NHC-Stabilized Radicals in the Formal Hydroacylation Reaction of Alkynes

Article abstract of DOI:10.1002/ejoc.201801185

Mechanistic details of transformations catalyzed by N-heterocyclic carbenes (NHC) are currently of great interest, targeting questions on the active catalyst in operation and the structure and reactivity of key intermediates. These mechanistic studies are

Full text of DOI:10.1002/ejoc.201801185

A Journal of
Accepted Article
Title: NHC-stabilized radicals in the formal hydroacylation of alkynes
Authors: Julia Rehbein, Jenny Phan, Stephanie Michaela Ruser, and
Kirsten Zeitler
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801185
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801185
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10.1002/ejoc.201801185
European Journal of Organic Chemistry
European Journal of Organic Chemistry
NHC-stabilized radicals in the formal hydroacylation of alkynes
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Manuscript Number:
ejoc.201801185R2
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Article Type:
Corresponding Author:
Julia Rehbein, Prof. Dr.
Universität Hamburg
Hamburg, GERMANY
Corresponding Author E-Mail:
julia.rehbein@ur.de
Order of Authors (with Contributor Roles): Julia Rehbein (Resources: Lead; Supervision: Lead; Writing – original draft: Lead)
Jenny Phan, M.Sc. (Investigation: Lead)
Stephanie Michaela Ruser, Diplom Chemiker (Investigation: Equal)
Kirsten Zeitler (provided starting materials: Equal)
Keywords:
Abstract:
NHC-catalysis
radicals
computational chemistry
mechanism
EPR spectroscopy
Mechanistic details of transformations catalyzed by N-heterocyclic carbenes (NHC) are
currently of great interest, targeting questions of the active catalyst being in operation
and the structure and reactivity of key intermediates. These mechanistic studies are
driven by the need to understand the big impact of subtle changes on the catalyst
system on its reactivity and also to clarify the situation around the elusive intermediates
in the classical catalytic cycle. In the activation process of aldehydes the formation of
an enaminol structure, coined the Breslow intermediate, is widely accepted. Previously,
however, we could prove that this enaminol has besides its ionic reaction pathway,
also the option to follow a radical pathway, by undergoing redox processes with the
starting material. In the present study we aim to elucidate if these radical pathways are
a more general phenomenon, specifically in the formal hydroacylation reaction of
alkynes. The observation of radical species and computational analysis of key
elemental steps in the radical and ionic pathways may lead to an onward development
of chemistry based on NHC-stabilized carbon radicals.
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10.1002/ejoc.201801185
European Journal of Organic Chemistry
FULL PAPER
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NHC-Stabilized Radicals in the Formal Hydroacylation Reaction of
Alkynes
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Jenny Phan[a], Stephanie-M. Ruser[b], Kirsten Zeitler[c], and Julia Rehbein[a] *
Abstract: Mechanistic details of transformations catalyzed by N-
heterocyclic carbenes (NHC) are currently of great interest, targeting
questions of the active catalyst being in operation and the structure
and reactivity of key intermediates. These mechanistic studies are
driven by the need to understand the big impact of subtle changes on
the catalyst system on its reactivity and also to clarify the situation
around the elusive intermediates in the classical catalytic cycle. In the
activation process of aldehydes the formation of an enaminol structure,
coined the Breslow intermediate, is widely accepted. Previously,
however, we could prove that this enaminol has besides its ionic
reaction pathway, also the option to follow a radical pathway, by
undergoing redox processes with the starting material. In the present
study we aim to elucidate if these radical pathways are a more general
phenomenon, specifically in the formal hydroacylation reaction of
alkynes. The observation of radical species and computational
analysis of key elemental steps in the radical and ionic pathways may
lead to an onward development of chemistry based on NHC-stabilized
carbon radicals.
explored with the help of computational chemistry and EPR
spectroscopy.
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[Gauss]
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Scheme 1. The observation of NHC-stabilized radicals I due to redox-processes
between the Breslow intermediate and remaining aldehyde in protic polar
solvents (Eox-peak potential from CV of O-methylated Breslow intermediate
against SCE in THF).
Introduction
Knowledge about the key steps in a reaction mechanism
allows for not only rationalizing reaction outcomes in hindsight but
especially allow for a target driven optimization and also further
development of new transformations.
The mechanistic postulate, based on our previous findings of
Breslow-type radicals, is incorporated into the classic ionic
reaction scheme (Scheme 2) and outlined in the following. It was
postulated in the past that both reactions – benzoin and HAC
reaction – have the first two elemental steps in common: The
nucleophilic addition of the NHC-catalyst to an aldehyde 1 leads
The realization that NHCs can stabilize radical centers1-5 and
therefore allow for a facile radical formation, is a fundamental one.
