Breslow Intermediates (Amino Enols) and Their Keto Tautomers: First Gas-Phase Characterization by IR Ion Spectroscopy

Article abstract of DOI:10.1002/chem.202003454

Breslow intermediates (BIs) are the crucial nucleophilic amino enol intermediates formed from electrophilic aldehydes in the course of N-heterocyclic carbene (NHC)-catalyzed umpolung reactions. Both in organocatalytic and enzymatic umpolung, the question whether the Breslow intermediate exists as the nucleophilic enol or in the form of its electrophilic keto tautomer is of utmost importance for its reactivity and function. Herein, the preparation of charge-tagged Breslow intermediates/keto tautomers derived from three different types of NHCs (imidazolidin-2-ylidenes, 1,2,4-triazolin-5-ylidenes, thiazolin-2-ylidenes) and aldehydes is reported. An ammonium charge tag is introduced through the aldehyde unit or the NHC. ESI-MS IR ion spectroscopy allowed the unambiguous conclusion that in the gas phase, the imidazolidin-2-ylidene-derived BI indeed exists as a diamino enol, while both 1,2,4-triazolin-5-ylidenes and thiazolin-2-ylidenes give the keto tautomer. This result coincides with the tautomeric states observed for the BIs in solution (NMR) and in the crystalline state (XRD), and is in line with our earlier calculations on the energetics of BI keto–enol equilibria.

Full text of DOI:10.1002/chem.202003454

Accepted Article
Accepted Article
Title: Breslow Intermediates (Aminoenols) and their Keto Tautomers:
First Gas-Phase Characterization by IR Ion Spectroscopy
Authors: Albrecht Berkessel, Mathias Paul, Katrin Peckelsen, Thomas
Thomulka, Jonathan Martens, Giel Berden, Jos Oomens, Jörg
M. Neudörfl, Martin Breugst, Anthony J. H. M. Meijer, and
Mathias Schäfer
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202003454
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1/2020

Chemistry - A European Journal
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Breslow Intermediates (Aminoenols) and their Keto Tautomers:
First Gas-Phase Characterization by IR Ion Spectroscopy
[
a]
[a]
[a]
[b]
[b]
Mathias Paul, Katrin Peckelsen, Thomas Thomulka, Jonathan Martens, Giel Berden,
[
b,c]
[a]
[a]
[d]
[a]
Jos Oomens,
Jörg-M. Neudörfl, Martin Breugst*, Anthony J. H. M. Meijer*, Mathias Schäfer*,
[
a]
and Albrecht Berkessel*
[
1,2]
Abstract: Breslow intermediates (BIs) are the crucial nucleophilic
amino enol intermediates formed from electrophilic aldehydes in the
course of N-heterocyclic carbene (NHC) catalyzed Umpolung reac-
tions. Both in organocatalytic and enzymatic Umpolung, the question
whether the Breslow intermediate exists as the nucleophilic enol, or
in the form of its electrophilic keto-tautomer, is of utmost importance
for its reactivity and function. We herein report the preparation of
charge-tagged Breslow intermediates/keto tautomers derived from
three different types of NHCs (imidazolidin-2-ylidenes, 1,2,4-tri-
azolin-5-ylidenes, thiazolin-2-ylidenes) and aldehydes. An ammon-
ium charge-tag is introduced by either the aldehyde unit or the NHC.
ESI-MS IR-Ion spectroscopy allowed for the unambiguous con-
clusion that in the gas-phase, the imidazolidin-2-ylidene derived BI
indeed exists as a diamino enol, while both 1,2,4-triazolin-5-ylidenes
and thiazolin-2-ylidenes give the keto-tautomer. This result coincides
with the tautomeric states observed for the BIs in solution (NMR)
and in the crystalline state (XRD), and is in line with our earlier
calculations on the energetics of BI keto-enol equilibria.
on the formation of the so-called Breslow-intermediates (BIs)
[chemically: (di)amino enols] E (Scheme 1) in which the genuine
polarity of e.g. an aldehyde substrate is inverted from electro-
philic to nucleophilic. Attack of the nucleophilic aminoenol E on
various electrophiles gives rise to the benzoin condensation, the
Stetter reaction, and other well-known NHC-catalyzed Umpolung
reactions. The Breslow intermediate was first postulated in 1958
[
3,4]
for thiamine-catalyzed transformations (X = S, Scheme 1).
The first successful generation of diamino enols E (X = NR) from
aldehydes and imidazolidin-2-ylidenes, and their characteriza-
[
5]
tion by in situ NMR, was reported by us in 2012, followed by
[
6]
isolation and X-ray characterization in 2013. For example, as
shown in Scheme 2a, the reaction of the imidazolidin-2-ylidene
C-1 (SIPr) with benzaldehyde (A-1) gives exclusively the di-
[
7]
aminoenol E-11, and none of the keto tautomer K-11.
