Structure-Reactivity Relationship in the Frustrated Lewis Pair (FLP)-Catalyzed Hydrogenation of Imines

Article abstract of DOI:10.1002/chem.201600716

The autoinduced, frustrated Lewis pair (FLP)-catalyzed hydrogenation of 16-benzene-ring substituted N-benzylidene-tert-butylamines with B(2,6-F₂C₆H₃)₃ and molecular hydrogen was investigated by kinetic analysis. The pK_a values for imines and for the corresponding amines were determined by quantum-mechanical methods and provided a direct proportional relationship. The correlation of the two rate constants k₁ (simple catalytic cycle) and k₂ (autoinduced catalytic cycle) with pK_a difference between imine and amine pairs (ΔpK_a) or Hammett's σ parameter served as useful parameters to establish a structure-reactivity relationship for the FLP-catalyzed hydrogenation of imines.

Full text of DOI:10.1002/chem.201600716

DOI: 10.1002/chem.201600716
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Hydrogenation |Hot Paper|
Structure–Reactivity Relationship in the Frustrated Lewis Pair
(FLP)-Catalyzed Hydrogenation of Imines
Sebastian Tussing, Karl Kaupmees, and Jan Paradies*[a]
Abstract: The autoinduced, frustrated Lewis pair (FLP)-cata-
lyzed hydrogenation of 16-benzene-ring substituted N-ben-
zylidene-tert-butylamines with B(2,6-F2C6H3)3 and molecular
hydrogen was investigated by kinetic analysis. The pKa
values for imines and for the corresponding amines were de-
termined by quantum-mechanical methods and provided
a direct proportional relationship. The correlation of the two
rate constants k1 (simple catalytic cycle) and k2 (autoinduced
catalytic cycle) with pKa difference between imine and amine
pairs (DpKa) or Hammett’s s parameter served as useful pa-
rameters to establish a structure–reactivity relationship for
the FLP-catalyzed hydrogenation of imines.
anes with reduced Lewis acidity.[6d] This first kinetic analysis
provided evidence for the autoinduced mechanism as a result
of the reduced free activation energy of the H2 activation by
the borane 2 and of the corresponding reaction product (3g)
manifesting in an overall tenfold rate increase (Scheme 1). The
Introduction
The application of frustrated Lewis pairs (FLP) has grown im-
mensely[1] since their first report to activate molecular hydro-
gen (H2) in the absence of transition metals.[2] The develop-
ment of new FLP-catalyzed reactions is in the focus of contem-
porary research resulting in spectacular transformations, for ex-
ample, the activation of strong CÀF bonds,[3] cross-couplings,[4]
or cycloisomerizations.[5] However, the fundamental under-
standing of FLP reactivity with the aim to establish a struc-
ture–reactivity relationship is in its infancies. For example, ki-
netic and thermodynamic parameters of FLP-catalyzed hydro-
genations were only recently experimentally determined,[6] al-
though such reactions are the most widely investigated.[7] The
interplay between the Lewis acid and the Lewis base in the H2
activation is of utmost importance to achieve new challenging
transformations, for example, the hydrogenation of ole-
fins,[6b,7c,8] or to achieve functional-group tolerance.[9] Systemat-
ic investigations are still underrepresented, although they pro-
vide highly valuable information for the targeted design and
rational choosing of FLPs for particular reactions. Such system-
atic studies placed the foundations for the great success of
transition-metal catalysis establishing this chemistry as one of
the most important and most diverse.[10] Key to this success
story is the profound understanding of structure and reactivity.
However, a direct measure to connect structure and thermody-
namic parameters with kinetic features of FLP-catalyzed hydro-
genations is not yet available.
