Decrypting Transition States by Light: Photoisomerization as a Mechanistic Tool in Br?nsted Acid Catalysis

Article abstract of DOI:10.1021/jacs.7b02539

Despite the wide applicability of enantioselective Br?nsted acid catalysis, experimental insight into transition states is very rare, and most of the mechanistic knowledge is gained by theoretical calculations. Here, we present an alternative approach (de

Full text of DOI:10.1021/jacs.7b02539

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Article
Decrypting Transition States by Light: Photoisomerization
as a Mechanistic Tool in Brønsted Acid Catalysis
Polyssena Renzi, Johnny Hioe, and Ruth M. Gschwind
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 04 May 2017
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Decrypting Transition States by Light: Photoisomerization as a
Mechanistic Tool in Brønsted Acid Catalysis
Polyssena Renzi, Johnny Hioe, Ruth M. Gschwind*
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Institut für Organische Chemie, Universität Regensburg, Dꢀ93040 Regensburg, Germany
KEYWORDS: Brønsted acid catalysis, reaction mechanism, enantioselectivity, photoisomerization, NMR.
ABSTRACT: Despite the wide applicability of enantioselective Brønsted acid catalysis, experimental insight into transition states
is very rare and most of the mechanistic knowledge is gained by theoretical calculations. Here, we present an alternative approach
(Decrypting Transition State by Light= DTS-hν), which enables the decryption of the transition states involved in chiral
phosphoric acids catalyzed addition of nucleophiles to imines. Photoisomerization of double bonds is employed as a mechanistic
tool. For this class of reactions four pathways (Type I Z, Type I E, Type II Z, Type II E) are possible, leading to different
enantiomers depending on the imine configuration (Eꢀ or Zꢀimine) and on the nucleophilic attack site (top or bottom). We
demonstrated that the imine double bond can be isomerized by light (365 nm LED) during the reaction leading to a characteristic
fingerprint pattern of changes in reaction rate and enantioselectivity. This characteristic fingerprint pattern is directly correlated to
the transition states involved in the transformation. Type I Z and Type II Z are demonstrated to be the competing pathways for the
asymmetric transfer hydrogenation of ketimines, while in the nucleophilic addition of acetylacetone to NꢀBoc protected aldimines
Type I E and Type II E are active. Accelerations on reaction rate up to 177% were observed for ketimines reduction. Our
experimental findings are supported by quantum chemical calculations and nonꢀcovalent interaction analysis.
1. INTRODUCTION
Chiral phosphoric acids represent an attractive and widely
applicable class of enantioselective organocatalysts in terms of
different activation modes.1ꢀ8 The pioneering work of
Akiyama9 and Terada,10 which introduced these compounds in
the role of catalysts, set the fundament for the further
development of Brønsted acid catalysis. Nowadays, the more
than 400 asymmetric transformations published in this area
prove the power and the broad applicability of this class of
compounds. Despite the high performance of chiral
phosphoric acids in terms of yields and enantioselectivity,
structural and experimental mechanistic studies are very rare
and most of the insight is provided by theoretical
calculations.11ꢀ17
In the context of our work on the NMR mechanistic
investigation on phosphoric acids catalyzed addition of
nucleophiles to imines, we sought an alternative method to
gain insight into the reaction mechanism. We questioned
whether Brønsted acid catalysis and photoisomerization of
double bonds might be successfully merged to provide an
experimental platform to access the transition states (TS)
involved in these transformations. If an isomerization of the
imine double bond is active during the reaction, it would be
possible to exploit the photoisomerization as a mechanistic
tool (Figure 1). We proposed, in fact, that changes in rate and
enantiomeric excess upon illumination create a characteristic
fingerprint pattern, which is associated with a particular
transition state (Figure 2).
Figure
1.
Merging
Brønsted
acid
catalysis
with
photoisomerization of double bonds: experimental access to active
transition states and potential optimization of catalysis.
