On the origins of stereoselectivity in the aminocatalytic remote alkylation of 5-alkylfurfurals

Article abstract of DOI:10.1039/c9ob00914k

In the manuscript, computational studies on the remote alkylation of 5-alkylfurfurals proceeding via formation of the corresponding trienamine intermediate are presented. By the means of density functional theory (DFT) calculations and the symmetry-adapte

Full text of DOI:10.1039/c9ob00914k

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DOI: 10.1039/C9OB00914K
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ON THE ORIGINS OF STEREOSELECTIVITY IN THE AMINOCATALYTIC
REMOTE ALKYLATION OF 5-ALKYLFURFURALS
Received 00th January 20xx,
Accepted 00th January 20xx
Mateusz Dyguda,a,b Artur Przydacz,a Agnieszka Krzemińskac and Łukasz Albrecht*a
DOI: 10.1039/x0xx00000x
In the manuscript, computational studies on the remote alkylation of 5-alkylfurfurals proceeding via formation of the
corresponding trienamine intermediate are presented. By the means of density functional theory (DFT) calculations and the
symmetry-adapted perturbation theory (SAPT) method, interesting insights into the mechanism of the reaction have been
provided explaining the influence and contribution of different molecular interactions on the observed reactivity as well as
on the enantio- and diastereoselectivity of the process. The studies have been extended to the thiophene analogue of the
starting furfural derivative and the results obtained verified experimentally.
Introduction
computational techniques enabling deeper insights into interactions
between catalyst and reactants in a given transition state, thus
Understanding of reaction mechanism leading to the identification of
key factors determining observed reactivity and selectivity is a long-
providing information on the molecular recognition profile.
standing goal in contemporary organic chemistry. It allows the Dearomatizative processes constitute a very powerful means for the
rational design of new reactions proceeding according to novel functionalization of aromatic frameworks with increasing popularity
observed in the past few years.5-9 Such transformations can proceed
reactivity schemes. Its profound importance is particularly visible in
the field of asymmetric catalysis where the stereoselectivity of a according to two main pathways: (1) permanent dearomatization -
given transformation constitutes the main challenge. Explanation on reactions resulting in the formation of dearomatized molecules from
aromatic starting materials;6 (2) temporary dearomatization –
how the chiral catalyst interacts with substrates and directs the
reaction enabling access to enantiomerically enriched products is of reactions proceeding through the formation of dearomatized
major significance in this area of research and leads to the intermediates that may rearomatize in subsequent reactions.7-9
identification of new transformations as well as allows new catalysts Recently, the latter approach has been utilized as a design principle
for new, aminocatalytic reactions of (hetero)aromatic compounds.7-
In such a setup compounds bearing both an (hetero)aromatic
design. Computational chemistry is a very powerful tool providing
insights into organic reaction mechanisms.1 Organic chemists
9
working in the field of asymmetric catalysis2 more and more eagerly framework and aldehyde (or ketone) moiety that are directly
connected (or through one sp3 carbon linker) are employed.
employ it in their research. This trend is particularly noticeable in the
field of asymmetric organocatalysis3 with many important Condensation of the aminocatalyst with such a starting carbonyl
mechanistic and stereochemical rationalizations being confirmed by compound to give iminium ion and subsequent deprotonation
means of computational studies.4 However, in most of the cases, results in the polyenamine intermediate formation that is of key
conclusions are made by the comparison of energies between
importance for further functionalization of starting (hetero)aromatic
plausible reaction transition states and no direct information on system.
contributions of different types of molecular interactions involved
Recently, we have developed a novel, dearomatizative approach for
are available. Therefore, further development in this field is directly
correlated with the possibility to employ more sophisticated
the functionalization of 5-alkylfurfurals (Scheme 1).9 It involved the
initial condensation of the starting furfural derivative 1 with the
aminocatalyst 2 bearing an H-bonding unit in the side-chain.
Subsequent deprotonation of the benzylic position in the alkyl chain
of the corresponding iminium ion resulted in the formation of the
trienamine intermediate 3. It was postulated that it preferentially
existed as the anti-Z,Z,Z isomer.
a.Institute of Organic Chemistry, Department of Chemistry
Lodz University of Technology
Żeromskiego 116, 90-924 Łódź, Poland.
b.Institute of Applied Radiation Chemistry, Department of Chemistry
Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland
c. Institute of Physics, Lodz University of Technology, Wólczańska 219, 90-924 Łódź
E-mail: lukasz.albrecht@p.lodz.pl; http://www.a-teamlab.p.lodz.pl
† Supplementary Information (ESI) available: Gibbs free energy profiles and energies and
Herein, we present the theoretical computations on the
aminocatalytic remote alkylation developed that have been
performed in order to understand the origins of enantio- and
Cartesian coordinates of all structures reported herein (PDF).
