Selective Conversion of Carbon Dioxide to Formaldehyde via a Bis(silyl)acetal: Incorporation of Isotopically Labeled C1 Moieties Derived from Carbon Dioxide into Organic Molecules

Article abstract of DOI:10.1021/jacs.9b08342

The conversion of carbon dioxide to formaldehyde is a transformation that is of considerable significance in view of the fact that formaldehyde is a widely used chemical, but this conversion is challenging because CO₂ is resistant to chemical transformations. Therefore, we report here that formaldehyde can be readily obtained from CO₂ at room temperature via the bis(silyl)acetal, H₂C(OSiPh₃)₂. Specifically, formaldehyde is released from H₂C(OSiPh₃)₂ upon treatment with CsF at room temperature. H₂C(OSiPh₃)₂ thus serves as a formaldehyde surrogate and provides a means to incorporate CH_x (x = 1 or 2) moieties into organic molecules. Isotopologues of H₂C(OSiPh₃)₂ may also be synthesized, thereby providing a convenient means to use CO₂ as a source of isotopic labels in organic molecules.

Full text of DOI:10.1021/jacs.9b08342

Article
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Selective Conversion of Carbon Dioxide to Formaldehyde via a
Bis(silyl)acetal: Incorporation of Isotopically Labeled C1 Moieties
Derived from Carbon Dioxide into Organic Molecules
Michael Rauch, Zack Strater, and Gerard Parkin*
Department of Chemistry, Columbia University, New York, New York 10027, United States
S
* Supporting Information
ABSTRACT: The conversion of carbon dioxide to form-
aldehyde is a transformation that is of considerable significance
in view of the fact that formaldehyde is a widely used chemical,
but this conversion is challenging because CO2 is resistant to
chemical transformations. Therefore, we report here that
formaldehyde can be readily obtained from CO2 at room temperature via the bis(silyl)acetal, H2C(OSiPh3)2. Specifically,
formaldehyde is released from H2C(OSiPh3)2 upon treatment with CsF at room temperature. H2C(OSiPh3)2 thus serves as a
formaldehyde surrogate and provides a means to incorporate CHx (x = 1 or 2) moieties into organic molecules. Isotopologues
of H2C(OSiPh3)2 may also be synthesized, thereby providing a convenient means to use CO2 as a source of isotopic labels in
organic molecules.
(HCO2SiR3), silyl acetals (H2C(OSiR3)2), methoxysilanes
(R3SiOCH3), and methane, as illustrated in Scheme 1.8−10
INTRODUCTION
■
Formaldehyde is a widely used chemical, with an annual
consumption of 30 million tons.1,2 Although formaldehyde is
obtained industrially by the partial oxidation of methanol,1 an
alternative direct synthesis from carbon dioxide is an important
objective from several perspectives, which include (i) the use of
CO2 as a renewable C1 source for the synthesis of organic
chemicals, (ii) efforts to counter the increasing levels of carbon
dioxide in the atmosphere via carbon capture and utilization
(CCU), and (iii) the role of carbon dioxide as the principal
precursor for the incorporation of isotopic carbon labels into
organic molecules.3−6 However, there are major difficulties
associated with using CO2 as a C1 source. In particular, because
CO2 is both kinetically and thermodynamically resistant to
chemical transformations, the initially formed species are
generally more reactive than CO2, such that it is difficult to
control selectivity. Indeed, the direct hydrogenation of CO2 to
afford formaldehyde is not practical because subsequent
hydrogenation to methanol is strongly exergonic.3 Therefore,
it is significant that we describe here a method to generate
formaldehyde selectively from carbon dioxide at room temper-
ature via a readily isolable bis(silyl)acetal, namely H2C-
(OSiPh3)2. Furthermore, we also report that H2C(OSiPh3)2
can be used as a convenient C1 synthon for the formation of
organic molecules, including isotopically labeled derivatives.