Scheme 1. Proposed mechanism for the hydrogenation of N-benzylidene-
tert-butylamine (1g).
gradual change of the responsible Lewis base for the H2 activa-
tion from the less basic imine to the amine with pronounced
basicity in the course of the reaction was found to be responsi-
ble for this unusual autoinduced mechanism, which is absent
for the strong Lewis acid B(C6F5)3.[6d] Consequently, the differ-
ence in acidity of the conjugate acids of the imine and the cor-
responding amine (DpKa) is a significant and readily predicta-
ble thermodynamic parameter directly linked to the FLP reac-
tivity. A broad range of pKa values can be experimentally deter-
mined in various media[6b,11] or can be acquired through quan-
In a recent study, we reported the mechanistic investigation
of the FLP-catalyzed hydrogenation of imine 1g by using bor-
[a] Dipl.-Chem. S. Tussing, Dr. K. Kaupmees, Prof. Dr. J. Paradies
Institute of Organic Chemistry, University of Paderborn
Warburger Strasse 100, 33098 Paderborn (Germany)
E-mail: jan.paradies@uni-paderborn.de
Supporting information for this article and ORCID for the corresponding
author available on the WWW under http://dx.doi.org/10.1002/
chem.201600716.
tum-mechanical calculations with satisfactory precision.[12]
A
second readily available parameter is the Hammett’s s parame-
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ter,[13] which connects electronic properties of substrates with
reactivity and allows the prediction of reaction rates and the
support of reaction mechanisms.
The selection of appropriate imine/amine pairs is of para-
mount importance to provide a broad range of DpKa values,
which need to be correlated with kinetic data. Therefore, we
initiated our investigation by the computational determination
of pKa values for a series of imines and amines, which are sum-
marized in Table 1. For the calculation of the pKa values, the
geometries of the iminium and ammonium ions, as well as the
corresponding neutral molecules, were optimized by using
DFT method at BP-TZVP level of theory with the COSMO solva-
tion model (e=1) as implemented in TURBOMOLE 6.5 pack-
age.[14] Subsequently, the pKa values were calculated for aceto-
nitrile as a solvent by using the COSMO-RS standard meth-
od.[15,12a] The method was validated by the calculation of pKa
values of 2,6-lutidine (15.6) and 2,4,6-collidine (16.2), which
were earlier employed in hydrogenation reactions.[9a] The ex-
perimental pKa values[11a] for lutidine and collidine are 14.13
and 14.98, respectively, indicating the absolute precision of the
COSMO-RS method. It must be noted that the precision of the
relative difference between imine and amine, the DpKa value,
as well as the trends within substitution series, is expected to
have higher precision due to the cancellation of errors. For our
initial studied amine/imine pair (1g/3g), a DpKa of 2.0 was de-
termined providing further support of the quantum chemical
approach. With the series of N-benzylidene-tert-butylamines
summarized in Table 1, we were able to cover a broad DpKa
range from 0 to 3.3 units. Because the imine nitrogen atom is
integrated into the p system of the molecule, the substitution
on the benzene ring has greater impact on the basicity of
imines. As a consequence, the calculated absolute pKa window
Herein, we present the elaboration of a structure–reactivity
relationship for FLP-catalyzed hydrogenations of imines based
on the correlation of acidity constants (pKa) and rates with the
Hammett’s s parameter. This was achieved by the kinetic in-
vestigation of N-benzylidene-tert-butylamine derivatives in the
FLP-catalyzed hydrogenation deliberately utilizing the less
Lewis acidic B(2,6-F2-C6H3)3 (2). Thereby, we probed the impact
of the Lewis base basicity to the reaction rates of the simple
and autoinduced catalytic cycle. Substituents on the phenyl
ring influence the imine’s and corresponding amine’s basicity
through electronic coupling, whereas the steric impact on the
reaction rates can be disregarded. A series of suitable imine/
amine pairs with fine-tuned DpKa window of the conjugate
acids is readily accessible, which enabled for the connection of
Hammett’s s electronic parameters to kinetics of FLP-catalyzed
hydrogenations. Because Hammett’s electronic parameters are
direct proportional to acid strengths, this approach connects
a readily available thermodynamic parameter (pKa) with FLP re-
activity establishing a structure–reactivity relationship for FLP
systems.