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Figure 2. Transition states and produced fingerprint pattern upon photoisomerization for phosphoric acids catalyzed addition of
nucleophiles to imines: a) Transition states proposed for the transfer hydrogenation of imines in the presence of Hantzsch ester
analogue to Goodman’s.14 The example shows that four pathways (Type I Z, Type I E, Type II Z, Type II E) lead to different
enantiomers depending on the imine configuration (E or Zꢀimine) and on the nucleophilic attack site (top or bottom). R and S refer
to the stereogenic center configuration in the product. b) Changes in characteristic fingerprint pattern (rate and enantiomeric excess
(ee)) upon illumination given the competition of two transition states. In case the major enantiomer is R only 4 out of 8 transition
state combinations can be active (the transition states labelled in blue correspond to the major pathway in operation in case of (R)ꢀ
configured major product; for a complete set of scenarios see the SI). ↑, increase in ee or reaction rate; ↓ decrease in ee or reaction
rate; ─ no change in ee; (R)ꢀTRIP 1a ((R)ꢀ3,3’ꢀBis(2,4,6ꢀtriisopropylphenyl)ꢀ1,1’ꢀbinaphthylꢀ2,2’ꢀdiyl hydrogenphosphate).
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A huge contribution in terms of mechanistic studies in this
Scenario 4), the light induced isomerization will reduce the
reaction rate without affecting the enantiomeric excess. When
both E and Zꢀtransition states are active, not only mechanistic
insights and change on reaction rate are possible, but also a
modulation of the enantioselectivity can be achieved. In the
case the light driven isomerization supports the isomer
producing the major enantiomer, improvement of synthetic
application is possible since the reaction would show both
acceleration and increase of the enantiomeric excess (Figure
2b, Scenario 3), the gold standard in stereoselective synthesis.
Vice versa, when the Eꢀimine is the precursor of the major
product and its concentration is reduced by the light, a
detrimental effect would be obtained for both reaction rate and
enantioselectivity (Figure 2b, Scenario 1).29
field was given by Goodman11ꢀ14 and Himo,15 but a direct
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experimental proof of the reaction mechanism is still not
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available. According to these studies,11ꢀ12,
ternary
complexes are postulated as active transition states. Since the
imine can adopt an Eꢀ or Zꢀconfiguration and the nucleophilic
attack can occur from the top or the bottom of the
imine/catalyst binary complex, four different stereochemical
arrangements in the transition state, denominated as Type I Z,
Type I E, Type II Z, Type II E (Type I= bottom attack; Type
II= top attack), are possible (Figure 2a). For a distinct chiral
phosphoric acid, the preference for one pathway is determined
by the nucleophile type, the size of imine substituents (Figure
2, R1 and R2) and its configuration (E or Z).12, 14 Moreover in
the previous studies, a fast isomerization of the imine double
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bond is assumed, thus the reaction occurs through the lowest
2. RESULTS AND DISCUSSION
14ꢀ15
transition state.11ꢀ12,
Our recent NMR structural
characterization of imine/(R)ꢀTRIP binary complexes
disclosed four different structures,16 which can be regarded as
precursors of the transition state models of Goodman (Type I
Z, Type I E, Type II Z, Type II E). However, deviating from
the models proposed so far, we found experimentally that the
E/Zꢀisomerization within these binary complexes is slow on
the NMR time scale. Additionally, only low concentrations of
the Zꢀimine in the binary complexes with TRIP 1a were
detected.17ꢀ18 Given the fact that photochemical processes offer
the possibility for an effective isomerization of double
bonds,19ꢀ26 we developed an experimental, easily applicable
method, which employs photoisomerization as a mechanistic
tool. In the following, this method will be referred to as DTSꢀ
hν (Decrypting Transition States by Light), since the
photoisomerization allows us to decrypt i.e to change the
experimentally nonꢀobservable transition states back into
easily readable data sets including reaction rates and
enantioselectivity. The changes in reaction rate and
enantiomeric excess values obtained upon in situ illumination
are, in fact, directly connected to the TS involved in BINOLꢀ
derived phosphoric acids catalyzed reactions generating a
characteristic fingerprint like pattern (Figure 2b). Furthermore,
