A crystalline monosubstituted carbene

Article abstract of DOI:10.1038/s41557-018-0153-1

By flanking a carbene carbon with two substituents, it is possible to synthesize persistent triplet carbenes and isolable singlet carbenes. Isolable singlet carbenes are among the most powerful tools in chemistry, and they have even found medicinal and materials science applications. Between the rich chemistry of disubstituted carbenes and the transient parent carbene are the monosubstituted carbenes that, so far, have only been observed in matrices at very low temperatures of just a few K. Herein, we describe the synthesis of a crystalline monosubstituted carbene. The key for isolating such a species was to design the correct substituent, namely a benzo[c]pyrrolidino heterocycle, which can single-handedly tame the intrinsic tendency of carbenes towards dimerization. The π-donor ability of the nitrogen atom, coupled with the steric bulk of chemically inert substituents at the two adjacent quaternary carbons, make these scaffolds very attractive for the isolation of a variety of other hitherto elusive electron-deficient species.

Full text of DOI:10.1038/s41557-018-0153-1

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https://doi.org/10.1038/s41557-018-0153-1
A crystalline monosubstituted carbene
RyoNakanoꢀ ꢀ, RodolpheJazzarꢀ ꢀ and GuyBertrandꢀ ꢀ*
By flanking a carbene carbon with two substituents, it is possible to synthesize persistent triplet carbenes and isolable singlet
carbenes. Isolable singlet carbenes are among the most powerful tools in chemistry, and they have even found medicinal and
materials science applications. Between the rich chemistry of disubstituted carbenes and the transient parent carbene are the
monosubstituted carbenes that, so far, have only been observed in matrices at very low temperatures of just a few K. Herein,
we describe the synthesis of a crystalline monosubstituted carbene. The key for isolating such a species was to design the cor-
rect substituent, namely a benzo[c]pyrrolidino heterocycle, which can single-handedly tame the intrinsic tendency of carbenes
towards dimerization. The π-donor ability of the nitrogen atom, coupled with the steric bulk of chemically inert substituents at
the two adjacent quaternary carbons, make these scaffolds very attractive for the isolation of a variety of other hitherto elusive
electron-deficient species.
arbenes are compounds with a neutral dicoordinate carbon
H
X
N
P
atom bearing either two singly occupied orbitals (triplet state)
or both a lone pair and a vacant orbital (singlet state). The
C
H
H
parent carbene CH2 has a triplet ground state and it is present in
interstellar space1; however, it is too reactive to be handled by stan-
dard laboratory techniques (Fig. 1). In contrast, the preparation of
persistent triplet carbenes2 and isolable singlet carbenes3,4 have been
accomplished by installation of two substituents on the carbene car-
bon, and the isolable singlet carbenes have found a myriad of appli-
cations5–11. Monosubstituted carbenes constitute the missing link
between the rich chemistry of the disubstituted carbenes and the
transient methylene. So far, their isolation has eluded the skills of
experimentalists, although they have been observed at a few K. For
example, during the course of our study, Eckhardt and Schreiner12
reported the first spectroscopic evidence for the aminomethylene
(H–C–NH2), which was generated by flash vapour pyrolysis of
cyclopropylamine and trapped in argon matrix at 12K. Herein, we
describe the synthesis of a crystalline monosubstituted carbene,
which features a small singlet–triplet gap and a low-lying LUMO.
During the past decade, we showed that the combination of a
π-donating substituent (phosphino or amino)13 and a π-innocent
substituent allows for the isolation of a series of disubstituted singlet
carbenes, such as acyclic (alkyl)(amino)carbenes14, cyclic (alkyl)
(amino)carbenes15,16 (B) and (phosphino)(alkyl)carbenes (C)17
(Fig. 1). Additionally, we reported that monosubstituted carbene
analogues, namely nitrene (D)18 and phosphinidene (E)19 could
also be isolated. These results clearly suggested that a monosubsti-
A
B
C
Parent
carbene
R
R
N
Dipp
Dipp
R
N
Dipp
R
R
N
N
N
P
N
P
P
N N
N
Dipp
N
R
N
R
R
D
E
F
Fig. 1 | Carbenes and isolated group 15 analogues. The parent carbene has
a triplet ground state and is too reactive to be isolated. Targeted singlet
monosubstituted carbenes (A) had only been observed in matrices at a few
K, whereas disubstituted carbenes featuring a π-innocent substituent, such
as B and C, have already been isolated. Nitrene (D) and phosphinidene
(E) are the only group 15 analogues of carbenes that have been isolated
so far. The pyrrolidino group used by Dervan et al.20–23 allows for the
characterization of aminonitrene (F), but not its isolation due to insufficient
kinetic protection; however, this scaffold inspired our design.