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diastereoselectivity of the process. These studies have been further reactant complex (RC) transition state (TS) or the product complex
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extended to predict the chemical and stereochemical behaviour of (PC). Intrinsic reaction coordinate19 (IRC) analysis allowed to
DOI: 10.1039/C9OB00914K
the thiophene analogue of 3 which has been experimentally verified. concatenate stereoisomers with the corresponding TS geometries.
Furthermore, the symmetry-adapted perturbation theory (SAPT) Due to the fact that dispersion may play a crucial role in stabilizing
method has been used to provide insights into different molecular reacting complex, the geometries of the corresponding TS obtained
interactions taking place in the postulated transition states, thus at M06-2X/6-31+G(d,p) level of theory were re-optimized.
enabling a better understanding of the developed organocatalytic Minnesota functional M06-2X was not parametrized directly to
transformation. Surprisingly and to the best of our knowledge, this support dispersion correction, which was required by the studied
highly useful tool has never before been employed to study the system. Hence, we decided to use B97D/6-31+G(d,p) functional of
mechanisms of organocatalytic reaction. The results obtained have Grimme, that includes dispersion correction with the original D3
been directly correlated with the chemical behaviour of molecules in damping function as implemented in G09.20
the transition state and used to predict enantio- and
Symmetry-Adapted Perturbation Theory (SAPT). SAPT21 method
diastereoselectivity of the process.
constitutes a valuable tool to study non-covalent interactions
between monomers. It allows to determine the interaction energy
without computing the total energy of monomers or dimer. SAPT
ensures the interaction energy decomposition into physically
meaningful terms such as electrostatic, 퐸푒(푙1푠0푡), exchange, 퐸(10)
,
푒푥푐ℎ
(20)
(20)
induction, 퐸
+ 퐸
+ 훿퐻(2퐹), and dispersion, 퐸(20)
+
ꢀ푛푑,푟푒푠푝
푒푥푐ℎ−ꢀ푛푑,푟푒푠푝
푑ꢀ푠푡
(20)
푒푥푐ℎ−푑ꢀ푠푝
퐸
, components written as:
(10)
푒푥푐ℎ
(20)
ꢀ푛푑,푟푒푠푝
(20) (20)
+ 퐸
푒푥푐ℎ−ꢀ푛푑,푟푒푠푝 푑ꢀ푠푝
퐸푆퐴푃푇0 = 퐸푒(푙1푠0푡) + 퐸
+ 퐸
+ 퐸
(20)
푒푥푐ℎ−푑ꢀ푠푝
(2)
+ 훿
퐻퐹
+ 퐸
where subscript resp corresponds to orbital relaxation effects, and
(2)
퐻퐹
훿
term describes higher-order induction effects computed from
the Hartree-Fock (HF) interaction energy. First electrostatic
(10)
푒푙푠푡
term, 퐸
,
describes
Columbic
multipole-multipole-type
(10)
interactions of charge clouds. Exchange interactions term, 퐸
,
푒푥푐ℎ
corresponds to repulsive forces. Electrostatic and exchange terms
Scheme 1. The postulated mechanism of the aminocatalytic remote
(20)
constitute the first-order term. Induction term,
퐸
+
ꢀ푛푑,푟푒푠푝
functionalization of 5-alkylfurfurals
(20)
푒푥푐ℎ−ꢀ푛푑,푟푒푠푝
퐸
+ 훿퐻(2퐹), covers both polarization and charge-transfer
(20)
푑ꢀ푠푡
(20)
푒푥푐ℎ−푑ꢀ푠푝
effects, while dispersion, 퐸
+ 퐸
, is an attractive force
Computational details
from electron-electron dynamic correlation. The second-order term
is composed of induction and dispersion forces. Due to a large
number of atoms in a studied system the SAPT022 method was used
as implemented in Psi423 software. The systematic studies of Sherrill
and co-workers22 recommend using the aug-cc-pVDZ24 basis set with
a SAPT0 method. Moreover, to study crucial interactions in TS the
diffusion functions added to angular momentum should be included
in basis set, as it is in the case of ‘aug-‘ basis sets. However, usage of
pVDZ basis causes underestimation of the dispersion component by
approximately 10-15%, but for the qualitative description should
serve well enough.