it has the potential to improve synthetic applications. For the
applicability of our DTSꢀhν approach, the reaction under
consideration has to fulfill three mechanistic conditions: (i) the
double bond can be photoisomerized without significant
photodegradation; (ii) no change in the principal reaction
mechanism is observed upon irradiation, i.e. no background
reaction is active, thus the illumination affects only the E/Zꢀ
ratio; (iii) the double bond isomerization has to be slow or
comparable to the enantioselective step, i.e. the overall rate is
affected by the change in the concentration of the E and Z
isomers. Reactions, which comply with these requirements,
respond differently to illumination depending on the active
transition states involved in the formation of the two product
enantiomers (Figure 2b). Considering the four proposed
transition states (Figure 2a) and that an imine can be
isomerized from the E to Z isomer by means of light,22, 27ꢀ28
four different scenarios are possible (Figure 2b) upon
competition of two transition states. When the product
formation proceeds via Type I Z and Type II Z transitions
states (Figure 2b, Scenario 2) the photoisomerization, which
converts the Eꢀimine present in solution partially to the Zꢀ
form, should result in the increase of reaction rate without any
change on the enantioselectivity. On the contrary, when Type I
E and Type II E transition states are involved (Figure 2b,
To test the applicability of the DTSꢀhν approach the
asymmetric transfer hydrogenation of ketimines 2aꢀi,
developed independently by List and Rueping,30ꢀ32 was chosen
as model reaction. The necessary mechanistic conditions were
fully satisfied. As reported in literature imines isomerization
occurs photoinduced or via thermal processes. Works on this
subject were described by Fisher long time ago employing low
temperature NMR measurement and external illumination with
a mercury lamp.27 Applying the LED based NMR illumination
device developed in our group,33 we explored the feasibility of
ketimines 2aꢀi isomerization by in situ irradiation of the NMR
sample by using a glass fiber coupled with a 365 nm LED. It
was possible, in this way, to follow the isomerization by
recording 1HꢀNMR spectra with regular intervals of time while
the sample was subjected to a continuous illumination at 180
K. Low temperature measurements were necessary in order to
prevent thermal back reaction and allow for Zꢀimine
characterization. As an example, sections of imine 2a1HꢀNMR
spectra are shown in Figure 3. The imine can be isomerized
both as a single component (Figure 3a; an Eꢀimine 2a solution
was subjected to 90 minutes of irradiation with a 365 nm LED
in CD2Cl2 at 180 K, the E/Zꢀimine ratio obtained was 1 to 1.6)
and inside the binary complex formed with the chiral
phosphoric acid (Figure 3b; a 1:1 mixture of Eꢀimine 2a and
(R)ꢀTRIP 1a was subjected to 90 minutes of irradiation with a
365 nm LED in CD2Cl2 at 180 K, the obtained E/Zꢀratio in the
binary complex was 1 to 1). No conformational change was
observed under blue or green light in agreement with the imine
UV absorption spectrum (λmax 2a = 268 nm). No byproducts of
photoinduced decomposition were detected after 24 hours of
continuous irradiation of the samples. Deuterated
dichloromethane was chosen as solvent since a better lineꢀ
width can be obtained for the imine/catalyst binary complexes
NMR spectra, as reported in our previous studies.16ꢀ17
A
reduced isomerization rate was observed in tolueneꢀd8 (Eꢀ
imine 2a, 90 minutes irradiation with the 365 nm LED in
tolueneꢀd8 at 180 K gave a mixture of E/Zꢀimines with a 1 to
0.3 ratio).
The other requirement that has to be met is that the
background reaction is not active thus the illumination affects
only the E/Zꢀratio. Two different experiments were performed
to prove this point. It is known in literature, that imines, in
particular aldimines, can be photoreduced without any
asymmetric induction in the presence of dihydropyridine
Hantzsch esters 3 in benzene or of a ketone as photosensitizer
in a protic solvent under illumination with a medium pressure
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mercury lamp.34ꢀ37 In our case, employing toluene as solvent no
Page 4 of 9
with respect to a control reaction run without illumination, we
observed after continuous irradiation with a 365 nm LED a
significant increase on reaction rate without any change on the
enantiomeric excess (Figure 4, product 4a). Comparing these
results with the changes in the characteristic fingerprint pattern
(rate and ee) upon illumination proposed in our method
(Figure 2b), this reaction proceeds according to Scenario 2, i.e.