tuted carbene A bearing a bulky π-donor substituent should pos- which are readily available from phthalimide derivatives accord-
sess a large enough singlet–triplet gap to be handled under standard ing to the synthetic protocol by Heidenbluth and Scheffler24
laboratory conditions.
and Chan et al.25. The addition of excess phenylmagnesium bro-
mide to N-methylphthalimide afforded 1a in 54% yield (Fig. 2,
Supplementary Methods and Supplementary Figs. 1 and 2). Since
Results and discussion
Design, synthesis and characterization of monosubstituted car- the formation of 1a involves the addition of four equivalents of the
benes. Forty years ago, Dervan et al. showed that the 2,2,5,5-tetra- Grignard reagent and elimination of two equivalents of magnesium
methylpyrrolidino group could stabilize nitrene F, although it was oxide, the observed yield encouraged us to attempt the synthesis
not isolable due to the lack of kinetic protection20–23. Increasing the of bulkier analogues. Using m-terphenylmagnesium halide deriva-
steric bulk of the substituents on the quaternary carbon adjacent tives, 1b and 1c were prepared and isolated as colourless crystals in
to the nitrogen of pyrrolidine heterocycles would certainly be very 34 and 37% yield, respectively (Fig. 2, Supplementary Methods and
beneficial, but is synthetically challenging. We thus turned our atten- Supplementary Figs. 3–7). Oxidation of 1a–c with NO·SbF6 led to
tion to 2,2,5,5-tetrasubstituted benzo[c]pyrrolidine heterocycles, the desired protonated carbene precursors 2a–c in 69, 54 and 98%
UCSD–CNRS Joint Research Laboratory (UMI 3555), Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California,
USA. *e-mail: guybertrand@ucsd.edu
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a
–
SbF6
Ar
O
Ar
Ar
Ar
Ar
Ar
H
NO·SbF6
ArMgX
+
N
Me
N
Me
N
Toluene
Reflux
CH2Cl2 or
MeCN
H
Ar
Ar
O
1a: 54%
1b: 34%
1c: 37%
2a: 69%
2b: 54%
2c: 98%
CF3
CF3
C3
C4
C6
N2
C1
C2
Ar =
N1
F3C
CF3
C5
c
a
b
Fig. 2 | synthesis of the protonated carbene precursors 2a–c. This
synthetic sequence has a broad scope of applications, including the
possibility of using very bulky substituents.
Ar
H
b
H
KHMDS
N
2a
N
N
MTBE
H
–78 °C
Ar
Ar
3a
4a
Not detected
Ar
H
H
KHMDS
H1
C1
N
N1
C2a
C2b
2b
N
N
Toluene-d8
–78 °C
H
4b
Ar
Ar
3b
Detected by 1H NMR
F3C
CF3
F3C
H
N
N
F3C
Ar
H
4c
Multiple
decomposed
products
H
KHMDS
2c
N
MTBE
–78 °C
Ar
Ar
Fig. 4 | solid-state structures of 4b and 3c. a, Solid-state structure
of 4b, with ellipsoids at a 50% level of probability. Solvent molecules,
hydrogen atoms (except on the alkenyl moieties) and ellipsoids of the
terphenyl substituents are omitted for clarity. Selected bond lengths are:
C1–C2ꢀ=ꢀ1.311(7)ꢀÅ; N1–C1ꢀ=ꢀ1.421(7)ꢀÅ; and N2–C2ꢀ=ꢀ1.415(7)ꢀÅ. Selected
bond angles are: N1–C1–C2ꢀ=ꢀ127.8(5)°; C1–C2–N2ꢀ=ꢀ126.9(5)°; C1–N1–
C3ꢀ=ꢀ118.4(4)°; C1–N1–C4ꢀ=ꢀ126.2(4)°; C3–N1–C4ꢀ=ꢀ115.4(4)°; C2–N2–
C5ꢀ=ꢀ117.3(4)°; C2–N2–C6ꢀ=ꢀ127.0(4)°; and C5–N2–C6ꢀ=ꢀ115.6(4)°. b, Solid-
3c
Room temperature
In solution
Storable in solid state
Fig. 3 | Deprotonation of aldiminium salts 2a–c. Increasing the steric bulk
of the aryl substituents prevents the dimerization of the carbene, and thus
allows for its isolation.