Results and Discussion
For the sake of easier discussion, we use the term “pKa of
imines and amines” for the pKa of the corresponding conjugate
acids.
Table 1. Hammett’s s electronic parameters, calculated pKa values[a] of the conjugate acids of N-benzylidene-tert-butylamine (1a–p) and N-benzyl-tert-
butyl-amine (3a–p) derivatives, difference of the corresponding pKa values (DpKa), and reaction rates of the simple catalytic cycle (k1) and autoinduced cat-
alytic cycle (k2).
[b]
[b]
Entry
R
s
pKa[a] (im)
pKa[a] (am)
DpKa
k1
k2
1
2
3
4
5
6
7
8
4-OtBu (a)
4-OMe (b)
4-OPh (c)
4-Me (d)
4-tBu (e)
3-Me (f)
4-H (g)
3-OMe (h)
4-F (i)
4-Cl (j)
4-Br (k)
3-Cl (l)
4-CF3 (m)
4-SO2Me (n)
4-NO2 (o)
2,2-Me-4-OMe (p)
À0.45
À0.27
À0.32
À0.17
À0.20
À0.07
0.00
0.12
0.06
0.23
0.23
17.4
17.0
16.3
15.9
15.7
15.5
15.3
15.2
15.1
14.5
14.4
13.8
13.4
13.0
12.3
17.3
18.0
17.9
17.3
17.3
17.2
17.2
17.3
17.4
16.9
16.6
16.5
16.4
16.3
16.1
15.6
17.3
0.6
0.9
1.0
1.4
1.5
1.7
2.0
2.2
1.8
2.1
2.1
2.7
2.9
3.2
3.3
0.0
7.78Æ2.4
13.2Æ5.5
7.96Æ3.3
9.22Æ5.7
9.41Æ5.9
7.77Æ4.7
5.62Æ3.2
4.67Æ2.5
6.47Æ0.7
6.35Æ3.5
6.15Æ3.3
3.67Æ1.5
3.54Æ2.0
3.70Æ1.9
2.51Æ1.1
10.1Æ0.1[c]
78.3Æ16.3
92.0Æ27.4
73.5Æ22.3
88.6Æ36.1
93.6Æ41.9
81.6Æ31.7
74.7Æ25.4
71.3Æ16.6
70.8Æ21.1
80.8Æ29.0
74.5Æ24.5
54.0Æ10.5
54.0Æ15.4
39.5Æ18.7
47.0Æ8.6
9
10
11
12
13
14
15
16
0.37
0.54
0.72
0.78
n.a.
[a] Calculated pKa values for the corresponding conjugate acid in acetonitrile. [b] Data are given in [LmolÀ1 hÀ1]. [c] Zero-order rate constant is given in
LmolÀ1 hÀ1. n.a.=not applicable.
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for imines is twice as big (12.3 to 17.4 pKa units) as for the
amines (15.6 to 18.0 pKa units). Substrates featuring electron-
donating groups, such as 4-Oalkyl/aryl and 4-alkyl, showed
high absolute pKa values with relatively small DpKa values (en-
tries 1–6). Substrates with electron-withdrawing substituents,
such as 4-NO2 and 4-CF3, gave comparably low absolute pKa
values and a large relative DpKa value (entries 10–15). The plot
of the imines’ and amines’ absolute pKa, as well as the relative
DpKa value of the imine/amine pair versus the corresponding
Hammett’s s parameter,[13b,16] resulted in direct proportional
correlation (Figure 1a and b) and can therefore be utilized to
subtle interplay between basicity and rate is more visual from
the semi-logarithmic plot of rates versus DpKa (Figure 2a) and
Hammett’s s parameters (Figure 2b). The graphical analyses
gave linear correlation for both the simple- and autoinduced
catalytic cycle (Figure 2). However, k1 displayed a stronger de-
Figure 2. Semi-logarithmic plot of rate constants k1 and k2 versus a) DpKa
and b) Hammett s parameters (1p, entry 16, has not been included).
pendence on the DpKa and s expressed through a more nega-
tive slope of the linear fit than k2 (1(k1)=À0.46; 1(k2)=À0.25).