via Type I Z and Type II Z transitions states. This means that
the Eꢀimine did not participate in the product formation and an
active isomerization of the double bond should be operated by
the catalyst in absence of light. When the system is irradiated
with the right wavelength, the amount of Zꢀisomer can be
enhanced causing the increase on reaction rate. Two Zꢀ
transition states are competing. Since an R configured product
4a is formed employing (R)ꢀTRIP 1a, as shown in Figure 2a,
Type I Z should be the major pathway followed, thus the
nucleophilic attack occurs from the bottom of the binary
complex. Different phosphoric acid catalysts 1b-c were tested
together with imine 2a observing in all cases the same change
in the characteristic fingerprint pattern (no change in ee,
increase in reaction rate).38 In dichloromethane, which was the
solvent of choice for the isomerization study, catalyst 1a gave
lower yield and ee than in toluene (30% yield, 70% ee for the
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product or byproduct formation could be detected when imine 2a
and Hantzsch ester 3 were irradiated with the 365 nm LED for
24 hours. The reduction under illumination was observed only
in the presence of catalyst 1a.
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Figure 3. In situ NMR photoinduced isomerization of model
imine 2a and its TRIPꢀcomplexes. a) The Meꢀ and OMeꢀ sections
of 1HꢀNMR spectra of imine 2a in CD2Cl2 at 180 K (600 MHz) in
the dark and after 90 min illumination (photostationary state)
show the effective isomerization from E to Z of free imine 2a; b)
control reaction after
5
hours in dichloromethane).39
Therefore, toluene, as described by List,30 was chosen as the
solvent to continue our investigation. Our method was then
tested on ketimines 2bꢀi (Figure 4). For all the imines
screened, firstly, the photoisomerization was studied by NMR
at low temperature in CD2Cl2, then the illumination was
carried out in the reaction conditions applied to compound 2a.
Figure 4 summarizes the results obtained in terms of yield and
enantioselectivity for the control reaction and under
illumination. For all compounds belonging to the family of
ketimines 2aꢀi, the illumination affects the reaction in the
same way. A significant increase in reaction rate is observed
(134ꢀ177% increase of yields after 5h considering the yield of
control reactions as reference value) with no change in
enantiomeric excess with respect to the control. Scenario 2 of
our method is followed proving experimentally that the
hydride transfer hydrogenation of ketimines catalyzed by
chiral phosphoric acids proceeds via Type I Z and Type II Z
transitions states. Having established our proposal, we focused
our attention to prove the generality of the DTSꢀhν method.
Type I E is postulated to be the active transition state in
phosphoric acid catalyzed reactions involving aldimines and
small symmetric nucleophiles.11ꢀ12
1
Low field sections of HꢀNMR spectra of an imine 2a/(R)ꢀTRIP
1a binary complex in CD2Cl2 at 180 K (600 MHz) showing the
characteristic signals of the 15NꢀH in the hydrogen bond in the
dark and after 90 min illumination (photostationary state). The
spectra clearly shows that the imine photoisomerization is also
possible inside the binary complex.
The second experiment was performed to prove that the light
is affecting only the imine isomerization and it has no effects
on the enantioselective step, i.e. the hydride transfer from the
Hantzsch ester 3. To prove our assumption, we decided to test
the reaction on a nonꢀisomerizable imine in the way a change
on reaction rate should be obtained only if the hydride transfer
is
affected
by
the
light.
Employing
Nꢀ
(diphenylmethylene)benzenamine as nonꢀisomerizable starting
material no significant change on the reaction outcome was
detected, so the influence of light on the hydride transfer could
be excluded (control reaction 37% yield; 365 nm LED
illumination 35% yield). With all the mechanistic conditions
met, we first examined the effect of light on the hydrogenation
of imine 2a, with Hantzsch ester 3 as hydride donor,
employing (R)ꢀTRIP 1a as catalyst. The reaction conditions
previously described by List were employed.30 To our delight,
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Figure 4. Effect of light on the asymmetric hydrogenation: screening of imines 2aꢀi. All reactions were carried out employing imine 2aꢀi
(0.36 mmols, 1 eq), Hantzsch ester 3 (1.4 eq) and (R)ꢀTRIP 1a (0.01 eq) in 4.4 mL toluene under continuous illumination with a 365 nm
LED lamp for 5 hours at 35°C. The control reactions were run in the same conditions without LED illumination. Isolated yield after
chromatography are shown. The ee values were determined by HPLC on chiral stationary phase; changes on ee are within the experimental
error.