Scheme 1. Reduction of CO2 by Hydrosilanes
These transformations, however, require the presence of a
catalyst, and although such catalysts have been known since
1981,11 many feature precious metals.8 As such, there is
considerable interest in discovering catalysts that employ
nonprecious metals.8 In this regard, we recently demonstrated
that the zinc hydride compound, [Tptm]ZnH, was an effective
catalyst for the hydrosilylation of CO2 by (EtO)3SiH to afford
the silyl formate, HCO2Si(OEt)3,12 while a system comprised of
i
[TismPr Benz]MgX (X = H, Me)13 and B(C6F5)3 was effective for
selective hydrosilylation of CO2 to the bis(silyl)acetal, H2C-
(OSiPh3)2, as illustrated in Scheme 2.14
RESULTS AND DISCUSSION
■
The formation of H2C(OSiPh3)2 is of particular note because
the selective reduction of CO2 to compounds with the
formaldehyde oxidation level is not well-precedented.8,14−19
1. Synthesis and Structural Characterization of the
Bis(silyl)acetal, H2C(OSiPh3)2. While the addition of the
H−H bond to CO2 is thermodynamically uphill,3,7 the
corresponding reaction of a Si−H bond is favorable and can
occur in a stepwise manner to afford a series of reduced products
with different carbon oxidation levels, namely silyl formates
Received: August 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b08342
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Scheme 2. Selective Reduction of CO2 to H2C(OSiPh3)2
Scheme 3. Synthesis of Isotopologues of H2C(OSiPh3)2
Such compounds, nevertheless, offer potential as a means to (i)
generate formaldehyde in an anhydrous medium and (ii)
incorporate CO2-derived carbon atoms into organic molecules.
Therefore, to achieve these objectives, we sought to generate
H2C(OSiPh3)2 on a larger scale than had been previously
i
reported.14 Significantly, the aforementioned [TismPr Benz]MgX/
B(C6F5)3 catalytic system can be readily modified from the
milligram to multigram scale, thereby allowing H2C(OSiPh3)2
to be isolated in a pure crystalline form and in excellent yield.
The ability to isolate H2C(OSiPh3)2 in a crystalline form is of
significance because it has previously only been isolated as an
oil18f or spectroscopically observed as a component of a
mixture.18b Moreover, the crystalline form of H2C(OSiPh3)2 has
also enabled the first structure determination of a bis(silyl)acetal
by X-ray diffraction (Figure 1).20 In addition to affording
H2C(OSiPh3)2, the approach also allows for the facile synthesis
silane. Specifically, addition of PhSiH3 effects reduction of
H2C(OSiPh3)2 to methane.
2. Generation of Formaldehyde from H2C(OSiPh3)2.
H2C(OSiPh3)2 is air-stable in both the solid state and solution at
room temperature. However, at elevated temperatures, a
solution of H2C(OSiPh3)2 in DMSO reacts with H2O to release
Ph3SiOH and generate formaldehyde (Scheme 4).21 The
deprotection may also be performed at room temperature in
Scheme 4. Generation of Formaldehyde
MeCN in the presence of H2SO4, as indicated by the observation
1
of a signal at δ 9.60 ppm in the H NMR spectrum. More
significant than releasing formaldehyde by hydrolysis is the fact
that it can also be generated by a nonhydrolytic pathway.
Specifically, formaldehyde can be produced rapidly at room
temperature by treatment of a solution of H2C(OSiPh3)2 in
acetonitrile with CsF22 (Scheme 4).23 The latter reaction is
accompanied by release of (Ph3Si)2O and a plausible mechanism
involves fluoride initiated generation of incipient [H2C-
(OSiPh3)O]−, followed by dissociation of Ph3SiO− (Scheme
5).24,25
Since the oxidation state of carbon in both CH2O and
H2C(OSiPh3)2 is zero, the synthesis of formaldehyde from CO2
via H2C(OSiPh3)2 involves the direct reduction from C(IV) to
C(0). As such, the process is to be contrasted with a sequence
that proceeds via methanol,26 which involves the circuitous
reduction from C(IV) in CO2 to C(-II) in CH3OH, followed by
oxidation to C(0) in CH2O. Thus, it is evident that the synthesis
of formaldehyde from CO2 via H2C(OSiPh3)2 manages redox
changes in a much more efficient manner than one which
Figure 1. Molecular structure of H2C(OSiPh3)2 (hydrogen atoms on
the phenyl rings omitted for clarity).