Especially the observation that radicals of type I (Scheme 1) are
formed even under non-oxidative conditions as in the benzoin
reaction is hinting at the potential of new transformations by NHCs.
The occurrence of radicals under anaerobic conditions also
speaks for low redox-potentials of the generally accepted
Breslow-type intermediate6-7 and hence the possibility that such
radicals are not restricted to simple benzoin-type reactions.
The objectives of this study were to analyze if radical species
like I also occur in the formal hydroacylation reactions (HAC) of
alkynes8,9 with standard thiazolylidene catalysts. Furthermore, the
radical structures were resolved and their potential reactivity in
comparison to the standard ionic reaction mechanisms was
via
2
after an additional “proton-shift”10 to the Breslow
intermediate 3. For aldehydes of type 1a the benzoin pathway is
shut down. In the ionic onwards pathway, the now nucleophilic
enaminol attacks either another aldehyde (1b, benzoin formation,
7) or intramolecularly the alkyne in 1a (HAC to chromanone 8). In
the latter case, the hereby formed α,β-unsaturated ketone 8 can
undergo a Stetter reaction with a second molecule 3aA. The 1,4-
diketone 10 is then released and can undergo further ring
contraction without the participation of the NHC.11
In case that the redox-potentials are suitable to allow for a
formation of the Breslow-type radical 5aA (and the necessary
counterpart 4a) one could either find these as resting states or as
reactive intermediates. The latter was the case in the benzoin
condensation, however it was to investigate, if such radicals can
undergo an in principle favored 6-exo-dig-cyclisation. To elucidate
the existence of NHC-stabilized radicals 5aA we focused on the
first part of the overall HAC transformation only, i.e. on the NHC-
driven catalyst cycle.12
[a]
M.Sc. J. Phan, Prof. Dr. Julia Rehbein Fakultät für Chemie und
Pharmazie Universität Regensburg, Institut für Organische Chemie,
Universitätsstrasse 1, 93053 Regensburg, Germany, e-mail:
julia.rehbein@ur.de; www.reaction-dynamics.de
[b]
[c]
Dipl. Chemiker S.-M. Ruser, Fachbereich Chemie, Universität
Hamburg, Institut für Organische Chemie, Martin-Luther-King-Platz
6, 20146 Hamburg
Prof. Dr. K. Zeitler, Universität Leipzig, Institut für Organische
Chemie, Johannis-Allee 29, 04103 Leipzig
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801185
European Journal of Organic Chemistry
FULL PAPER
2.012±0.069 (see SI), indicating that the spin is more delocalized
over the heterocycle than over the substrate core. This hypothesis
was confirmed by DFT analysis of the geometries and the
electronic structures of the potential radicals (Figure 1). In a
second step it was tried to elucidate if the radicals are formed from
the primary adduct 2aA or from the Breslow intermediate 3aA. It
was shown previously that in protic polar solvents the enaminol
structure 3bB is the most likely direct precursor of the radical, as
it can easily undergo redox-processes (either SET or proton
coupled electron transfer, see SI for details on computations) with
remaining aldehyde, whereas a direct HAT processed from the
primary adduct 2aA+ are associated with high barriers.5 We
therefore analyzed the kinetic behavior of the radical formation in
the HAC process of 1a + A at the optimized reaction temperature
(70 °C) (Figure 2).
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Scheme 2. Catalytic cycle of the HAC cascade vs. the benzoin reaction
emphasizing the common intermediates and including the proposed radical
steps. Radical intermediates 4b + 5bB have been characterized previously.9
5aA + 4a
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Results and Discussion
To elucidate if radicals are formed in the processes of
hydroacylation reaction a 1 : 1 ratio of substrate (1a) and catalyst
(A) were reacted under inert conditions in THF at 70 °C (Scheme
3). Samples were taken at different time intervals and cooled
down to 0 °C to stop the reaction.13 All samples were EPR active,
partially showing complex time-dependent changes in the EPR
signal, but similar spectral features (see below).
5aA+
5aA
Figure 1. Top: Recorded EPR spectrum was obtained by treatment of aldehyde
1a with equivalent amounts of catalyst A and K2CO3 in THF at 70 °C. Down:
Plotted spin density distribution (iso-value 0.03) of postulated radicals 5aA and
5aA+ (uM06-2X/6-311+G**).
At the respective reaction temperatures, the time dependence of
the radical concentration is in stark contrast to what has been
observed for the benzoin formation. Here, the radical
concentration increased slowly over time with k = 0.044 s‒1 to
reach a maximum concentration after 70 minutes (Figure 2) that
remained constant for the remaining 70 min of measurement time.
As mentioned above, the radicals in HAC are already formed
slowly at room temperature, indicating that although the radical
formation and the formation of its precursor are less feasible than
in the benzoin reaction, they have barriers that can be crossed at
298 K.
Scheme 3. Aldehydes of the HAC reaction tested in the EPR studies.