System setup. Initial optimization of all structures was performed at
the semi-empirical level using AM110 as implemented in Gaussian09
ver. A.01.11 The trienamine 3 can exist as one of four diastereomers,
Z,Z,Z, Z,Z,E, E,Z,Z or E,Z,E. The most stable Z,Z,Z-diastereomer was
indicated by geometry optimizations with the M06-2X12/6-
31+G(d,p)13, B3LYP14/6-31+G(d,p) and MPW1K15/6-31+G(d,p)
density functional theory (DFT) compared with coupled cluster
theory with single, doubles and perturbative treatment of triples
excitations CCSD(T)16/6-31+G(d,p) (see Supplementary Information,
Table S1). Based on potential energy analysis for diastereomers, the
M06-2X/6-31+G(d,p) functional was selected for further
investigation with respect to CCSD(T)/6-31+G(d,p). Subsequently, a
number of one-dimensional scans of potential energy surfaces (PESs)
along with reaction coordinates have been calculated. The polarized
continuum solvent model (PCM)17 of dichloromethane (DCM) was
applied using the self-consistent reaction field (SCRF).18 Structures of
the stationary points were confirmed by vibrational analysis (3N-6
real normal modes of vibrations indicate local minimum, while one
imaginary frequency corresponds to the transition state) to be either
Results and discussion
Finding the most stable diastereomer of trienamine 3. Studies were
initiated with the goal of a finding the most stable isomer of the
corresponding trienamine intermediate 3. The analysis of the total
energy confirmed that among possible isomers of trienamine
reactant 3, the Z,Z,Z-configured intermediate with an anti-
conformation around the C-N bond is the most thermodynamically
stable and is anticipated to participate in the developed reaction (see
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Supplementary Information, Table S1) as previously correctly particular case are compensated by the π-stacking stabilization. The
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predicted.9 The anti-Z,Z,Z-trienamine 3 may be approached by the β- highest energy barrier was obtained for the pro-S,R-TS (11.8
DOI: 10.1039/C9OB00914K
nitrostyrene 4 from either the upper or bottom side. Furthermore, kcal·mol-1) with the weakest phenyl-conjugated π-system π-stacking
the Michael acceptor 4 can position itself synperiplanar (with respect interactions.
to the phenyl ring in anti-Z,Z,Z-trienamine 3) or anticlinal. Given
these considerations, the formation of four different iminium ions,
namely R,S, R,R, S,S and S,R can be expected.
Figure 1. Four possible transition state geometries pro-R,S-TS, pro-
R,R-TS, pro-S,S-TS and pro-S,R-TS, with the participation of the furan
analogue 3, located with B97D/6-31+G(d,p) with their energy
barriers (ΔG‡) and key distances reported in kcal·mol-1 and Å,
respectively
Scheme 2. Stereodetermining step in the aminocatalytic remote
functionalization of 5-alkylfurfural 1
Energy barriers for TS structures with furan-derived trienamines 3.
Therefore, four TSs for the reaction of anti-Z,Z,Z-trienamine 3 with β-
nitrostyrene 4 have been located, as presented in Figure 1. For each
TS geometry, the energy barriers (ΔG‡) were computed using
B97D/6-31+G(d,p). The obtained energies of activation indicate that
the most favourable reaction goes through the pro-R,S-TS with the
lowest energy barrier equalling to 6.8 kcal·mol-1. In this case, the
electrophile 4 approaches anti-Z,Z,Z-trienamine 3 from the upper
side, and the corresponding pro-R,S-TS has two types of stabilization:
by hydrogen bonds (formed between the nitro moiety of electrophile
4 and the sulphonamide group in 2) and by π-stacking interactions
between the phenyl ring in 4 and the conjugated π-system in 3.
Higher energy barriers were obtained for pro-R,R-TS (8.6 kcal·mol-1)
and pro-S,S-TS (8.6 kcal·mol-1) geometries. Both pro-R,R-TS and pro-
S,S-TS maintain the π-stacking stabilization, however, in contrast to
pro-R,R-TS, the pro-S,S-TS lacks the hydrogen bond stabilization.
