which is 21.7 kcalmolꢀ1 more stable than carbene 2S.
Interestingly, although carbene 2S is an energy minimum, a
transition state TS for the rearrangement 2S!3S was located
only 1.0 kcalmolꢀ1 higher in energy than carbene 2S, obvi-
ously precluding the isolation of the latter. To be complete, we
also investigated the trans thioketoketenimine 4S(s-trans),
[*] A. DeHope, V. Lavallo, B. Donnadieu, Prof. W. W. Schoeller,
Prof. G. Bertrand
UCR-CNRS Joint Research Chemistry Laboratory (UMI 2957)
Department of Chemistry
University of California
Riverside, CA 92521-0403 (USA)
Fax: ( +1)951-827-2725
E-mail: gbertran@mail.ucr.edu
[**] We are grateful to the NSF (CHE 0518675) for financial support of
this work.
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To bring evidence for the carbene nature of their products,
the authors first claimed that addition of some crystals of
isothiazolium perchlorate 1S to the “carbenes” 2S in THF
afforded the carbene dimers 5S with an E configuration
(Scheme 4).[12] Since the two substituents of the carbene have
Figure 1. Different isomers of isothiazole carbene 2S with their relative
energies (kcalmolꢀ1) in parentheses, and geometry (interatomic dis-
tances in Š) of the transition state (TS) for the rearrangement 2S!
3S.
Scheme 4. Formation of carbene dimer 5S as reported in refer-
ence [12].
which appeared to be 6.0 kcalmolꢀ1 higher in energy than the
four-membered heterocycle 3S.
similar steric bulk, the formation of only one stereoisomer is
very unlikely.[18] Despite their crystalline nature, the “dimers”
1
We prepared the 2,4,5-triphenylisothiazolium perchlorate
1S (Ar= Ph)[15] and carried out the deprotonation reaction
under the experimental conditions described in the original
paper.[12] After filtration of the reaction mixture and evapo-
ration of the solvent and tert-butyl alcohol, 2-imino-2H-thiete
3S was the only observable species (Scheme 3). This hetero-
have only been characterized by H and 13C NMR spectros-
copy, as well as mass spectrometry. Assuming the presence of
only one isomer, at least 15 13C NMR signals are expected, all
of them in the same range, which makes any attributions
highly debatable. Since the “carbenes” 2S do not exist, we
have of course not been able to reproduce the reported
results.
The authors reported that morpholine and piperidine
react with isothiazolium salts 1S, in the presence of potassium
tert-butylate to give adducts 6S, which have been fully
characterized (including by a single-crystal X-ray diffraction
study in the case of piperidine).[12] They explained these
results as follows: “Evidently, the transient isothiazol-3-
ylidenes react in situ with morpholine in a typical insertion
reaction into the polarized NH bond”. However, an alter-
native rationalization for the formation of adducts 6S is that
in the presence of potassium tert-butylate, the amines undergo
a base-assisted addition to the isothiazolium perchlorate 1S.
We carried out the reaction of 1S (Ar= Ph) with the lithium
salt of morpholine and cleanly obtained adduct 6S (84%
yield) (Scheme 5). Since the authors stated that the amine
adducts “can also be obtained directly from the correspond-
Scheme 3. Deprotonation of triphenylisothiazolium perchlorate 1S
leads to the corresponding 2-imino-2H-thiete 3S.
cycle[16] was isolated in 91% yield and fully characterized
including by
a single-crystal X-ray diffraction study
(Figure 2).[17] As predicted by calculations, monitoring the
reaction by 13C NMR spectroscopy did not allow the obser-
vation of any intermediates; moreover no signal in the range
reported for the carbene carbon of 2S was observed.
Scheme 5. Addition of morpholine to carbene 2S as reported in
reference [12] (top); nucleophilic addition of morpholine lithium salt to
1S leads to adduct 6S (middle); addition of morpholine to 2-imino-
2H-thiete 3S affords 7S (bottom).
Figure 2. Molecular structure of 2-imino-2H-thiete 3S in the solid
state. Thermal ellipsoids represent 50% probability.
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Addition of morpholine lithium salt to triphenylisothiazolium
perchlorate 1S: A solution of morpholine lithium salt (prepared by
reaction of nBuLi with morpholine) (129 mg, 1.39 mmol) in THF was
added at ꢀ788C to a stirred suspension of isothiazolium perchlorate
1S (487 mg, 1.39 mmol) in THF. The reaction mixture was warmed to
room temperature and stirred for 30 minutes. After the solvent was
removed and the residue was extracted with hexanes, 6S was obtained
as a crystalline solid. Yield: 84%; m.p.: 1178C (reported[12] 1178C).
The spectroscopic data are similar to those already reported.[12]
Addition of morpholine to 2-imino-2H-thiete 3S: Morpholine
(0.2 mL, 2.23mmol) was added at 0 8C by syringe to a stirred solution
of 3S (140 mg, 0.45 mmol) in THF. The reaction mixture was stirred at
room temperature for 1 h, and then the solvent was removed to yield
a yellow solid. Recrystallization from 5:1 hexanes/THF at room
temperature afforded 7S as yellow crystals. Yield: 85%; m.p.: 1868C.
ing stable carbenes”, we added morpholine at room temper-
ature to the heterocycle 3S. A clean reaction occurred, but
instead of derivative 6S, we isolated compound 7S (85%
ꢀ
yield) resulting from the aminolysis of the C S bond of 3S
(Scheme 5). Single crystals of zwitterion 7S were subjected to
an X-ray diffraction study (Figure 3).
Received: May 23, 2007
Published online: July 27, 2007
Keywords: carbenes · heterocycles · ring-opening reactions
.
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Experimental Section
All manipulations were performed under argon by using standard
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