Trapping of Difluorocarbene by Frustrated Lewis Pairs

Article abstract of DOI:10.1002/anie.202001354

Frustrated Lewis pairs consisting of diphenylphosphino and boryl groups located at the ortho-position can trap difluorocarbene affording stable zwitterionic adducts. The reaction can be reversed to release difluorocarbene at elevated temperatures.

Full text of DOI:10.1002/anie.202001354

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Accepted Article
Title: Trapping of Difluorocarbene by Frustrated Lewis Pairs
Authors: Vladimir O. Smirnov, Alexander D. Volodin, Alexander A.
Korlyukov, and Alexander Dilman
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10.1002/anie.202001354
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Trapping of Difluorocarbene by Frustrated Lewis Pairs
Vladimir O. Smirnov,[a] Alexander D. Volodin,[b] Alexander A. Korlyukov,[b,c] and Alexander D. Dilman*[a]
Dedicated to Rolf Huisgen on the occasion of 100th birthday.
[a]
V. O. Smirnov, Prof. Dr. Alexander D. Dilman
N. D. Zelinsky Institute of Organic Chemistry
119991 Moscow, Leninsky prosp. 47, Russian Federation
E-mail: adil25@mail.ru
[b]
[c]
A. D. Volodin, Prof. Dr. A. A. Korlyukov
A. N. Nesmeyanov Institute of Organoelement Compounds
119991 Moscow, Vavilov str. 28, Russian Federation
Prof. Dr. A. A. Korlyukov
N. I. Pirogov Russian National Research Medical University
Ostrovitianov str., 1, 117997 Moscow, Russian Federation
Supporting information for this article is given via a link at the end of the document.
Abstract: Frustrated Lewis pairs consisting of diphenylphosphino-
and boryl groups located at the ortho-position can trap
difluorocarbene affording stable zwitterionic adducts. The reaction
Herein we report on the interception of difluorocarbene with
a phosphine/borane FLP to generate zwitterionic phosphonium
borate species. This process is expected to proceed via primary
a
can be reversed to release difluorocarbene at elevated temperatures. nucleophilic attack of the Lewis basic phosphorus at
difluorocarbene followed by rapid trapping of the intermediate
ylide nucleophile by Lewis acidic boron.
The concept of frustrated Lewis pairs (FLP) has emerged as a
First, we evaluated intermolecular version of FLP involving
valuable tool for discovery of unconventional reactions.[1] Indeed,
triphenylphosphine and pinacol ester of phenylboronic acid or
a mixture of a Lewis acid and a Lewis base, which can coexist
methyl borate (Scheme 2). However, a combination of the
with each other without forming a bond, can interact with various
phosphine, potassium bromodifluoroacetate and the boron
molecules. The cooperative effect can be further enhanced by
reagents caused only decomposition of the bromodifluoro-
placing acidic and basic sites within one reagent.[1b] As FLPs,
acetate anion, but no products can be detected by NMR
pairs of boranes and phosphines are typically used, which after
trapping some species, are converted into borates and
phosphonium ions, respectively.
spectroscopy. Even the use of preformed phosphobetaine
reagent, which is known to generate ylide
1
upon
decarboxylation under mild heating,[11a] was unsuccessful
(Scheme 2, bottom equation).
Difluorocarbene is a key intermediate in the manufacture of
fluorinated polymers.[2] Moreover, difluorocarbene has been
extensively used for the synthesis of various gem-difluorinated
compounds[3] and difluorocyclopropanes.[4] Since this carbene
exists in a singlet state,[5] the presence of an empty orbital favors
its electrophilic reactivity. There are many examples of
interaction of difluorocarbene with nucleophilic reagents,[3] while
interaction with electrophiles is uncommon.[6,7] The interaction of
difluorocarbene with triphenylphosphine was first proposed in
1964 to generate phosphorus ylide 1,[8] and this process is
reversible.[9] Due to facile decomposition of 1 back to the
phosphine and carbene, this ylide has not yet been
characterized spectroscopically, but it can be successfully
coupled with carbonyl compounds and other electrophiles.[10-12]
Scheme 2. Attempted trapping of ylide 1.