yield, respectively (Fig. 2, Supplementary Methods, Supplementary state structure of 3c, with ellipsoids at a 50% level of probability. The carbene
Figs. 8–16 and Supplementary Table 1).
hydrogen atom was assigned to residual electron density, but could not be
Deprotonation of 2a with potassium hexamethyldisilazide refined; thus, the carbene bond angle cannot be discussed. Hydrogen atoms
(KHMDS) in methyl tert-butyl ether (MTBE) at −78°C resulted in (except on the carbene carbon) and ellipsoids of the terphenyl substituents
immediateandquantitativeformationofthecarbenedimer4a(Fig.3, are omitted for clarity. Selected bond lengths are: C1–N1ꢀ=ꢀ1.325(8)ꢀÅ; and
Supplementary Methods and Supplementary Figs. 17 and 18). All N1–C2aꢀ=ꢀN1–C2bꢀ=ꢀ1.515(6)ꢀÅ. Selected bond angles are: C1–N1–C2aꢀ=ꢀ
attempts to detect the putative transient carbene 3a by monitoring C1–N1–C2bꢀ=ꢀ124.1(2)°; and C2a–N1–C2bꢀ=ꢀ111.9(5)°.
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a
c
H
LUMO
HOMO
Singlet–triplet gap
N
CO
CO
Rh
H
50.0
0.53
2.0
Cl
N
–0.11
5
P
Ph
–0.85
40.0
30.0
20.0
10.0
0
0
34% yield
6
–2.00
Not isolated
–2.0
–4.0
–6.0
–8.0
–4.54
36.5
–4.69
26.9
(1) [Rh(cod)Cl]2
(2) CO
–5.37
33.9
(PhP)5
–6.27
46.4
H
N
Se
Se
7
65% yield
H
KHMDS
O
O
iPr
iPr
iPr
N
2c
N
H
THF
or MTBE
N
N
N
N
N
iPr
iPr iPr
3c
H
N
BDAC
AAC
3c
DAC
Et
Et
N
b
Et
8
91% yield
Et
H
Et
H
N
Et
Et
9
Et
51% yield
(88% NMR yield)
Rac-10
50% yield
(72% NMR yield)
HOMO
LUMO
Fig. 5 | theoretical and experimental study of the electronic nature of 3c. a, DFT calculations at the B3LYP/def2-TZVPP level of theory show the influence
of carbene substituents on the energy of the HOMO and LUMO, and singlet–triplet energy gap. The substituents were truncated as shown. b, Kohn–Sham
molecular orbitals (HOMO, left; LUMO, right) of the core structure of 3c (isovalueꢀ=ꢀ0.02). c, The CO stretching frequency of 5 coupled with the 31P and
77Se NMR chemical shifts of 6 and 7, respectively, allows for an estimate of the σ-donating and π-accepting properties of 3c. The reactivity of 3c with non-
activated alkenes shows its electrophilicity, and the stereospecific formation of syn-9 and anti-10 from cis- and trans-3-hexene, respectively, demonstrates
its singlet ground state. THF, tetrahydrofuran.
the reaction using low-temperature NMR spectroscopy failed. In the (diisopropylamino)(tert-butyl)carbene (1.2976(17)Å)14, but
contrast, during the deprotonation of 2b under similar experimen- shorter than in the bis(diisopropylamino)carbene (1.363(6) and
tal conditions, but using toluene-d8 as the solvent, we observed at − 1.381(6)Å)27. The carbene hydrogen atom was assigned to residual
78°C a sharp but weak singlet at 13.4ppm on the 1H NMR spectrum, electron density but could not be refined, and thus the carbene bond
which quickly disappeared (Fig. 3 and Supplementary Fig. 19). To angle cannot be discussed. While carbene 3c can be stored in the
confirm that this signal could be attributed to the desired carbene 3b, solid state for at least one month at room temperature under an inert
we performed density functional theory (DFT) calculations (GIAO- atmosphere, it gradually decomposes in solution at room tempera-
1
B3LYP/6-31G*), which predicted the H NMR CH signal of 3b at ture, or even at −40°C, giving multiple products. It should be noted
13.9ppm. In addition, the 13C NMR signal for the carbene car- that formation of the corresponding dimer 4c was not observed.