R
R
R
N
N
OH
-
N
O
O
+
δ
X
H
δ+ R'
X
R'
X
H
R'
X: N-R, S
E, enol tautomer
K, keto tautomer
Introduction
Scheme 1. Breslow intermediate as enol (E) and keto (K) tautomer.
Both in vitamin-B1-dependent enzymes and in organocatalytic
Umpolung, catalysis by N-heterocyclic carbenes (NHCs) hinges
Although biologically important as well (see below), the keto
tautomer K (Scheme 1) of the Breslow-intermediate has receiv-
ed considerably less attention than the amino enol E. In our
earlier study on the stoichiometric interaction of the 1,2,4-tri-
phenyltriazolin-5-ylidene carbene C-2 with various aldehydes
[a]
Dr. M. Paul, Dr. K. Peckelsen, MSc. Thomas Thomulka, Dr. J.-M.
Neudörfl, PD Dr. M. Breugst, Prof. Dr. M. Schäfer, Prof. Dr. A.
Berkessel
Cologne University, Department of Chemistry
Greinstrasse 4, D-50939 Cologne (Germany)
Fax: (+49) 221-470-5102
E-mail: berkessel@uni-koeln.de, mathias.schaefer@uni-koeln.de,
mbreugst@uni-koeln.de
[
e.g. benzaldehyde (A-1), Scheme 2a], we observed rapid and
exclusive formation of the ketone K-21, and no corresponding
[
7,8]
enol (E/Z) E-21 (Scheme 2a).
The ketone K-21 was shown
observed
exclusively
not observed
Homepage: www.berkessel.de, http://www.oc.uni-koeln.de/ms-
oc/frames01.htm, phyorg.uni-koeln.de
Dr. J. Mertens, Dr. G. Berden, Prof. Dr. J. Oomens
Radboud University, Institute for Molecules and Materials, FELIX
Laboratory, Toernooiveld 7c, 6525 ED Nijmegen,
The Netherlands
Dipp
Dipp
N
Dipp
N
N
O
OH
Ph
[
b]
N
H
Ph
N
N
O
C-1
O
Dipp
Dipp
Dipp E-11
(
a)
K-11
H
Ph
H
Ph
Ph
N
A-1
Ph
N
Ph
A-1
[
[
[
c]
d]
**]
Prof. Dr. J. Oomens
OH
N
O
N
N
N
Van’ t Hoff Institute for Molecular Sciences, University of
Amsterdam, Science Park 904, 1098 XH Amsterdam, The
Netherlands
N
Ph
Ph
C-2
N
Ph
N
H
Ph
Ph
Ph
Ph
Ph
E-21
K-21
Prof. Dr. A. J. H. M. Meijer
Dipp: 2,6-bis(2-propyl)phenyl
Department of Chemistry, University of Sheffield, Sheffield S3 7HF,
U.K.
O
Dipp/Me
N
O
Me
N
Dipp
N
Me
Me
OH
Ph
Me
Me
Me
Me
6 5
C F
H
Ph
A-1
H
6 5
C F
The authors thank the entire FELIX staff for skillful assistance.
Funding from LASERLAB-EUROPE (grant agreement no. 654148,
European Union’s Horizon 2020 research and innovation program),
by the Deutsche Forschungsgemeinschaft (DFG, grant numbers
SCHA 871/10-1 and BE 998/16-1), and by the Fonds der Chemi-
schen Industrie is gratefully acknowledged. We are grateful to the
Regional Computing Center of the University of Cologne for pro-
viding computing time of the DFG-funded High Performance Com-
puting (HPC) System CHEOPS as well as for their support. A
license for the OpenEye tools, obtained via the free academic
licensing program, is gratefully acknowledged.
(b)
A-2
S
S
S
OH
E-3Dipp
1
C-3Dipp/Me
E-3Me
2
transient, NMR
transient, NMR
Dipp
Me
Me
N
OH
K-3Dipp
1
K-3Me2
(c)
S
6 5
C F
E-3Dipp
2
isolatable, X-ray
Scheme 2. Breslow intermediates and keto tautomers derived from saturated
and unsaturated/aromatic NHCs, in solution and in the solid state.
Supporting information for this article is given via a link at the end of
the document.