Then, we switched to intramolecular version of FLP. Thus, a
series of phosphines 2 bearing a dioxyboryl fragment in the
ortho-position were prepared[13,14] and evaluated in reaction with
potassium bromodifluoroacetate (Scheme 3). The reactions
were performed in dimethylformamide at room temperature, and
a series of compounds 3a-c containing five-membered phospha-
bora-cycle were isolated in individual state after column
chromatography. Contrary to the phenylene-based FLPs,
ferrocene-based analogues (1,2- or 1,1’-pinacolboryl(diphenyl-
phosphino)-substituted ferrocenes) did not gave carbene
trapping products. We also evaluated borate ester 4, which was
generated in situ by treatment of ortho-hydroxy-substituted
Scheme 1. Reactions of difluorocarbene.
1
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Scheme 3. Synthesis of compounds 3 and 5.
Scheme 4. Reactions of compounds 3 and 5.
phosphine with pinacolborane, which afforded product
containing six-membered phospha-bora-cycle.
5
the C,P bond, which is typical for gem-difluorinated
phosphonium salts[12] (see Supporting Information for details).
NMR spectra of obtained compounds have the expected
31P…19F splitting pattern thereby supporting the proximity of the
phosphino and the CF2 fragments. The presence of two sets of
diastereotopic methyl groups in 3a,b and 5 supports the spiro-
arrangement of these systems. Structures of compounds 3a and
5 were verified by single-crystal X-ray analysis (Figure 1). These
structures contain tetrahedral boron and phosphorus atoms
flanking difluoromethylene fragment.
Notably, when 3a was heated for 2 hours at 80 °C in DMF
with
a
mixture
of
1,1-diphenylethylene
and
4-
chlorobenzaldehyde (2.4 equiv each), the aldehyde insertion
product 7 was formed preferably (7 - 64 %, 6 - 3%; 19F NMR
control). This clearly shows that release of free difluorocarbene
from 3 is stepwise, from the ylide formed after B-CF2 bond
scission. Correspondingly, from miscroscopic reversibility
principle, the formation of adduct 3 from FLP 2 and the carbene
also proceeds stepwise through the initial carbene-phospine
interaction followed by cyclization of the ylide (Scheme 5, upper
equation).
To further probe the energetic profile of reactions involving
FLP, we performed reactions of 2a with potassium
bromodifluoroacetate in the presence of either 1,1-
diphenylethylene or 4-chlorobenzaldehyde at room temperature.
In these experiments only compound 3a was formed, while
neither 6 nor 7 were detected. This means that the formation of
product 3a is a kinetically controlled process, while the formation
of products 6 and 7 is thermodynamically controlled (Scheme 5).
Figure 1. X-ray structures of 3a and 5. Hydrogen atoms are omitted for clarity.
We briefly evaluated the reactivity of these compounds. First,
the reversible character of the difluorocarbene trapping was
verified (Scheme 4). Heating of compound 3a in 1,1-
diphenylethylene for
difluorocyclopropane 6 in combination with starting FLP 2a.
Notably, the release of difluorocarbene proceeded to
3
hours at 100 °C afforded
a
significant extent even at 80 °C (53% yield of
difluorocyclopropane at 66 % conversion of 3a after 3 hours).
When complex 3a was combined with 4-chlorobenzaldehyde
and heated at 80 °C, product 7 arising from insertion of the
aldehyde between the boryl and the difluoromethylene
fragments was formed (X-ray structure of 7 is shown). The
reaction likely proceeds via heterolytic dissociation of the C-B
bond with the formation of the difluorinated ylide followed by
interaction with the aldehyde.[15] Basic hydrolysis of 7 gave
expected difluoromethyl alcohol ArCH(OH)CHF2 via cleavage of
Scheme 5. Kinetic vs. thermodynamic control.
2
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10.1002/anie.202001354
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Zwitterionic phosphonium/borate structures of 3 and 5 are
stable towards moisture. However, the reactive C-B bond can be
cleaved in the presence of either potassium hydrogen difluoride
or even under neutral conditions, as evidenced for compound 5,
simply by heating in methanol (Scheme 6).[16] In both cases,
zwitterionic trifluoroborate 8 or phenoxide 9 were obtained
bearing the difluoromethyl group attached to the phosphorus
atom. However, reaction of 3a with acidified KHF2 involves
cleavage of boron-oxygen bonds leaving the B-CF2 bond intact.
This selectivity is associated with higher affinity of proton
towards boronate oxygen versus carbon, while exchange of B-O
to B-F strengthens the B-C bond. At the same time, the degree
of deoxofluorination of the boryl fragment of 3a is determined by
acidity of the medium. Acidification with equivalent amount of
toluenesulfonic acid leads to fluoro(hydroxy)-substituted product
Scheme 7. Comparison of Ph3P and FLP 2a.