bon was predicted at 321ppm, but it could not experimentally be
observed because of the short lifetime of 3b. The observed down- Theoretical and experimental study of the electronic nature of
field shifts are due to paramagnetic components in chemical shift carbene 3c. To gain further insight into the electronic properties of
tensors, which are correlated to the n→π* (HOMO→LUMO) tran- the monosubstituted carbene 3c, calculations were carried out at the
sition26. All attempts to isolate 3b led to the isolation of dimer 4b, B3LYP/def2-TZVPP level of theory (Fig. 5a, Supplementary Data
which was characterized by single-crystal X-ray diffraction and Supplementary Fig. 57). The singlet–triplet gap (33.9kcalmol−1)
(Fig. 4a, Supplementary Methods, Supplementary Figs. 20–21 and lies between those of the bis(diisopropylamino)carbene (BDAC)
Supplementary Table 3). Finally, deprotonation of 2c at −78°C (36.5kcalmol−1) and (diisopropylamino)(tert-butyl)carbene (AAC)
in MTBE afforded carbene 3c, which was first characterized in (26.9kcalmol−1). The six-membered diamidocarbene (DAC)—
solution by NMR spectroscopy (Supplementary Methods and known as the most π-accepting cyclic carbene isolated so far—was
Supplementary Figs. 22–25). The observed signals (1H: 13.8ppm, calculated to possess the largest singlet–triplet gap of 46.4kcalmol−1
1
13C: 320.0ppm, JC–H =95Hz) are in perfect agreement with the among the carbenes shown in Fig. 4a. Compared with the acyclic
results of the DFT calculations. Single crystals of 3c were grown carbenes BDAC and AAC, the monosubstituted carbene features
by layering heptane over an MTBE solution at −40°C (Fig. 4b and the lowest-lying LUMO (–0.85eV), partially due to through-space
Supplementary Table 2). As expected, the X-ray diffraction study orbital interaction with the benzene backbone (Fig. 5b). While the
revealed a nitrogen–carbon bond (1.325(8)Å) longer than in imin- LUMO of DAC (–2.00eV) was much lower than that of the mono-
ium 2c (1.264(6)Å). This bond is also slightly longer than that of substituted carbene, our calculations suggested that direct comparison
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solution of N-methylphthalimide (161 mg, 1.0 mmol) in toluene (10 ml) at room
temperature. The mixture was heated in an oil bath at 120 °C and concentrated
until the volume was reduced to around 10 ml. Then, the Schlenk flask was
sealed and stirred at 120 °C for 1 d. After cooling to room temperature, the
mixture was quenched by a saturated aqueous NH4Cl solution and extracted with
dichloromethane (3 ×50 ml). The combined organic phase was dried over MgSO4,
filtered through a pad of Celite and evaporated to dryness, and the residue was
purified by flash silica-gel column chromatography (hexane/EtOAc =97/3 to
90/10). All fractions containing 1c were combined and evaporated to dryness.
The obtained crude 1c was washed with hexane and benzene repeatedly, then
dried in vacuo at 120 °C overnight to afford 1c as a colourless solid (783 mg,
0.37 mmol, 37% yield). 1H, 13C{1H} and 19F{1H} NMR spectra can be found in
Supplementary Figs. 5–7.
of the level of the LUMO between acyclic and cyclic carbenes could
be erroneous (Supplementary Fig. 57). Experimentally, the overall
donor properties of 3c were estimated using the infrared CO stretch-
ing frequencies28 of the corresponding cis-((3c)Rh(CO)2Cl) complex
5 (Fig. 5c, Supplementary Methods, Supplementary Figs. 29–31 and
Supplementary Table 5). The observed values (2,086 and 2,006cm−1;
average wave number νav =2,046cm−1) indicate that 3c is a weaker
donor than BDAC (νav =2,030cm−1) and AAC (νav =2,020cm−1), and
is as weak an overall donor as DAC (νav =2,045cm−1)29,30. To differenti-
ate between the σ-donating and π-accepting ability of the carbene, the
phosphinidene adduct 6 (Supplementary Methods and Supplementary
Figs. 32–35) and selenium adduct 7 (Supplementary Methods,
Supplementary Figs. 36–39 and Supplementary Table 6) were prepared
by reacting the in situ-formed 3c with (PhP)5 and elemental selenium,
respectively (Fig. 5c)31–33. Note that, despite our efforts, 6 could not
be isolated in pure form but was characterized from the crude reac-
Synthesis of iminium salt 2c. A mixture of 1c (1.07 g, 0.50 mmol) and NO·SbF6
(160 mg, 0.60 mmol) in acetonitrile (15 ml) was stirred at room temperature
for 3 h. The resulting solution was filtered through a cannula equipped with a
glass filter, and evaporated to dryness. Then, the obtained solid was thoroughly
dried in vacuo at 140 °C overnight. After cooling to room temperature, the
solid residue was washed with a minimum amount of dichloromethane and
dried in vacuo at 140 °C overnight to afford 2c as an orange solid (1.15 g,
0.49 mmol, 98% yield). 1H, 13C{1H} and 19F{1H} NMR spectra can be found in
Supplementary Figs. 14–16. Recrystallization from hot 1,1,2,2-tetrachloroethane
solution afforded single crystals suitable for X-ray crystallographic analysis
(Supplementary Table 1).