of isotopologues. For example, D2C(OSiPh3)2, H213C-
(OSiPh3)2, and D213C(OSiPh3)2 have been synthesized by
reactions that use the appropriate combinations of Ph3Si(H/D)
and (12C/13C)O2 (Scheme 3). As an illustration, D213C-
(OSiPh3)2 is obtained by the catalytic addition of Ph3SiD to
13CO2.
While the reduction of CO2 by Ph3SiH in this system does not
proceed beyond the acetal stage, further reduction of H2C-
(OSiPh3)2 may be achieved by employing a different hydro-
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Scheme 5. Possible Mechanism for Formation of
Formaldehyde
involves the unnecessary overreduction to methanol at the
C(-II) level.
Another noteworthy feature of the synthesis via H2C-
(OSiPh3)2 is that the method generates monomeric form-
aldehyde in an aprotic solvent. In this regard, despite its
widespread use, pure formaldehyde is not usually encountered in
its monomeric CH2O form because it readily polymerizes at
temperatures lower than 80 °C.2 Specifically, formaldehyde is
obtained commercially as either (i) the cyclic trimer, 1,3,5-
trioxane (metaformaldehyde), (CH2O)3, (ii) polymeric paraf-
ormaldehyde, HO(CH2O)xH (x = 8−100), or (iii) the aqueous
solution, formalin, in which it exists primarily as H2C(OH)2.2,27
These forms of formaldehyde, however, suffer disadvantages
compared to that of the monomeric form. For example, 1,3,5-
trioxane and paraformaldehyde are less reactive than monomeric
formaldehyde, and paraformaldehyde exhibits low solubility that
also hampers its applications.28 Moreover, formalin is not
compatible with substrates that are incompatible with an
aqueous medium,28 such that it is beneficial to develop reagents
that can serve as surrogates for formaldehyde in aprotic
media.28,29 The use of H2C(OSiPh3)2 as a reagent thus provides
monomeric formaldehyde in an aprotic solvent by a procedure
that does not require either (i) thermal cracking of
paraformaldehyde,30α-polyoxymethylene31 or 1,3,5-trioxane,32
or (ii) the use of acidic reagents.2,8,33
Figure 2. NMR spectra of isotopologues of formaldehyde in
acetonitrile solution.
B(C6F5)3 resulted in the formation of trimeric 1,3,5-
trioxane,18c,36 instead of monomeric formaldehyde.
3. H2C(OSiPh3)2 as a Formaldehyde Surrogate. In view
of the fact that H2C(OSiPh3)2 can be used to generate
formaldehyde, and the interest in developing reagents that can
serve as surrogates for formaldehyde in aprotic media,28 we have
investigated its ability to serve as a methylene source in which
the carbon is derived from CO2.37 Excellent evidence that
H2C(OSiPh3)2 may serve this role is provided by its ability to
participate in a Wittig reaction to form a terminal olefin. For
example, in the presence of CsF, H2C(OSiPh3)2 reacts
immediately with the phosphonium ylide MeOC(O)C(H)PPh3
in acetonitrile to afford methyl acrylate in quantitative yield at
room temperature (Scheme 6); benzyl acrylate can likewise be
Furthermore, the synthetic method can also be used as a very
convenient means to produce a variety of isotopically labeled
formaldehyde derivatives. For example, D2CO, H213CO, and
D213CO have been synthesized from the corresponding labeled
bis(silyl)acetal and are readily identified by NMR spectroscopy
(Figure 2). As an illustration, in acetonitrile solution, CH2O is
identified by the observation of a singlet at 9.60 ppm in the 1H
NMR spectrum, while 13CH2O exhibits a doublet with a 1JC−H
coupling constant of 178 Hz (Figure 2).