However, given the results it should not be claimed that the
hydrogen bond stabilization is less important than the π-stacking
stabilization. No difference in energy barriers obtained for pro-R,R-
TS and pro-S,S-TS should be considered as a result of weaker π-
stacking stabilization occurring in the pro-R,R-TS that in this
Energy barriers for TS with thiophene analogue 7. Four TS
geometries of Z,Z,Z-trienamine reactant with sulfur in the
heteroaromatic ring corresponding to four possible products R,R-8,
R,S-8 or S,R-8, S,S-8 have been located, as presented in Figure 2. For
each TS the energy barriers (ΔG‡) were computed using B97D/6-
31+G(d,p). The obtained energies of activation indicate that the most
favourable reaction, for reactant complex with thiophene analogue
goes through the pro-R,S-TS with the energy barrier that equals to
8.9 kcal·mol-1. The pro-R,S-TS is stabilized by both hydrogen bonds
and π-stacking interactions, in contrast to other located TS
geometries, where the activation energies are higher and equal to
11.0 kcal·mol-1 (for pro-R,R-TS), 10.7 kcal·mol-1 (for pro-S,S-TS) or
14.0 kcal·mol-1 (for pro-S,R-TS). As presented in Figure 2, more
interactions result in lower energy barriers. The energy barriers
obtained for complexes with thiophene analogue are higher than
those obtained for the furan-derived system. The difference
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between pro-R,S-TS for a furan derivative and pro-R,S-TS for barriers (ΔG‡) and key distances reported in kcalV·miewolA-1rticalenOdnlinÅe,
thiophene derivative is 2.1 kcal·mol-1.
respectively
DOI: 10.1039/C9OB00914K
SAPT results for TS geometries for reactions involving furan-derived
trienamine 3. To get a deeper insight into key interactions that
influence TS stabilization, the SAPT0/ aug-cc-pVDZ method was used
to obtain different interaction energy terms. Results are collected in
Table 1. The lowest energy barrier was expected to be obtained for
the TS that is stabilized to the highest degree by molecular
interactions. Indeed, the strongest attraction is observed for the pro-
R,S-TS structure with the lowest total interaction energy, calculated
as a sum of electrostatic, exchange, induction, and dispersion terms,
that equalled to -75.2 kcal·mol-1. It is not surprising that pro-R,S-TS
and pro-R,R-TS are characterized by the strongest electrostatic
attraction with -80.4 and -78.8 kcal·mol-1, respectively, which
probably comes from the hydrogen-bonding interactions between
the nitro moiety of electrophile 4 and the sulphonamide group in 2.
The lack of hydrogen-bond attraction results in weaker electrostatic
interaction observed for pro-S,S-TS and pro-S,R-TS with energies
equalling to -67.5 and -68.7 kcal·mol-1, respectively. The exchange
term, describing the repulsion forces, is the highest in pro-S,S-TS case
and equals to 149.6 kcal·mol-1. Repulsion forces play also an
important role in the geometries of pro-R,S-TS (141.1 kcal·mol-1) and
pro-R,R-TS (137.9 kcal·mol-1). However, for these cases, they are
compensated by electrostatic attraction resulting from H-bonding
interactions. For all TSs, the first-order term (a combination of
electrostatic and exchange terms) is repulsive, and the inclusion of
second-order induction and dispersion terms provides system
stability. It is worth to note that the second-order induction is
attractive. In general, based on the literature examples, in the case
of the hydrogen-bonded complexes, the dispersion term constitutes
half of the total interaction energy, while in the π-stacking systems
the dispersion term is usually bigger than overall total interaction
energy.24 Interestingly, for the studied system, the second-order
dispersion term exceeds half of the total interaction energy.
However, it is still lower than the whole total interaction energy. It
means that both hydrogen-bond and π-stacking characters overlap.
Table 1. The components contributing to the interaction energy in
the corresponding TS computed using SAPT0 for located TS
geometries with the participation of furan-derived trienamine 3. The
values are reported in kcal·mol-1
pro-R,S- pro-R,R- pro-S,S- pro-S,R-
TS
TS
TS
TS
Electrostatic
Exchange
-80.4
141.1
-83.8
-52.1
-78.8
137.9
-82.4
-50.1
-67.5
131.6
-72.2
-46.9
-68.7
149.6
-91.7
-46.9
Induction
Dispersion
Total interaction
energy
-75.2
-73.4
-55.0
-57.7
Figure 2. Four possible transition state geometries pro-R,S-TS, pro-
R,R-TS, pro-S,S-TS and pro-S,R-TS, with the participation of thiophene
analogue 7, located with B97D/6-31+G(d,p) with their energy
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Thermodynamically, the most possible reaction goes through the role of these molecular interactions in recognition ofVbieowtAhrtriceleaOctniloinne
pro-R,S-TS with the lowest energy barrier equalling to 6.8 kcal·mol-1 partners. Furthermore, the model reaction between thiophene-
DOI: 10.1039/C9OB00914K
and leads to the formation of R,S-configured product 6. The pro-R,S- derived aldehyde 7 with β-nitrostyrene 4 was performed in order to
TS has the strongest stabilization that comes from hydrogen bonds compare the reactivity of both systems (Scheme 3). It was found that
and π-stacking interactions. Moreover, in order to study such sulphur-containing heterocycle was less reactive when compared to
systems, the second-ordered corrections are required to ensure the oxygen counterpart. This is in accordance with computed energy
proper description of interactions and the total energies.
barriers which were in general higher for the thiophene-derived
system. Experimentally observed stereoselectivities were similar
confirming the accuracy of obtained values of transition states
energies. Notably, the comparison of differences in total interactions
energies from SAPT analysis between pro-R,S-TS and pro-R,R-TS for
furan and thiophene analogues (1.8 kcal·mol-1 vs 1.0 kcal·mol-1)
might be an indication of slightly lower diastereoselectivity observed
in the latter case.