tion mixture by H, 13C, 31P and H–31P heteronuclear multiple bond
correlation NMR analyses. The 31P NMR signal of 6 appeared at +
111ppm—close to that of AAC (+126.3ppm) and downfield shifted
from those of BDAC (+69ppm) and DAC (+83ppm). The 77Se NMR
of 7 showed a signal at +979ppm—downfield shifted compared with
those of BDAC (+593ppm), AAC (+640ppm) and DAC (+847ppm).
Overall, the theoretical and experimental data led to a conclusion that
3c is one of the most electrophilic (π-accepting) carbenes ever isolated.
Thanks to its electrophilicity and sterically open nature, the
monosubstituted carbene 3c shows unusually high reactivity as a
stable singlet carbene (Fig. 5c). Indeed, it undergoes cyclopropa-
nation reactions with unactivated alkenes to afford 8, 9 and 10
under mild conditions (Supplementary Methods). It should be
noted that, despite its synthetic importance, only two examples of
cyclopropanation of unactivated alkenes with stable carbenes have
been reported, with both involving high temperatures and terminal
alkenes34,35. The stereospecific formation of syn-9 and anti-10 from
cis- and trans-3-hexene, which was unambiguously confirmed by
NMR (Supplementary Figs. 43–54) and X-ray crystallographic anal-
yses (Supplementary Tables 8 and 9) demonstrates that 3c reacts as
a singlet carbene in a concerted manner36.
1
1
Synthesis of carbene 3c. In a 15ml scintillation vial, a mixture of 2c (94.7mg, 40µ
mol) and KHMDS (10.0mg, 50µmol) was chilled for 1h in a glovebox coldwell
cooled with a dry ice/acetone bath. Then, pre-cooled tert-butyl methyl ether
(2.0ml) was added and the mixture was stirred with cooling for 10min. The yellow
solution was quickly passed through a glass filter and layered by cold heptane
(around 15ml). The bi-layered solution was stored at −40°C overnight to afford 3c
as yellowish crystals (47.2mg, 22µmol, 55% yield). 1H, 13C{1H} and 19F{1H} NMR
spectra can be found in Supplementary Figs. 22–25, and the X-ray data are given in
Supplementary Table 2.
Data availability
Crystallographic data for the structures reported in this article have been deposited
at the Cambridge Crystallographic Data Centre under deposition numbers CCDC
1814366 (2c), 1814371 (3c), 1814368 ((3c)Rh(cod)Cl), 1814370 (4b), 1835936 (5),
1814367 (7), 1814369 (8), 1814372 (9) and 1835937 (10). Copies of the data can
be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. All other
data supporting the findings of this study are available within the article and
its Supplementary Information, or from the corresponding author upon
reasonable request.
Conclusions
Received: 10 January 2018; Accepted: 29 August 2018;
Published: xx xx xxxx
About three decades after the discovery of the first stable disubsti-
tuted carbenes—namely, a (phosphino)(silyl) carbene37 and an imid-
azol-2-ylidene38—this work demonstrates that monosubstituted
carbenes can also be isolated. Due to its peculiar steric and elec-
tronic properties, the monosubstituted carbene exhibited reactivity
that was previously limited to transient carbenes. Importantly, we
expect the bulky benzo[c]pyrrolidino substituents developed here
to be a robust and general platform for the stabilization and isola-
tion of related non-octet species, which have so far eluded the skills
of experimentalists.
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All reactions were performed under an atmosphere of argon using standard
Schlenk or dry box techniques. All solvents were dried and degassed using standard
procedures. The following compounds were prepared according to literature
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Thanks are due to the NSF (CHE-1661518) for financial support of this work, and the
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Author contributions
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Competing interests
The authors declare no competing interests.
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Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/
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Reprints and permissions information is available at www.nature.com/reprints.
Correspondence and requests for materials should be addressed to G.B.
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