Ph3P and 2a was used, a mixture of 3a and the difluoroalkene
was formed, but, importantly, their ratio did not depend on the
concentration of aldehyde. These experiments indicate that
under these conditions the interaction of phosphorus atom with
difluorocarbene is the key factor determining the rate of these
processes.
To analyze the origin in reactivity differences of Ph3P and
FLP 2, we performed quantum chemical calculations[17] at PBE0-
gCP-D3(BJ)/def2-TZVP[18] level using CPCM model[19] to
account for solvation (DMF as solvent). Ylides appearing from
the interaction of phosphines with CF2 are formed without any
barrier, with the ylide Y1 from Ph3P being slightly more favorable
and having slightly shorter P-CF2 bond than that in FLP-derived
ylide (Y2), which agrees well with steric effects (Figure 2).
However, ring closure of ylide Y2 requires only 4.5 kcal of
activation energy, while the barrier of the interaction of Y1 with
the borane is twice as higher. Moreover, the thermodynamics of
Scheme 6. Reactions of compounds 3 and 5.
10, while in the presence of concentrated hydrochloric acid, the
BF2-fragment is formed (product 11).
Ability of intramolecularly bound FLPs
difluorocarbene compared to inefficiency
2
to catch
simple
of
phosphine/borane combinations is remarkable and may suggest
the influence of the boryl group on the trapping process. Indeed,
the ortho-boryl fragment makes trapping of the carbene possible.
On the other hand, due to steric effects, the bulky boryl fragment
could slow down the interaction of the phosphorus atom with the
carbene. To gain further insight into this reactivity issue, we
performed
a series of comparative experiments for the
interaction of phosphines with a difluorocarbene source and
aldehyde (Scheme 7). In a reference run, triphenylphosphine
gave difluoroalkene arising from the Wittig reaction of the
intermediate ylide.[11a] However, under the same conditions, FLP
2a provided trapping adduct 3a, while the difluorostyrene was
not detected. When equimolar mixture of
Figure 2. Calculated free energy profiles for reactions of Ph3P + CF2 + PhBPin
(black) and FLP 2 + CF2 (blue).
3
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(13) ortho-(Dioxyboryl)phenylphosphines have found applications as
ambiphilic systems with little “frustrated” character. Preparation of
pinacol derivative 2a and its analogue 2b and their reactions with
singlet oxygen were recently described, see: (a) S. Porcel, G. Bouhadir,
N. Saffon, L. Maron, D. Bourissou, Angew. Chem. Int. Ed. 2010, 49,
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Chem. Soc,. 2013, 135, 9326–9329; c) For other applications of
phosphine-borane compounds of this pattern as a catalysts, see: O.
Basle, S. Porcel, S. Ladeira, G. Bouhadir, D. Bourissou, Chem.
Commun. 2012, 48, 4495–4497.
the interaction of these ylides with boron centers is notably
different. The intermolecular reaction of Y1 with PhBPin to give
product P1 has virtually no benefit in free energy. At the same
time, transformation of structure Y2 to P2 is highly exergonic. Of
special note is that while free energies of reactions leading to P1
and P2 differ by 17.5 kcal/mol, their enthalpies are similar (-34.1
for P1, and -35.0 kcal/mol for P2, see Supplementary
information for details). Therefore, the difference between
triphenylphosphine/borane combination and FLP 2 in reaction
with difluorocarbene is essentially entropic in nature.
In
summary,
trapping
of
difluorocarbene
with
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adducts containing the difluoromethylene fragment between
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described. A release of difluorocarbene from the adducts can be
performed at elevated temperatures. Concerning the P-CF2-B
unit, the C-B bond can be selectively cleaved either by
protodeboronation or by aldehyde insertion, while dialkoxyborate
fragment can be deoxofluorinated without affecting the parent
zwitterionic structure.
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Keywords: difluorocarbene • organofluorine • frustrated Lewis
pairs • phosphinoboranes • intermediates
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Entry for the Table of Contents
Table of Contents
Difluorocarbene is reversibly trapped by intramolecurlar frustrated Lewis pairs. The reaction proceeds stepwise via interaction of the
carbene with the phosphorus atom followed by formation of the carbon-boron bond.
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5
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