SAPT results for TS geometries for reactions involving trienamine
derived from thiophene 7. Analogical analysis for key interactions
was carried out for the SAPT results obtained for all TS geometries of
reactions involving thiophene-derived systems and values are
collected in Table 2. The strongest attraction (82.4 kcal·mol-1) is
noticed for pro-R,S-TS structure, which has the lowest energy barrier
equalling to 8.9 kcal·mol-1. The same as in a previously discussed
example the first-order term is repulsive for all complexes, and the
second-order terms are attractive. The sum of both leads to the final
attractive character of interactions. Herein, the dispersion term
exceeds half of the total interaction energy but is still lower than
overall interaction energy, which is probably a proof of interplay
between hydrogen-bond and π-stacking characters.
Table 2. The components contributing to the interaction energy in
the corresponding TS computed using SAPT0 for located TS
structures with the participation of the thiophene analogue 7. The
values are reported in kcal·mol-1
pro-R,S- pro-R,R- pro-S,S- pro-S,R-
TS
TS
TS
TS
Electrostatic
Exchange
-79.7
144.6
-93.9
-53.4
-80.7
144.2
-89.4
-55.5
-67.0
132.0
-74.5
-48.4
-76.6
146.5
-88.9
-47.5
Scheme 3. Reactivity comparison of furan- and thiophene-derived
systems in the aminocatalytic remote functionalization
Induction
Dispersion
Conclusions
Total interaction
energy
In conclusion, we have developed theoretical studies on the
mechanism of remote functionalization of 5-alkylfurfural derivatives
proceeding under aminocatalytic conditions. The reaction involves
dearomatization of the central heteroaromatic framework to give
trienamine intermediate. The most stable intermediate has been
identified and the role of aminocatalyst in providing stabilization of
the corresponding transition state explained. Furthermore, by means
of SAPT analysis insight into crucial molecular interactions was
gained providing valuable information on the reaction mechanism.
The reactivity of the thiophene analogue of the starting 5-
alkylfurfural derivative has been also theoretically evaluated and the
results verified experimentally.
-82.4
-81.4
-57.9
-66.5
In order to verify theoretical data, they were compared with the
results of the performed experiments. It was found that a previously
proposed mechanistic scenario is in accordance with the calculation.
The pre-assumed participation of Z,Z,Z-configured trienamine 3 was
unequivocally confirmed by theory. For the developed reaction to
proceed in an enantio- and diastereoselective fashion two factors
were of key significance. Firstly, the recognition of the electrophile
by the H-bonding unit resulting from the catalyst. Secondly, the
alignment of β-nitrostyrene 4 with regard to the trienamine
intermediate. Performed calculation indicated the importance of
two groups of molecular interactions in controlling the
stereochemistry of the reaction: (1) recognition of the nitro group by
the H-bonding unit of the catalyst; (2) π-stacking interaction between
phenyl ring of the β-nitrostyrene 4 and conjugated π-system in 3. In
this context, the results of SAPT analysis clearly indicate the crucial
Conflicts of interest
There are no conflicts to declare.
Notes
The authors declare no competing financial interest.
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5
6
(a) Asymmetric dearomatization reactions (Ed.: S.-L. You),
Acknowledgments
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Wiley-VCH, 2016. (b) X.-C. Zhuo, C. ZhDeOngI: 1a0n.1d03S9./-CL.9OYoBu0,09A1c4cK.
Chem. Res. 2014, 47 , 2558. (c) W.-T. Wu, L. Zhang and S.-L.
You, Chem. Soc. Rev. 2016, 45, 1570. (d) W. Sun, G. Li, L. Hong
and R. Wang, Org. Biomol. Chem. 2016, 14 , 2164.
This project was financially supported by funds from Lodz University
of Technology (Działalność statutowa). The calculations described in
this paper are performed using the PLATON project's infrastructure
at Lodz University of Technology Computer Centre.
For selected examples, see: (a) T. Dohi, A. Maruyama, N.
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C. Rodriguez-Escrich, R. L. Davis, H. Jiang, J. Stiller, T. K.
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