To prove the effective involvement of Type E transition states
for aldimines, we applied our method to the nucleophilic
addition of acetylacetone 6 to NꢀBoc protected imines 5aꢀc
employing, also in this case, (R)ꢀTRIP 1a as catalyst.10 For all
the three compounds tested 5a-c, we observed upon
illumination a significant reduction on reaction rate and no
effect on the enantioselectivity with respect to the control
reaction (Figure 5). According to these results, Scenario 4
(Figure 2b) is fully met for aldimine 5 reactions. Type I E and
Type II E are both involved. When the Eꢀaldimine is
converted by isomerization to the Zꢀform, the amount of
product precursors is reduced causing, in this way, a drop in
Figure 5. Effect of light on the nucleophilic addition of
reaction rates.
acetylacetone 6 to aldimines 5aꢀc. All reactions were carried out
employing aldimines 5aꢀc (0.23 mmols, 1 eq), acetylacetone 6
(1.1 eq) and (R)ꢀTRIP 1a (0.1 eq) in 2.3 mL dichloromethane
under continuous illumination with a 365 nm LED lamp for 3
hours at room temperature. The control reactions were run in the
same conditions without LED illumination. Isolated yield after
chromatography are shown. The ee values were determined by
HPLC on chiral stationary phase.
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Figure 6. Type I/II E/Z transition states for the transfer hydrogenation reaction of imine 2b using Hanztsch ester model 3’. The pathways
following Type I/II Z possess the lowest barrier, which is in agreement with the illumination experiment. Red colored structures: (R)ꢀTRIP
1a. Blue colored structures: ketimine 2b. Green colored structures: Hanztsch ester model 3’. Numbers in light blue: thermodynamic
difference between Eꢀimine 2b/(R)ꢀTRIP 1a and Zꢀimine 2b/(R)ꢀTRIP 1a. Numbers in red: ∆GTS of the transition states. Numbers in
orange: absolute barrier height ∆G‡. All energies are given in SI unit kJ/mol.43
To confirm the two active transition states proposed by the
photoisomerization experiment for ketimines (Type I Z and
Type II Z), quantum chemical calculations of the transition
states and the ground states of the binary complex for ketimine
2b hydrogenation were performed. For the calculations we
chose pꢀMeꢀketimine 2b, (R)ꢀTRIP 1a as catalyst and a
reduced model of Hantzsch ester 3’ as nucleophile (Figure
6).40ꢀ42 Despite of the presence and the bulkiness of the 3,3’ꢀ
substituents on the Brønsted acid catalyst 1a, the nucleophile,
i.e. Hanztsch ester 3’, can still approach from two sites, e.g.
bottom and top (Figure 2aꢀb and Figure 6). Depending on the
configuration of the imine, the top and the bottom attack will
produce respectively the Rꢀ and the Sꢀproduct. All together,
we found four transition states leading to the different product
enantiomers, which are comparable with previous
computational studies by Goodman.11ꢀ12, 14 In the case of our
model reaction, the lowest transition state was also found for
the nucleophilic attack to the Zꢀimine from the bottom side
(Type I Z). The second lowest transition state was located
marginally above the Type I Z TS and was calculated for the
bottom attack to the Eꢀimine (+1.7 kJ/mol, Type I E). The
third TS corresponds to the top attack to the Zꢀimine (+8.3
kJ/mol, Type II Z) and the highest transition state was
predicted for the top attack to the Eꢀimine (+17.3 kJ/mol; Type
II E). The order of the stability of the transition states is
qualitatively identical with the previous computational study,
which also showed that the transition state Type I Z is
energetically favored, followed by Type I E.11ꢀ12, 14 Assuming a
fast equilibrium between E/Zꢀisomers in the binary complex
(CurtinꢀHammett) as applied previously, the major product
would be correctly the Rꢀenantiomer.
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Figure 7. NCI plot and plots of reduced density gradient s(ρ) vs. electron density multiplied by the sign of the second Hessian eigenvalue
sgn(λ2)ρ of the transition states of Type I E (a), and Type I Z (b). The hydrogen bond in Type I E is weakened allowing the imine to avoid
steric repulsion with the 3,3’ꢀsubstituent of the catalyst. The region of 2.0 Angstroms around the hydrogen atom in the hydrogen bond
(imine HB and ester HB) are shown. The hydrogens and isopropyl groups are omitted for the sake of clarity. Green colored: Hanztsch ester
3’, red colored: (R)ꢀTRIP 1a, and blue colored: imine 2b. The chosen isovalue is 0.4, and the color range is ꢀ7.0 to 7.0. The Type I E
exhibits weaker hydrogen bond (greenish colored surface for the imine HB and larger sgn(λ2)ρ) compared to the Type I Z.
However, according to the small energetic difference of 1.7
kJ/mol between Type I Z and Type I E, a low enantiomeric
excess of 30% ee is calculated. This value deviates more than
56% from the experimental value (86% ee). The effect
observed from our photoisomerization experiment on the
reaction rate clearly showed that the isomerization between Eꢀ
and Zꢀimine is slower than the enantioselective step. This
means that the thermodynamic of the ground state binary
complex between E and Z has to be taken into account for the
calculations of the barriers. Consequently, the paths following
the Type I Z and Type II Z are the two energetically least
demanding and hence active in the product formation. The
calculated enantiomeric excess value from the barrier height
difference between Type I Z and Type II Z amounts to 93% ee,
which is quite close to the found experimental value of 86%
ee. This is further confirmed by our photoisomerization
experiment (Scenario 2 in Figure 2b: increase in rate but no
change in ee values), proving that the Eꢀimine did not
participate in the product formation, and the two Zꢀtransition
states are competing.42
previously.15 Thus, the hydrogen bond between the imine and
the catalyst is weakened upon binding of the Hanztsch ester
and facilitating the transfer of the hydride to the imine. This is
corroborated by the NCI analysis of the ground16 and
transition states showing more negative sgn(λ2)ρ values for
the ground state. The fact that the ester HB is stronger than the
imine HB is also reflected in the NCI plot by showing more
negative sgn(λ2)ρ values for the ester HB (sgn(λ2)ρ = ꢀ0.03 to
ꢀ0.05 for imine HB; sgn(λ2)ρ = ꢀ0.06 for ester HB).
Moreover, a comparison between the Eꢀ and Zꢀtransition states
showed that the OꢀHimine/catalyst TS bond is much longer in the Eꢀ
transition states (185ꢀ188 pm) than in the Zꢀtransition states
(164ꢀ172 pm) indicating a weaker hydrogen bond in Type I E.
As evidenced by the NCI analysis, the critical point (s(ρ)= 0)
of the imine HB in Type I E is located at sgn(λ2)ρ≈ ꢀ0.03,
while in Type I Z it is calculated at sgn(λ2)ρ≈ ꢀ0.05.
Previously, the steric repulsion due to the 3,3’ꢀsubstituent of
the catalyst was proposed to be the possible reason for the
destabilization of the Eꢀconfigured TS.12, 15 However, our NCI
analysis showed that the 3,3’ꢀsubstituents of TRIP in the
transition states do not exhibit a strong repulsive interaction
with the imine but rather a communication via weak attractive
van der Waals interactions is established (see Figure S14 in
Supporting Information for the NCIꢀplot). All together the
NCI analysis and structural analysis showed that the
destabilization of the Eꢀtransition state is due to the structural
adaptation of the transition states: the hydrogen bond between
imine and phosphoric acid is elongated and weakened. This
allows for the interconversion of repulsive into attractive
interactions between the 3,3’ꢀsubstituents of catalyst 1a and
the imine.
The competition between these transition states is additionally
supported by the structural and the nonꢀcovalent interaction
(NCI) analysis of the hydrogen bonded systems (for a basic
explanation of NCI analysis see SI).44ꢀ45 The structural analysis
of the transition states revealed that the OꢀH distance within
the hydrogen bond between the imine and the catalyst (Figure
7; imine HB) is significantly elongated compared to the
ground state binary complexes (d(OꢀH)imine/catalyst TS= 164ꢀ188
pm; d(OꢀH)imine/catalyst GS= 138ꢀ149 pm).17 In contrast, the
hydrogen bond between the ester and the catalyst (Figure 7;
ester HB) is the shortest in the transition state complex (d(Oꢀ
H)ester/catalyst TS= 159ꢀ164 pm), which was already proposed
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Page 8 of 9
Financial support was provided by the European Research
Council (ERCꢀCoG 614182 − IonPairsAtCatalysis) and by the
German Science Foundation (DFG ꢀ GRK 1626, Chemical
Photocatalysis).
1
2
3
3. CONCLUSIONS
In summary, the DTSꢀhν method provided the first
experimental insight into Brønsted acid catalyzed reactions of
imines. Photoisomerization of double bonds was exploited as a
mechanistic tool to identify the active transition states.
According to the scenarios proposed in Figure 2b, the
detection of active transition states can be achieved by
comparing the changes in reaction rate and enantiomeric
excess values obtained after illumination with a dark control
reaction. Two model systems were investigated. For the
asymmetric transfer hydrogenation of imines 2aꢀi the
characteristic fingerprint pattern of changes obtained (increase
on reaction rate, no change on enantioselectivity; Figure 2b
Scenario 2) upon illumination showed the competition
between the two Zꢀtransition states. According to the
configuration of the major product (R)ꢀ4a, the nucleophilic
attack to the Zꢀimine occurs from the bottom side (Type I Z).
For the nucleophilic addition of acetylacetone 6 to NꢀBoc
protected imines 5aꢀc, Type I E and Type II E were identified
as the active transition states. The isomerization to the
corresponding Zꢀimine is in fact detrimental for the reaction
rate whereas the enantioselectivity was not affected (Figure
2b, Scenario 4). Our experimental results corroborate earlier
computational predictions that the Type I Z is the lowest
transition state.11, 15 Additionally, our combined experimental
observations and quantum chemical calculations reveal that
both ground state and transition state energetics have to be
considered to select the active transition state combinations.
Due to the slow isomerization between E and Zꢀimine in the
binary complex, the CurtinꢀHammett principle does not apply.
Hence, in the hydrogenation the ground state energy
difference must be considered in the calculation of the energy
barrier. The lowest barriers were predicted for pathways
proceeding via Type I Z and Type II Z transition states. This
was further rationalized by structural and NCI analysis, which
showed a significantly weaker hydrogen bond between Eꢀ
imine and catalyst 1a due to the steric property of the 3,3’ꢀ
substituent of the compound 1a. The more flexible and
compact structure of Zꢀimines allows these compounds to bind
closer to the catalyst with respect to Eꢀimines. A stronger
hydrogen bond is formed which is essential for the stability of
the TS.
4
5
6
7
8
9
ABBREVIATIONS
kB, Boltzmann constant; T, temperature; Nuc, nucleophile; ee,
enantiomeric excess. Catalyst 1a is abbreviated in the text as (R)ꢀ
TRIP;
(R)ꢀ3,3’ꢀBis(2,4,6ꢀtriisopropylphenyl)ꢀ1,1’ꢀbinaphthylꢀ
2,2’ꢀdiyl hydrogenphosphate; Boc; tertꢀButoxycarbonyl.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge via the
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AUTHOR INFORMATION
Corresponding Author
ruth.gschwind@chemie.uniꢀregensburg.de
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
ACKNOWLEDGMENT
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are summarized in the SI. In the case more than two
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ORCA 3.0.3 was used. More details for calculations were
provided in the SI.
transition states contribute, this method would also allow to
identify Z only, E only or mixed transition states following
the fingerprint pattern described in Figure 2b.
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ee; (R)ꢀMacMillan catalyst 1c = control: 19% yield, 91% ee;
365 nm LED: 35% yield; 91% ee. All reactions were carried
out employing imine 2a (0.36 mmols, 1 eq), Hantzsch ester
3 (1.4 eq) and 0.1 mol% of catalysts (expect for catalyst 1c
for which 10 mol% were used) in 4.4 mL Toluene.
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43. The combination of pathways Type I E vs Type I Z yields to
almost 100% ee (barrier height difference of 15.4 kJ/mol).
Other combinations result to the inverted enantiomeric
products.
44. Johnson, E. R.; Keinan S.; MoriꢀSánchez, P.; Contrerasꢀ
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40. All calculations were done at B2KꢀPLYP/CBS//TPSSꢀ
D3/def2ꢀSVP level of theory in the gas phase. Vibrational
and thermochemical analysis were calculated at TPSSꢀ
D3/def2ꢀSVP. Solvent correction was added using CPCM in
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