Control experiments where one of the components was left out
remained EPR silent. Also, at temperatures below the reaction
temperature the EPR signals were observed only after elongated
reaction time (3 h) and in low concentrations, quite contrary to the
benzoin reaction5. The obtained spectra at early times (20 min,
70 °C) were rather independent of the substituents in 3- or 4-
position of the substrate featuring 13 equidistant lines with α =
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10.1002/ejoc.201801185
European Journal of Organic Chemistry
FULL PAPER
is one of the two partially rate determining steps in the overall
catalytic cycle. The subsequent nucleophilic addition of 3bB to 2b
(ES3) has the highest activation barrier within this mechanistic
scenario and is the second rate-limiting step. The following
dissociation of the NHC-benzoin complex [B + 7] to complete the
catalytic cycle (ES4) is almost barrier-free (6.6 kcal/mol).
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Figure 2. Plotted peak maxima of recorded EPR spectra against the time (top:
0.662 mW, 1 :1 1d : A; 0.662 mW, 1 : 0.1 1b : B). Data of 1b as published in
citation 5. The absolute radical concentrations were determined by using a
calibration with TEMPO yielding a maximum radical concentration in case of 1b
+ A of 5 mmol/L (see SI).
To find a rational for these differences in radical formation and
depletion processes, DFT calculations ((u)M06-2X/6-311+G**;
Gaussian09.D01)14-19 were conducted to derive barriers of the
various elemental steps of the ionic and radical pathway of the
formal hydroacylation and the related benzoin reaction as a
reference (Scheme 4 and 5).
The formation of the primary adduct 2 is feasible at room
temperature in both processes with similar barrier heights
(benzoin: average ΔG‡ = 13.6 kcal/mol; hydroacylation: ΔG‡ =
13.4 kcal/mol, ES1, Schemes 4, 5.10 This finding is somewhat
surprising as the steric impact of both ortho-substituted
benzaldehyde derivatives and the catalyst A are significantly
higher than in case of the simple thiazolylidene B and PhCHO
combination.
From the primary adduct 2 onwards several scenarios are
possible. Within the polar mechanistic picture of the benzoin
formation an intramolecular - in case of protic polar solvents -
solvent mediated proton transfer leads to the Breslow
intermediate 3 associated with an activation barrier of 17.6
kcal/mol (ES2). Without the incorporation of the protic solvents
this step is inaccessible at room temperature (36.5 kcal/mol). This
step crosses the highest point on the potential energy surface and
Scheme 4. Benzoin reaction: Driving forces and activation barriers of elemental
steps associated to the benzoin formation and the radical formation.20-23
For the HAC process the formation of the Breslow-
intermediate via an intramolecular proton shift in 3aA cannot be
facilitated by the aprotic solvent THF. Considering the high barrier
of 36.5 kcal/mol of the similar step for 2bB, the enaminol
formation potentially is at least one of the rate-limiting step
together with the cyclization step (23.0 kcal/mol) in this sequence
that will require the relatively high temperatures of 70 °C.
According to the calculated reaction profile of the HAC-process
the chromanone formation is irreversible (ΔRG = ‒37.5 kcal/mol).
Experimentally, this could be confirmed by subjecting
independently synthesized chromanone 8a to the reaction
conditions (1 eq cat, 1 eq base, THF, fpt-degassed, 70 °C). Here
neither radical formation was observed nor formation of the
starting material.24
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10.1002/ejoc.201801185
European Journal of Organic Chemistry
FULL PAPER
Where in the mechanism do the radicals come into play? In
case of the benzoin reaction the most likely pathway discussed
previously5 – under the premise of 2bB+ and 3bB being present
only - suggested a radical formation out of 3bB via a single
electron transfer (SET) to 1b. Measured peak potentials (see SI)
of a broad variety of aldehydes and also calculated ionization
potential (IP) of the key intermediates support this hypothesis
happening faster than the PCET to 1b. Since 2bB+ feature twice
as high BDEs of the α-CH bonds compared to 2bB,5 the only
radical formation step accessible then is via the Breslow
intermediate 3bB.
In case of HAC, these conditions are changed now, as the
reaction is conducted in aprotic media. Hence, a sufficient amount
of 2aA should be present in solution. As mentioned above an
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together with our previous studies including kinetic isotope effects. interesting temperature dependence of the radical formation
process was observed. Whilst the cyclisation only occurs at
elevated temperatures the formation of a radical species was
observed already at room temperature. The barriers of the PCET
to form the radicals 4a and 5aA (Scheme 5) indicate that at low
temperatures this pathway is in operation already, providing
access to the Breslow intermediate 3aA via a second small barrier
of 15.0 kcal/mol. At reaction temperature of 70 °C the radical
concentration is sped up and increasing steadily, reaching an
equilibrium concentration after several minutes, suggesting that
onward pathways from 4a and 5aA feature higher barriers than
the radical formation. This explanation is corroborated by the
cyclisation barrier of 23.0 kcal/mol (Scheme 5). The radical itself
is not able to cyclize as indicated by the high barrier of 35.3
kcal/mol.