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Chemistry - A European Journal
10.1002/chem.202003454
FULL PAPER
to be catalytically incompetent, indicating that its formation from
become accessible - this is why IR ion spectroscopy is referred
to as an "action spectroscopy" approach. The multi-photon
excitation character of room-temperature IR ion spectroscopy
leads to the typical features of gas-phase IRMPD spectra such
[
7]
benzaldehyde (A-1) and carbene C-2 is irreversible. It is
worthy of note, however, that in 2012 the first keto form of a
thiamine-derived Breslow intermediate was identified by
Tittmann et al. by high-resolution protein X-ray crystallography in
-
1
as the observed bandwidths (typically >20 cm ) and frequency
shifts (typically a few %) which become apparent in comparison
[
9]
pyruvate oxidase. In this enzyme, acetyl thiamine serves as an
intermediate en route to acetyl phosphate. As pyruvate decarb-
oxylation first affords the enol, the interconversion with its keto
form must be feasible in the enzyme.
[
15,17-20]
to linear IR spectra.
In the following, we will describe the
application of this methodology to the assignment of keto/enol
tautomeric structures, in the gas-phase, to Breslow intermedi-
ates generated from NHCs such as C-1-3 (Scheme 2) and
several aldehydes.
As briefly summarized in Scheme 2a, the reactions of
imidazolidin-2-ylidenes (such as C-1, SIPr) with aldehydes have
thus far led exclusively to diamino enols E. In contrast, the
ketones K were the only observable products in the reaction of
Results and Discussion
1
,2,4-triazolin-5-ylidenes (such as C-2) with aldehydes, and no
enols could be isolated or traced spectroscopically. According to
Synthesis of charge-tagged analytes - NHCs and aldehydes:
[
10]
our recent computational assessment of these findings,
the
Due to our quite satisfactory experience with ammonium charge-
[
15,17]
thermodynamic stability of the enol form of Breslow inter-
mediates, relative to their keto tautomers, largely hinges on
three parameters: (i) the saturation of the carbene moiety (as
opposed to aromatic NHCs), (ii) electron deficiency of the
aldehyde part, as well as (iii) the dispersive stabilization of the
diaminoenol effected by dispersion energy donor (DED) N-
substituents such as Dipp [2,6-di(2-propyl)phenyl] or Mes (2,4,6-
tags in our earlier ESI-MS IR ion spectroscopy studies,
we
+
decided to also employ the -NMe
3
substituent in the current
investigation. Scheme 3 summarizes the NHCs/azolium salts
and aldehydes used in this study. The imidazolidin-2-ylidene C-1
("SIPr") is easily accessible by deprotonation of the correspond-
[
21]
ing azolium salt. The 1,2,4-triazolin-5-ylidene C-2 (the "Enders
-Teles carbene") is readily available in pure form by mild vacuum
[
11,12]
[22]
trimethylphenyl).
The third NHC shown in the middle of
pyrolysis of its methanol adduct.
The charge-tagged thi-
2
+
Scheme 2b (C-3) represents Nature's Umpolung catalyst,
azolium salt C-4+H was prepared by a synthetic route (see SI
for detailed information) related to the one used by Lee et al. for
the preparation of an analogous sulfonate-tagged thiazolium
thiamine. Based on our theoretical investigation mentioned
[
10]
above,
we have recently been able to generate and
solution, the much more
[
23]
characterize, by NMR in THF-d
8
salt. Among the aldehydes employed, A-1-3 are commercially
available, while the charge-tagged benzaldehyde A-4 was
prepared from commercial 4-(dimethylamino)-benzaldehyde as
delicate thiamine-derived BIs E-3Dipp1 and E-3Me2 (Scheme 2b)
as reaction intermediates on the way to the ketones K-3Dipp1 and
[
13,14]
[15]
K-3Me2, respectively.
Me2 harbor one enol-stabilizing element each, namely an N-
Dipp substituent (K-3Dipp1), or a pentafluorophenyl residue [E-
Me2, from pentafluorobenzaldehyde (A-2)]. Combining these
stabilizing elements in one and the same molecule (E-3Dipp2)
allowed the first isolation and XRD-characterization of
thiamine-derived Breslow intermediate in its amino enol form
As the key to success, E-3Dipp1 and E-
described by us earlier.
3
N-Heterocyclic carbenes/azolium precursor:
Dipp
N
Ph
N
Me
N
3
Me
N
H
a
N
N
S
Ph
Me N
3
C-1
Dipp
C-2 Ph
C-4+H2+
[
14]
(
Scheme 2c).