Scheme 6. Formation of C−C Bonds
The facile formation of formaldehyde from H2C(OSiPh3)2 is
also of relevance because although the intermediacy of
formaldehyde is occasionally invoked in reactions involving
the reduction of CO218c,34 there are few examples where it has
been either spectroscopically observed or trapped.16,35 Fur-
thermore, there are few situations where a CO2-derived product
has been investigated with respect to its potential to release
formaldehyde, and in no case has a solution of monomeric
formaldehyde been obtained from such a product. In this regard,
although ArNH2 (Ar = 2,6-Pri2C6H3) was used to trap
formaldehyde during hydroboration of CO2 via formation of
the imine, ArNCH2, subsequent hydrolysis afforded a formalin
solution,16 rather than formaldehyde. Moreover, it is pertinent
to note that treatment of H2C(OSiEt3)2 (albeit synthesized from
formic acid rather than CO2) with a catalytic amount of
obtained by an analogous procedure employing PhCH2OC-
(O)C(H)PPh3. The importance of CsF in promoting this
reaction is underscored by the fact that, in its absence,
H2C(OSiPh3)2 does not react with MeOC(O)C(H)PPh3 in
acetonitrile over a period of 1 day at elevated temperature.38−40
It is also important to note that the formation of MeOC(O)-
C(H)CH2 does not require isolation of H2C(OSiPh3)2, such
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that the conversion of CO2 to MeOC(O)C(H)CH2 can be
performed in a single reaction vessel.
room temperature.43 Furthermore, a CN double bond is
generated by reaction of H2C(OSiPh3)2 with PhNHNH2 to
afford the hydrazone species, PhN(H)NCH2 (Scheme 7).
More interestingly, H2C(OSiPh3)2 can also be used as a
formaldehyde surrogate in the Pictet−Spengler reaction44,45 for
the formation of heterocyclic compounds, as illustrated by the
formation of 1,2,3,4-tetrahydro-β-carboline (tryptoline) via the
reaction with tryptamine hydrochloride (Scheme 8). The latter
reaction is of considerable interest because β-carbolines have
significant biological activities and are of considerable
pharmacological relevance with respect to, for example, their
antitumor, antimicrobial, and antiviral properties.45
H2C(OSiPh3)2 can also be used to form C−C single bonds.
For example, H2C(OSiPh3)2 reacts with 5,5-dimethyl-1,3-
cyclohexanedione (dimedone) to afford 2,2′-methylenebis-
(5,5-dimethylcyclohexane-1,3-dione) (formaldomedone), in
which the two dimedone moieties are coupled via a CH2
group (Scheme 6).