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Conclusions
NHC-stabilized radicals were found in the catalytic cycle of the
formal hydroacylation reaction of NHC-activated aldehydes onto
alkynes, suggesting that the radical formation is a more general
phenomenon in NHC-activation of aldehydes. The comparison of
kinetics and computational data of the NHC-stabilized radical
species of the HAC process with the related benzoin
condensation lead to the conclusion that in the HAC process start
- contrary the benzoin reaction in protic polar media - the radical
formation pathway can start from the primary aldehyde NHC-
adduct. This first PCET step in combination with a second PCET
steps opens an interesting alternative pathway towards the
Breslow intermediate avoiding the cumbersome proton-shift. The
cyclisation onto the alkyne then occurs via the enaminol providing
the chromenone in an irreversible fashion.
Scheme 5. Formal hydroacylation: Driving forces and activation barriers of
elemental steps associated to the cyclisation and the radical formation.
Experimental Section
Spectroscopy. All EPR spectra were measured on a Bruker Elexsys E500
On the other hand, if one assumes a situation where a high
population of 2bB is present in solution, the calculated proton
coupled electron transfer step (PCET, Scheme 4, bottom) is
predicted to be feasible kinetically (ΔG≠ = 13.3 kcal/mol), arriving
at the radicals 4b + 5bB which are less stable by 11.2 kcal/mol
than the starting materials. However, if one looks onwards, there
is another low energy PCET to arrive at the Breslow intermediate
3bB with an overall substantial driving force of ‒8.3 kcal/mol. This
combination of two low-barrier PCETs starting from 2bB and 1b
poses an interesting alternative to the otherwise necessary
(solvent- or otherwise promoted) proton shift within 2bB. In protic
polar solutions though, the protonation of 2bB to 2bB+ is
CW spectrometer. The samples were prepared in dry solvents under
nitrogen atmosphere and degassed by the freeze-pump-thaw technique.
Computations. All calculations were performed with the software suite
Gaussian 09 (Revision D.01).13 Density functional theory calculations were
carried out at the M06-2X/6-311+G** level of theory.14-17 Solvent effects
were considered implicitly by utilization of the polarizable continuum model
using the integral equation formalism (IEF-PCM). Computational results
were visualized with Gabedit18 as well as GaussView19 and rendered
structures were generated with CYLview20 and IQmol21. For further details
see SI.
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10.1002/ejoc.201801185
European Journal of Organic Chemistry
FULL PAPER
11
By addition of a strong enough base the sequence is driven to a Retro-
Michael reaction followed by a 1,3-hydride shift and finally an Oxa-
Michael-type 5 membered cyclisation to benzofuranone derivative 7. See
citation 2.
Acknowledgements
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Generous financial support is provided by the DFG, Emmy-
Noether-Grant RE3036 (JR).
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13
In our study the reaction proceeded within the time of the mechanistic
analysis (210 min) only to the chromanone intermediate. We did not
observe the Stetter reaction.
Keywords: NHC-catalysis; radicals; computational chemistry;
It was ensured that no conversion takes place below 50 °C by following
the reaction by NMR.
mechanism; EPR spectroscopy
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17
Reasoning for the choice of the functional see SI and citation 5.
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CYLview 1.0b, C. Y. Legault, Université de Sherbrooke, 2009,
http://www.cylview.org.
9
J. F. Franz, P. J. W. Fuchs, K. Zeitler, Tetrahedron Lett. 2011, 52, 6952–
6956.
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Version 2.11, http://www.iqmol.org/index.html.
Based on the analysis of the crude reaction product by 1H NMR.
10
S. Gehrke, O. Hollóczki, Angew. Chem. Int. Ed. 2017, 56, 16395–16398;
Angew.Chem. 2017, 129,16613–16617. Under the recently suggested
concerted addition/deprotonation of the precatalyst to the substrate one
would even expect a lower barrier.
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The NHC-catalysed
transformations still
surprise with their
mechanistic details. In
the formal
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NHC-stabilized radicals
J. Phan, S.-M. Ruser, K. Zeitler, J. Rehbein*
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hydroacylation
reaction of alkynes
radical intermediates
were discovered and
their origin and
reactivity analysed by
EPR spectroscopy
and computational
chemistry and
NHC-Stabilized Radicals in the Formal
Hydroacylation Reaction of Alkynes
NHC-stabilized radicals
J. Phan, S.-M. Ruser, K. Zeitler, J. Rehbein*
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