The investigations summarized above concerned Breslow
Dipp: 2,6-bis(2-propyl)phenyl
Aldehydes:
CHO
CF3
CHO
I
intermediates both in solution and in the crystalline state. We
have recently extended our mechanistic investigations in the
field of carbene chemistry also to the gas-phase, using ESI-MS
IR-ion spectroscopy, in combination with quantum-chemical
calculations, as a powerful tool to determine tautomeric ion
structures of charge-tagged analytes, and to even follow the
C H -CHO
C F -CHO
6
5
6
5
A-1
A-2
F3C
Me3N
A-3
A-4
Scheme 3. N-Heterocyclic carbenes/azolium precursor and aldehydes used in
this study.
[
15-19]
kinetics of their interconversion.
For IR ion spectroscopy,
Reaction of the imidazolidin-2-ylidene C-1 (SIPr) with the
charge-tagged aldehyde A-4: Under strictly anaerobic conditions
selected ions are exposed to infrared photons provided from an
appropriate wavelength tunable light source, e.g. a free electron
–
1
8
(glove box), a solution of the NHC C-1 in [D ]THF reacted readily
laser (FEL; wavenumber range 600−1900 cm ). As the density
of ions in typical storing devices often used in these experiments
renders transmission based IR spectroscopy inefficient and
difficult, the extent of precursor ion depletion and product ion
formation is recorded as the IR radiation energy is tuned (FEL:
with the sparingly soluble aldehyde A-4 at room temperature, as
indicated by the development of an orange-colored homo-
geneous phase. After ca. 40 min, NMR analysis (see SI for
spectral data) indicated the clean and quantitative formation of
the diamino enol E-14 (Scheme 4). The formation of the latter is
−
1
−1
from 600 to 1800 cm and OPO: 2800−3700 cm ). In infrared
ion spectroscopy, the energy of many resonantly absorbed
photons leads to global vibrational excitation of all oscillators in
the irradiated ion, by virtue of intramolecular vibrational redistri-
1
evidenced inter alia by the typical temperature-sensitive H NMR
OH-resonance at δ = 4.59 ppm. On the other hand, the typical
"
ketone resonance", a singlet around δ ca. 6 ppm expected for
[
15,17-20]
K-14, is completely absent. Upon slow evaporation of the
bution (IVR).
Ultimately, the photo-activated ion reaches
solvent, crystals suitable for X-ray crystal structure analysis were
internal energies where one or more dissociation pathways
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Chemistry - A European Journal
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obtained. The result, which additionally and unambiguously
identifies the reaction product as the enol form E-14, is shown in
Scheme 4.
kJ/mol. Figure
1
furthermore displays the minimum con-
formations of E-14 and K-14. It is interesting to note that our
calculated minimum structure for the cation E-14 corresponds
quite well to its crystal structure, as shown in Figure 2.
Scheme 4. Left: Formation of the charge-tagged Breslow intermediate E-14
from SIPr (C-1) and the aldehyde A-4. Right: X-ray crystal structure of the
charge-tagged BI E-14, with one molecule of THF H-bonded to the enol's OH-
group.
When the above reaction mixture was subjected to ESI-MS
Figure 2. Overlay of the X-ray crystal structure (grey) of the diaminoenol E-14
and its calculated energetic minimum conformation (green) computed at the
B3LYP(GD3BJ)//cc-pVTZ level of theory.
3
analysis in a THF/CH OH solution, the molecular ion of the 1:1-
adduct formed from C-1 and A-4 could clearly be detected at
m/z 554 (see Figure S1.1 in the SI). Figure 1 shows the
experimental IR-spectrum obtained for this ion, together with the
spectra calculated for both the enol-ion found in the crystal
structure, and the keto-form of the NHC-aldehyde adduct (see
also Table S1.3 in the SI). The comparison of the experimental
spectrum with the two calculated ones leaves no doubt that also
in the gas phase, the carbene-aldehyde adduct exists exclusive-
ly as the diaminoenol E-14. Most importantly, there is an
Additionally, our computations on the DSD-BPLYP-D3BJ//M06-
L-D3 level of theory confirmed the match of the enol E-14 ion
with the recorded spectrum (see Figure S1.6 in the SI).
Nevertheless, we also looked at alternative ion structures, such
as a zwitterionic primary adduct of imidazolidin-2-ylidene C-1
with the charge-tagged aldehyde A-4, which is found to be +24
-
1
kJmol less stable than the E-14 ground state. The IR spectrum
of the zwitterionic primary adduct is also in reasonable
agreement with the recorded IR ion spectrum, with the exception
of the imidazolidine methylene C-H wagging mode at around
-
1
excellent match of the dominating signal observed at 1538 cm
with the enol's calculated prominent C=C(OH) stretch of E-14 at
-
1
1
1
524 cm . No trace of the carbonyl resonance expected at ca.