In addition to forming C−C bonds, H2C(OSiPh3)2 can also
be used to produce C−N, C−O, and C−S bonds, thereby
providing a means to obtain products that correspond to both
functionalization and reduction of CO2,41 as illustrated in
Scheme 7. For example, H2C(OSiPh3)2 reacts readily with
Not only is H2C(OSiPh3)2 capable of delivering a methylene
moiety, but it can also provide a CH moiety in the formation of
benzazole derivatives, which are often components of drugs.46,47
For example, the benzimidazole motif is commonly encountered
in biologically active compounds46 and may be readily
constructed by the reaction of an o-phenylenediamine with
H2C(OSiPh3)2, as illustrated by the formation of N-methyl-
benzimidazole upon reaction of H2C(OSiPh3)2 with N-methyl-
1,2-phenylenediamine in DMSO (Scheme 8).4 8
Benzothiazoles47a are also important medicinal motifs that can
likewise be synthesized by this approach. Thus, benzothiazole is
obtained from the reaction of 2-aminothiophenol with H2C-
(OSiPh3)2. The formation of N-methylbenzimidazole and
benzothiazole via a bis(silyl)acetal derived from CO2 is
noteworthy because reductive cyclization reactions involving
CO2 to incorporate CH moieties are undeveloped,48b,49 and we
are aware of no examples of bis(silyl)acetals that are used to
provide heterocycles of this type.37,50,51 In this regard, it is
pertinent to note that the formation of N-methylbenzimidazole
and benzothiazole is accompanied by the formal oxidation of the
CH2 moiety, which is in accord with the ability of DMSO to
serve as an oxidizing agent.52
Scheme 7. Formation of C−N, C−O, and C−S Bonds
The ability of H2C(OSiPh3)2 to afford acrylate, hydrazone,
and heterocyclic compounds not only demonstrates its synthetic
utility, but the transformations are also of interest because they
are associated with the complete deoxygenation of CO2, which is
in contrast to many other transformations of CO2 in which at
least one C−O bond is typically preserved.48a
HO(CH2)3OH in the presence of H2SO4 to afford 1,3-dioxane,
while the corresponding reaction of HS(CH2)3SH gives 1,3-
dithiane; the latter reaction is of particular interest because
reactions of CO2 that afford two C−S bonds are uncommon.42
Likewise, hexamethylenetetramine, (CH2)6N4, a useful indus-
trial chemical, can be obtained upon reaction with ammonia at
Scheme 8. Heterocycle Formation
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The utility of the above method to synthesize isotopologues of
formaldehyde is of significance because it provides a means to
incorporate isotopic labels into molecules with biological and
medicinal applications. In this regard, the isotopic labeling of a
drug candidate provides a critical means to evaluate its
absorption, distribution, metabolism, and excretion proper-
ties.53 Deuterium-labeled modifications of drugs are also of
current interest due to enhanced stability by virtue of the kinetic
isotope effect,54 while the incorporation of 13C labels is of benefit
to the application of clinical 13C magnetic resonance spectros-
copy55 and for investigating metabolic networks.56 Although
carbon dioxide is considered to be the universal precursor for
incorporating isotopic labels (11C, 13C, and 14C),6,57 direct
approaches are limited due to the aforementioned low reactivity
of this molecule.58 The conversion of carbon dioxide into
isotopically labeled formaldehyde is, thus, of considerable
interest since its greater reactivity facilitates the incorporation
of a carbon label.59 However, the synthesis of isotopically
labeled formaldehyde from CO2 using LiAlH4 is hampered by
the formation of considerable quantities of labeled formic acid
and methanol.60,61
An illustration that isotopically labeled formaldehyde derived
from CO2 via the bis(silyl)acetal, H2C(OSiPh3)2, can be
employed in this manner is provided by the formation of 13C-
labeled methyl acrylate MeOC(O)C(H)13CH2. Specifically,
MeOC(O)C(H)13CH2 is obtained by reaction of MeOC(O)-
C(H)PPh3 with 13CH2O generated in situ by addition of CsF to
H213C(OSiPh3)2, which is more direct than the literature
method which employs 13CH3I rather than 13CO2.62 Likewise,
MeOC(O)C(H)13CD2 and MeOC(O)C(H)CD2 were also
obtained by this new approach.63
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b08342.
■
S
Experimental details and characterization data (PDF)
Crystal data for H2C(OSiPh3)2 (CIF)
AUTHOR INFORMATION
Corresponding Author
*parkin@columbia.edu
ORCID
Gerard Parkin: 0000-0003-1925-0547
Notes
The authors declare no competing financial interest.
CCDC-1910241 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: + 44 1223 336033.
■
ACKNOWLEDGMENTS
■
This research was supported by the U.S. Department of Energy,
Office of Science, Office of Basic Energy Sciences, Catalysis
Science Program, under Awards DE-SC0019204 and DE-FG02-
93ER14339. M.R. acknowledges the National Science Founda-
tion for a Graduate Research Fellowship under Grant No. DGE-
16-44869.
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