This can be clearly understood by the significantly higher
impact of electronic modification to the imine’s nitrogen atom
compared to the less electronically coupled amine’s nitrogen.
The absolute 1 values are small compared with those observed
in other imine reactions,[19] denoting the cancellation of nega-
tive Hammett correlation of imine basicity by positive Ham-
mett correlation of iminium ion electrophilicity. The correlation
of the relative rate enhancement by the autoinduced catalytic
cycles k2/k1 versus the corresponding DpKa values revealed the
highest rate enhancement for imine/amine pairs with largest
differences in pKa. However, this observation must not lead to
the assumption that for these substrates, the highest yields
will be obtained within the shortest reaction time, because the
induction period is prolonged by the reluctant activation of H2,
which is the rate-determining step for the reaction.
Figure 1. Plot of Hammett parameter s versus a) calculated pKa of imines
and amines; b) versus DpKa values of corresponding imine/amine pairs (1p,
entry 16, has not been included).
establish
a structure–reactivity relationship. The negative
slopes in the Hammett plots (1(im)=À3.77; 1(am)=À1.67) in-
dicate increasing positive charge in concert with the stabiliza-
tion of protonated species. Stabilization of positive charge is
more significant for the imine than for the amine, as was ex-
pressed by the more negative Hammett correlation for the
imine (Figure 1a). As can be seen from Figure 1b, the differ-
ence of the pKa (DpKa) of imine/amine pairs increased with in-
creasing ÀI effect of the substituent.[17]
Next, we acquired the two rate constants for the standard
(k1) and autoinduced (k2) cycle in the FLP-catalyzed hydrogena-
tion of the 16 imines. The reactions were performed on 0.36m
scale, 7 mol% borane 2, 4 bar hydrogen pressure, and 110 8C
in [D6]benzene by using hexamethylbenzene as internal stan-
We put our theory to the test by the investigation of
a imine/amine pair featuring a DpKa of zero (entry 16, 1p/3p).
According to the small DpKa value, the reaction should pro-
ceed through both cycles with comparable rates. Indeed, the
plot of the concentration of 3p versus time gave a linear rela-
tionship suggesting a reaction of zero order (see Figure 3a, k=
10.1Æ0.1 LmolÀ1 hÀ1). The apparent zero-reaction order for
1p/3p arose from the constant concentration of Lewis base
with identical pKa making the H2 activation independent from
the nature of the Lewis base. For comparison, the sigmoidal
curve for the formation of 3a (1a: pKa =17.4, 3a: pKa =18.0;
DpKa =0.6) is depicted in Figure 3. This imine has a comparable
pKa to 1p; however, as soon as small amounts of the amine
3a are formed, the autoinduced catalytic cycle takes over. Be-
cause the rate constant for the zero-reaction order is different
form the autoinduced mechanism, the quantitative comparison
is impossible. However, from a qualitative point of view, the
autoinduced reaction with 1a provides 47% yield of 3a within
one hour. In contrast, 3p was produced in the same amount
1
dard. The reactions were monitored by H NMR spectroscopy,
and concentrations were determined by integration. The two
different rate constants k1 for the simple catalytic cycle and k2
for the autoinduced catalytic cycle were determined by em-
ploying the rate law for autoinduced catalytic reactions (see
the Supporting Information).[18] Qualitatively, all substrates
(except of 1p, DpKa =0, see below) displayed autoinduced cat-
alysis, as was evident from the significantly higher rate con-
stants k2 (Table 1). Hydrogenation reactions of electron-rich
substrates exhibiting comparably high pKa (and consequently
a relative small DpKa) displayed high rates for both cycles with
k2 being 8–10 times higher than k1. In contrast, reactions of
electron-poor substrates reacted comparably slower and result-
ed in smaller absolute rate constants, however, with signifi-