-
1
-
1
1260 cm . However, all our experimental efforts conducted so
far to identify such primary adduct ion structures either in the
condensed, the gas phase or in the solid state have been
unsuccessful. Therefore, we conclude that this alternative ion
structure is not relevant for the discussion here.
705 cm for K-14 is found in the recorded spectrum. Addition-
-
1
-1
-1
ally, four significant bands at 1322 cm , 1280cm , 1190 cm ,
-
1
and 1136 cm find matching modes in the computed spectrum
of E-14 (see Table S1.1 in the SI).
Reaction of the 1,2,4-triazolin-5-ylidene C-2 ("Enders-Teles
carbene") with the charge-tagged aldehyde A-4: When exposed
8
to a solution of the NHC C-2 in [D ]THF, the aldehyde iodide A-4
did not dissolve readily, but its reaction could be promoted, at
room temperature, by the addition of sodium tetraphenylborate.
Ph
Ph
N
Ph
N
A-4
N
OH
O
A-4
N
N
N
N
N
H
Ph
C-2
N
Ph
Ph
Ph
Ph
Ph
I
I
Dipp:
2,6-bis(2-propyl)phenyl
K-24
NMe3
E-24
NMe
3
Scheme 5. Formation of the charge-tagged ketone K-24 from the 1,2,4-
triazolin-5-ylidene C-2 and the aldehyde A-4.
Figure 1. Top/bottom: black trace - recorded IR ion spectrum of the ion at m/z
1
13
Examination of the reaction mixture by H and C NMR reveal-
ed that, in this case, NHC-aldehyde interaction had led exclus-
ively to the ketone tautomer K-24 (Scheme 5). Indicative NMR
5
54. Top: blue trace - linear IR spectrum calculated for E-14; minimum ion
structure of E-14 is shown on the right. Bottom: purple trace - linear IR
spectrum for K-14; minimum structure of K-14 is shown on the right. Energies
quoted are relative electronic energies.
1
resonances are, for example, H NMR singlets at δ = 6.10 (major
conformer) and δ = 5.98 ppm (minor conformer), originating from
the proton at C-5 of the heterocyclic ring. Similarly, the presence
1
3
The exclusive presence of E-14 in the gas-phase agrees with its
energetic preference relative to K-14, which amounts to 52.7
of the ketone's carbonyl group is evidenced by C NMR reso-
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Chemistry - A European Journal
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FULL PAPER
nances at δ = 195.7 ppm (major conformer) and δ = 194.4 ppm
nent example is ergothionein, a 2-mercaptohistidine trimethyl-
betaine, which preferably adopts a thione tautomeric ion struc-
ture in MeOH solution, which is also carried over to and identi-
(
minor conformer).
ESI-MS analysis of the reaction mixture clearly identified the
ion of the NHC (C-2) - aldehyde (A-4) adduct at m/z 461, and its
IR ion spectrum is shown in Figure 3, together with the com-
puted IR-spectra of the ketone K-24 and its enol tautomer E-24.
Comparison of the experimental IR-spectrum with the calculated
ones clearly indicates that also in the gas phase, the carbene-
aldehyde adduct exists exclusively as the ketone K-24 (Com-
pare Table S1.2 in the SI).
[27]
fied in the gas phase.
Scheme 6. Benzaldehyde derivatives A-5,6,7 and X-ray crystal structures of
the ketones K-25, K-26 and K-27 formed upon reaction of A-5,6,7 with the
NHC C-2.
Unfortunately, no crystals of the ketone K-24, suitable for X-ray
structural analysis could be obtained thus far. We would like to
mention at this point, however, that the reaction of the triazolin-
5
-ylidene C-2 with the three alkyl-substituted benzaldehydes
A-5,6,7 shown in Scheme 6 yielded crystalline adducts that
could be analyzed by single crystal X-ray diffraction. As may be
anticipated from the preceding results in solution and in the gas
phase, all three adducts exist as keto-tautomers (K-25, K-26,
and K-27) in the crystalline state (Scheme 6).
Figure 3. Top to bottom: black trace - IR ion spectrum. Top: purple trace -
calculated spectrum for gas-phase ground state E-24 (B3LYP(GD3BJ)//cc-
pVTZ); gas-phase ground state ion structure of E-24 is shown on the right.
Middle: blue trace - calculated linear IR spectrum for keto tautomer K-24
2+
Reaction of the charge-tagged thiazolium salt C-4+H with the
(
B3LYP(GD3BJ)//cc-pVTZ); ion structure of K-24 is shown on the right.
2
+
Scaling factor 0.97. Bottom: red trace - calculated linear IR spectrum for K-24
aldehydes A-1-3: The charge-tagged thiazolium salt C-4+H
(
(
M06L(GD3BJ)/6-31+G(d,p)); ion structure of K-24 is shown on the right
M06L/6-31+G(d,p) (relative energy vs. ground state enol structure 13.0 kJ/
was reacted, in the presence of base, with the aldehydes A-1,
A-2 and A-3 in THF at room temperature. In each case, ESI-MS
analysis clearly indicated the formation of the 1:1-adducts.
Figure 4 summarizes and compares the experimental and the
calculated IR-spectra of the three adducts obtained.
mol; Scaling factor 0.96; see Figure S1.7 and SI on computations for details).
In other words, the energetic ordering in PCM (CH
the gas phase (see text for discussion).
3
OH) is reversed relative to
2
+
Thiazolium salt C-4+H plus benzaldehyde (A-1) (Figure 4a):
The dominant and indicative feature of the recorded IR ion
spectrum of the molecular ion at m/z 305 (see Figures S1.2. and
S1.3 in the SI) is the pronounced carbonyl C=O-stretching band
The carbonyl band in the experimental spectrum at ca. 1720
-
1
cm is particularly indicative, and it is well reproduced by theory.
-
1
Similarly, the calculated C=C stretch for the enol (1532 cm ) is
completely absent in the experimental spectrum (see SI for a
complete Table of observed and computed IR frequencies). The
observed preference of the system C-2 + A-4 to exist as the
keto-tautomer K-24 reflects the thermodynamic preference for
the ketone in THF and methanol solution (the relative energy
-
1
at 1670 cm , clearly indicating the ketone tautomeric form K-41.
Overall, the spectrum calculated for the keto form K-41 matches
the recorded one well, which is not the case for the spectrum
calculated for the enol form E-41. In particular the bands at 910
-
1
-1
cm (N-C-S stretch), 1100 cm (aromatic C-C stretches) and the
-
1
most abundant signal at about 1280 cm resulting from O-H
bending and (HO)C-phenyl stretching modes in the computed IR
spectrum of E-41 do not find equivalent bands in the acquired
spectrum of the molecular ion at m/z 305.
3
difference between K-24 and E-24 is 14.2 kJ/mol in CH OH
according to polarisable continuum model (PCM) calculations.
This is due to the improved stabilizing interactions of the keto
moiety in a polar solvent shell. This suggests that the K-24
isomer will be the only one in solution. Moreover, this finding
indicates that the keto ion structure K-24 is kinetically trapped
after effective electrospray phase transfer and desolvation,
preventing the formation of the gas-phase ground state ion
structure, i.e. the enol tautomer E-24. The calculated barrier
height for the transformation from K-24 to E-24 is 283.2 kJ/mol,
in line with the experimental observation. Similar cases of non-
The observation of the ketone tautomer K-41 is in line with
the higher electronic energy calculated for the enol form (41
kJ/mol). For comparison, our earlier computational analysis (re-
lying on a slightly different method) of the thermodynamics of the
keto/enol tautomers derived from N-phenylthiazolin-2-ylidene
with benzaldehyde (A-1) had resulted in an energetic difference
[
10]
of 20 kJ/mol, again in favour of the keto form. The gas-phase
results presented here are well in line with earlier studies of ours
concerning the interaction of benzaldehyde (A-1) with the Dipp-
[
24-26]
thermal behavior have previously been reported.
A promi-
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Chemistry - A European Journal
10.1002/chem.202003454
FULL PAPER
substituted thiazolin-2-ylidene C-3Dipp in solution (see Intro-
duction, Scheme 2b): while the enol E-3Dipp1 was observed as a
transient species, the ketone K-3Dipp1 was formed as the
thermodynamic product which could be isolated and character-
the recorded IR ion spectrum of the molecular ion at m/z 395
(see Figure S1.4 and S1.5 in the SI) identifies the adduct
produced from C-4 and the aldehyde A-2 as the keto tautomer
K-42. The presence of the carbonyl C=O-stretching band at
[
14]
-1
ized by X-ray crystallography.
1705 cm is again indicative, supported further by the good
match of the experimental spectrum with the one calculated for
the keto form K-42, and its mismatch with the spectrum calculat-
ed for the enol E-42 (Figure 4b).
Also for this pair of reactants, the gas-phase results are
paralleled by those obtained with the trimethyl-substituted
thiazolin-2-ylidene C-3Me in solution (see Introduction, Scheme
2
b): while the enol E-3Me2 was observed as a transient species,
the ketone K-3Me2 represents the thermodynamically favored
[
13]
product (NMR).
gap between the enol and the keto-tautomer decreases by ca.
kJ/mol when moving from benzaldehyde (A-1) to its
Note, however, that the calculated energetic
1
4
pentafluoro derivative A-2. This trend of increasing enol stabili-
zation with increasing electron deficiency of the aldehyde com-
ponent was found by some of us already earlier in a com-
putational study on the keto-enol thermodynamics of Breslow
[
10]
intermediates.
2
+
Thiazolium salt C-4+H plus 2,4-bis(trifluoromethyl)benzalde-
hyde (A-3) (Figure 4c): In this case, an IR ion spectrum of the
molecular ion at m/z 441 of only limited resolution could be
obtained. Nevertheless, the experimental spectrum is again
-
1
dominated by the carbonyl C=O-stretching band at 1702 cm ,
clearly evidencing the formation of the ketone tautomer K-43.
This assignment is supported by the overall good match with the
spectrum calculated for the keto form K-43, which is not the
case for the spectrum calculated for the enol form E-43. The
energetic difference between ketone and enol form was
calculated as 27.3 kJ/mol in favor of the ketone. This value
reflects the electron-deficient character of the aldehyde A-3 and
is well in line with the results described above for the combina-
2
+
tion of the charge-tagged NHC C-4+H with the aldehydes A-1
and A-2.
Conclusionꢀ
In conclusion, we have for the first time characterized Breslow
intermediates
- the pivotal species derived from Nature's
Umpolung catalyst, vitamin B1 - in the gas phase by IRMPD
spectroscopy. Our study bridges earlier results obtained in
solution and in the solid state to the gas phase, and
demonstrates that the general principles found before for enol
stabilization (nature of the NHC involved, electronic structure of
the aldehyde component) apply just as well to the gas-phase
chemistry of Breslow intermediates. In enzymatic catalysis,
solvent influence on protein-bound cofactors involved is largely
excluded. Therefore, the results disclosed herein with regard to
the keto and enol forms of Breslow intermediates can be
assumed to more closely model the chemistry of the enzyme-
Figure 4. Top to bottom: black trace - IR ion spectra. (a, top): Red trace –
calculated IR spectrum for K-41; minimum energy structure of K-41 is shown
on the right. (a, bottom): purple trace – IR spectrum calculated for gas-phase
ground state of E-41; minimum energy structure of E-41 is shown on the right.
[
2]
bound thiamine cofactor. In this context, it is worthy of note
that the enol form of the Breslow intermediates derived from the
highly active Umpolung catalysts thiazolin-2-ylidene and 1,2,4-
triazolin-5-ylidene is in fact not the thermodynamically favored
tautomer (in neither phase). Preventing the (irreversible)
formation of catalytically incompetent keto-tautomers of the
(
b) Ditto for K-42 and E-42. (c) Ditto for K-43 and E-43. Energies are relative
electronic energies in the gas phase.
2
+
Thiazolium salt C-4+H plus pentafluorobenzaldehyde (A-2)
Figure 4b): As in the case discussed above for benzaldehyde,
(
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Chemistry - A European Journal
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Breslow intermediates under catalytic turnover conditions is thus
a remarkable feat of Nature's (and the chemist's) ingenuity.
interactions, whereby it is noted that in this case this correction did not
change results significantly compared to the bare B3LYP function-
[
32,33]
al.
The cc-pVTZ basis set was used throughout with the ultrafine
[
34,35]
setting for the integrals.
This computational procedure was found to
[
15]
give good correlation with experiment in previous work. Frequency
calculations in the harmonic approximation were carried out to
characterize all stationary points obtained to confirm them as either local
minima or transition states. All minimum energy structures were identified
through the absence of imaginary frequencies. Transition states were
identified through the presence of a single imaginary frequency.
Experimental Section
Materials
The aldehydes A-1,2,3,5,6,7 are commercially available and were used
without further purification. The aldehyde A-4 was prepared as described
[
15]
by some of us earlier. The imidazolidin-2-ylidene SIPr (C-1) was
All calculations, except where indicated, performed on these systems
were done in vacuo. Where solvent is indicated, all calculations were
done using the polarisable continuum model with the parameters for
[
21]
prepared as reported by Arduengo et al.
C-2 was prepared as described by Enders et al.
synthesis and characterization of the charge-tagged thiazolium salt C-
The 1,2,4-triazolin-5-ylidene
[
22]
The details of the
[
36,37]
MeOH, as implemented in Gaussian.
Frequencies were scaled by
2
+
−
1
4
+H are given in the Supporting Information.
0
.97 in the wavenumber range of 600–1900 cm and convoluted with a
−
1
Gaussian line shape function with a FWHM of 12 cm to facilitate
[
15,38]
Mass Spectrometry
comparison with experiment.
Energy differences quoted throughout
Analyte solution NHC C-1 with charge-tagged aldehyde A-4 was diluted
the paper are based on electronic energies. All transition states were
checked to connect the correct energy minima through an intrinsic
−
5
(
c ∼ 10 M) with dry THF. The solution of NHC C-2 with charge-tagged
aldehyde A-4 was measured with addition of CH OH. Thiazolium salt C-
CN for (+)ESI-MS and IR
[
39,40]
3
reaction coordinate calculation.
The SI on computations was created
2
+
[41]
4
+H aldehyde adducts were diluted with CH
3
using in-house developed software based on the OpenEye toolkit. The
[
42]
ion spectroscopy experiments. All (+)ESI, tandem-MS and accurate ion
mass measurements were conducted on an LTQ-Orbitrap XL instrument
overlay (Figure 2) was created using ROCS.
Additionally, ion structures of E-14/K-14 and of E-24/K-24 as well as
zwitterionic and epoxide alternative ion structures were investigated with
a DSD-BPLYP-D3BJ//M06-L-D3 method. This alternative approach was
adapted from a method that was successfully used to describe the
(
Thermo Fisher, Bremen Germany). Accurate ion mass measurements
were executed in the orbitrap analyzer with a resolution of 30000 fwhm
with external calibration (Δm < 3 ppm) or with addition of internal
standards (Δm < 2 ppm) by a lock mass procedure. Typical (+)ESI-MS
[
10]
thermodynamics of keto-enol tautomers of related systems. Details of
these computations are reported in the SI.
−
1
conditions: Flow rate: 5 µL min ; Capillary voltage: 3.20 kV; Sheath gas:
.99 [arb. units]; Aux gas: 2.00 [arb. units]; resolution: 30000 fwhm.
4
Additional MS-data and spectra are presented in the SI.
NMR Spectroscopy
All synthesized compounds were fully characterized in solution by 1D
1
1
1
1
1
13
Infrared Ion Spectroscopy
and 2D NMR spectroscopy. H, H COSY, H, H NOESY, H, C HMQC,
1
13
A modified 3D quadrupole ion trap mass spectrometer (Bruker, Amazon
Speed) was used for the infrared (IR) ion spectroscopy study, which has
H, C HMBC NMR spectra were recorded at room temperature, unless
otherwise stated. All spectroscopic data are presented in the SI.
[
20,28]
been described in detail elsewhere.
The 3D quadrupole ion trap was
operated at ambient temperature (∼320 K) with He buffer gas at a
X-Ray Crystallography
−
3
pressure of ∼10
mbar. Wavelength tunable laser radiation was
Supplementary crystallographic data are summarized in the SI. CCDC:
E-14: 1588473; K-25: 1824031; K-26: 1824032; K-27: 1824033;
C-4+H·2I: 2006541; S-3: 2006542. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via:
www.ccdc.cam.ac.uk /data_request /cif.
generated by the Free Electron Laser for Infrared eXperiments (FELIX) in
−
1
the 600−1900 cm range for all photo dissociation experiments with a
repetition frequency of 10 Hz. The FEL pulse energies were
approximately 50-100 mJ per 5 µs long macropulse. The full width at
half-maximum bandwidth of the FEL is approximately 0.4% of the central
wavelength. Gas-phase precursor ions for IR ion spectroscopy were
generated by electrospray ionization in positive ion mode from solutions
Keywords: Breslow intermediate · carbenes · density functional
calculations · mass spectrometry · Umpolung.
−
1
of 0.5 µM in methanol at a flow rate of 120 µL h . Ions were irradiated for
s, corresponding to interaction with 10 laser pulses. The IR spectra
result from a series of mass spectra recorded while the FEL was
1
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FULL PAPER
Mathias Paul, Katrin Peckelsen, Thomas
Thomulka, Jonathan Martens, Giel
Berden, Jos Oomens, Jörg-M. Neudörfl,
Martin Breugst*, Anthony Meijer*,
Mathias Schäfer*, and Albrecht
Berkessel*
Page No. – Page No.
Breslow Intermediates (Aminoenols) and
their Keto Tautomers: First Gas-Phase
Characterization by IR-Ion Spectroscopy
Breslow Intermediates in the Gas-Phase. In N-heterocyclic carbene (NHC) cata-
lyzed Umpolung, the reaction of the substrate aldehyde with the NHC gives the
Breslow intermediate (BI) as pivotal species. The combination of IR-Ion spectro-
scopy (IRMPD) with quantum chemical computations allows to determine whether
the BI exists as nucleophilic aminoenol, or as its keto tautomer in the gas phase -
decisive for its reactivity both in enzymatic catalysis and in organocatalysis.
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