cantly greater k2 being up to 18 times higher than k1. The
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with H2 at 77 K, when the NMR tube was immersed into liquid-N2
container of a controlled depth (15 cm) and time (10 s) to create
1
reproducible pressure. The sample was again checked by H NMR
spectroscopy and subjected to controlled motion (Heidolph Poly-
max 1040, 3 rpm) at the desired reaction temperature (Heidolph
HeiTEC equipped with a heating block suitable for NMR tubes),
1
marking the starting point (t0) of the kinetic measurement. H NMR
spectra were recorded in suitable time intervals, including the
measuring time (2 min) and the reaction time, the latter was used
for further calculations. The conversion of the reaction was deter-
mined either by signal integration of the tert-butyl groups of the
starting material (SM) and of the reaction product (Prod.) or the
decay of the CH=N signal, using hexamethylbenzene (HMB) as an
internal standard. All calculations and data analysis were per-
formed with Microsoft Excel 2010, polynomial fitting, and linear re-
gression with Originlab OriginPro 2015.[20] For details and exempla-
ry analysis, see the Supporting Information.
Figure 3. Concentration versus time plot for 3p and a for comparison (aver-
age of three independent experiments; zero-order rate constant for 1p:
k=10.1Æ0.1 LmolÀ1 hÀ1)
.
of time in significantly lower yield (ca. 29% yield). As was dem-
onstrated by these examples, the rational choice of the imine
as Lewis base component of the FLP enables for the deliberate
selection of the reaction mechanism through which and to
which extent the catalytic hydrogenation proceeded.
Acknowledgements
The work of K.K. was supported by the post-doctoral research
grant PUTJD115 from the Estonian Research Council. The
German Science Foundation (DFG) is gratefully acknowledged
for financial support through PA 1562/6-1.
Conclusion
In summary, we have presented kinetic data for the autoin-
duced FLP-catalyzed hydrogenation of 16 imines. First, the
imines and amines were characterized by their quantum-me-
chanically acquired pKa values. The pKa and DpKa of the corre-
sponding imines and amines were correlated with the respec-
tive Hammett parameters providing a linear relationship. The
rate constants k1 and k2 for the simple and autoinduced cata-
lytic cycles were determined with k2 being 8–18 times higher
than k1. Linear relationships were obtained by semi-logarithmic
plot of the rate constants versus difference in the imine/amine
pair (DpKa) and Hammett s parameters. The rate constant for
the simple catalytic cycle k1 was more susceptible to electronic
changes than k2. Significant differences in rates are annihilated
when substrates with very small DpKa of staring material and
product are subjected to hydrogenation. The study clearly
shows the connection of FLP reactivity with the electronic
nature of the Lewis base establishing a structure–reactivity re-
lationship for imine hydrogenations. Thereby, the FLP system
and/or the substrates can now be specifically selected by the
corresponding pKa as an easy accessible thermodynamic pa-
rameter providing a key to the rational design of FLP-catalyzed
reactions.
Keywords: autoinduced catalysis · frustrated Lewis pairs ·
Hammett correlation · hydrogenation · imines
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Experimental Section
General procedure for kinetic measurements
In a glovebox, the imine (1a–p; 0.400 mmol, 1.00 equiv), B(C6F2H3)3
(2; 7 mol%, 0.070 equiv), and hexamethylbenzene (6.4 mg,
0.040 mmol, 0.10 equiv) were dissolved in C6D6 (1.10 mL), and the
solution was divided in two equal parts and transferred into seala-
ble NMR tubes equipped with JYoung Teflon tap. The substrate to
1
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Received: February 16, 2016
Published online on April 9, 2016
Chem. Eur. J. 2016, 22, 7422 – 7426
www.chemeurj.org
7426
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim