Selective aldehyde reductions in neutral water catalysed by encapsulation in a supramolecular cage

Article abstract of DOI:10.1039/d1sc00896j

The enhancement of reactivity inside supramolecular coordination cages has many analogies to the mode of action of enzymes, and continues to inspire the design of new catalysts for a range of reactions. However, despite being a near-ubiquitous class of reactions in organic chemistry, enhancement of the reduction of carbonyls to their corresponding alcohols remains very much underexplored in supramolecular coordination cages. Herein, we show that encapsulation of small aromatic aldehydes inside a supramolecular coordination cage allows the reduction of these aldehydes with the mild reducing agent sodium cyanoborohydride to proceed with high selectivity (ketones and esters are not reduced) and in good yields. In the absence of the cage, low pH conditions are essential for any appreciable conversion of the aldehydes to the alcohols. In contrast, the specific microenvironment inside the cage allows this reaction to proceed in bulk solution that is pH-neutral, or even basic. We propose that the cage acts to stabilise the protonated oxocarbenium ion reaction intermediates (enhancing aldehyde reactivity) whilst simultaneously favouring the encapsulation and reduction of smaller aldehydes (which fit more easily inside the cage). Such dual action (enhancement of reactivity and size-selectivity) is reminiscent of the mode of operation of natural enzymes and highlights the tremendous promise of cage architectures as selective catalysts.

Full text of DOI:10.1039/d1sc00896j

Showcasing research from Dr. Symes’ laboratory, School
of Chemistry, University of Glasgow, UK.
As featured in:
Selective aldehyde reductions in neutral water catalysed
by encapsulation in a supramolecular cage
Encapsulation of small aromatic aldehydes inside a
supramolecular coordination cage allows reduction of
these aldehydes with the mild reducing agent NaCNBH3 to
proceed with high selectivity and in good yields, whereas
very poor conversion is achieved in the absence of cage. Our
results suggest that the specific microenvironment inside the
cage acts both to stabilise the reaction intermediates and
favour the encapsulation smaller aldehydes over more bulky
substrates. Such dual action (enhancement of reactivity and
size-selectivity) is reminiscent of the mode of operation of
natural enzymes.
See Stephen Sproules,
Mark D. Symes et al.,
Chem. Sci., 2021, 12, 5082.
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Selective aldehyde reductions in neutral water
catalysed by encapsulation in a supramolecular
cage†
Cite this: Chem. Sci., 2021, 12, 5082
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
Avishek Paul,‡ Michael A. Shipman,‡ Dolapo Y. Onabule, Stephen Sproules
*
and Mark D. Symes
The enhancement of reactivity inside supramolecular coordination cages has many analogies to the mode
of action of enzymes, and continues to inspire the design of new catalysts for a range of reactions. However,
despite being a near-ubiquitous class of reactions in organic chemistry, enhancement of the reduction of
carbonyls to their corresponding alcohols remains very much underexplored in supramolecular
coordination cages. Herein, we show that encapsulation of small aromatic aldehydes inside
a supramolecular coordination cage allows the reduction of these aldehydes with the mild reducing
agent sodium cyanoborohydride to proceed with high selectivity (ketones and esters are not reduced)
and in good yields. In the absence of the cage, low pH conditions are essential for any appreciable
conversion of the aldehydes to the alcohols. In contrast, the specific microenvironment inside the cage
allows this reaction to proceed in bulk solution that is pH-neutral, or even basic. We propose that the
cage acts to stabilise the protonated oxocarbenium ion reaction intermediates (enhancing aldehyde
reactivity) whilst simultaneously favouring the encapsulation and reduction of smaller aldehydes (which
fit more easily inside the cage). Such dual action (enhancement of reactivity and size-selectivity) is
reminiscent of the mode of operation of natural enzymes and highlights the tremendous promise of
cage architectures as selective catalysts.
Received 14th February 2021
Accepted 11th March 2021
DOI: 10.1039/d1sc00896j
rsc.li/chemical-science
protonated amines bound within their cavities.9 Moreover,
these cages have been used to promote a number of catalytic
reactions, such as the hydrolysis of orthoformates,10 acetal
Introduction
Supramolecular coordination cages fascinate chemists on
account of their ability to enforce well-dened microenviron-
ments on species hosted in their cavities.1 This has led to
applications in areas such as molecular recognition,2 catalysis,3
resolutions and separations,4 and the stabilisation of otherwise
unstable species,5 to name but a few. However, perhaps the
most promising area of application of such cages is their
potential to accelerate organic transformations.6
The potential for enhanced or altered reactivity inside cages
is very well exemplied by the work of Raymond, Bergmann and
co-workers using assemblies of the type M4L6 (M ¼ GaIII, AlIII,
InIII, FeIII, TiIV, or GeIV, and L ¼ N,N0-bis(2,3-dihydroxybenzoyl)-
1,5-diaminonaphthalene).7 These cages have been shown to
facilitate the formation of (and stabilise) hydrolysis-prone
species such as iminium and phosphonium cations in water,8
and also to give rise to dramatically increased pKa values for
hydrolysis,11 Nazarov cyclisations,12 terpene cyclisations,13 and
Prins reactions.14 Such observations have led Raymond and his
colleagues to propose that the underlying cause of the enhanced
reactivity in the above-named reactions is related to the ability
of the cage to stabilise positively-charged transition states,
possibly through interaction of the aromatic units (in the
ligands forming the edges of the cage) with the carbocations
that develop in the substrates during these reactions.15
Our initial interest in such cages stemmed from our ongoing
attempts to up-grade furan derivatives to higher value products
by electrosynthesis.16 For example, the furan derivative furfural
(furan-2-carbaldehyde) is a major renewable chemical feed-
stock, the controlled (electro)reduction of which can yield fur-
furyl alcohol and 2-methylfuran, which are precursor chemicals
for the sustainable production of polymers and fuels.17,18
However, the electroreduction of furfural can also lead to other
products of somewhat lower value, including dimeric and
polymeric species.19,20 Encapsulation of furfural inside a small
supramolecular cage might prevent the oligomerisation of
reactive intermediates during (electro)reduction and hence
favour the production of furfuryl alcohol and/or 2-methylfuran.
However, before such a hypothesis can be tested, it is rst
WestCHEM, School of Chemistry, University of Glasgow, University Avenue, Glasgow,
G12 8QQ, UK. E-mail: mark.symes@glasgow.ac.uk; stephen.sproules@glasgow.ac.uk
† Electronic supplementary information (ESI) available: Full characterisation of
products, LC-MS data, and additional computational analysis. See DOI:
10.1039/d1sc00896j
‡ These authors contributed equally.
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necessary to establish whether (and how) furfural binds within only one example of the hydrogenation of aldehydes to the
a given cage, and how this might be expected to affect its corresponding alcohols in a supramolecular coordination cage
reactivity.
has yet been reported (very recently), requiring the use of
Amongst the numerous diverse coordination cage architec- strongly electron-withdrawing groups on the aldehyde
tures that have been reported to date, the anionic tetrahedral substrate.25 Therefore, the work reported herein constitutes the
FeI4IL6 iminopyridine complex (where L is the bis-imine product rst general demonstration of the conversion of non-activated
resulting from the reaction between 4,40-diaminobiphenyl-2,20- aldehydes to their corresponding alcohols inside a supramo-
disulfonic acid and 2-formylpyridine) reported by Nitschke and lecular coordination cage.
co-workers in 2008 seemed to be an excellent rst choice of cage
for these purposes on account of its ease of synthesis (self-
assembling in aqueous solution from commercial reagents)
Results and discussion
and its amenability to interrogation by solution-phase NMR
In order to determine the extent of any encapsulation of furfural
spectroscopy.21 Moreover, Nitschke and co-workers have previ-
1
by the FeI4IL6 cage, H NMR spectroscopy was used to monitor
ously shown that furan binds inside this cage with Ka ¼ (8.3 ꢀ
the changes that occur upon incubation of the cage with 10
equivalents of furfural at 50 ꢃC for 1 h in D2O (Fig. 1). Although
it was not possible to assign peaks specically to encapsulated
furfural in this spectrum, NOESY NMR spectroscopy (see Fig. S1
0.7) ꢁ 103 and a rate constant for uptake of 2.1 ꢀ 0.3 Mꢂ1 sꢂ1 at
298 K,22 meaning that encapsulation of furan by the cage is
essentially quantitative aer equilibration overnight at 50 ꢃC. It
seemed to us likely, therefore, that furfural would be similarly
in the ESI†) revealed a number of cross-peaks between this new
readily encapsulated. These FeI4IL6 cages have been the subject
set of peaks and those corresponding to free cage, which were
of fairly intense study over the past 10 years or so,23 but the
attributed to the dynamic exchange between free cage and cage
potential for catalytic activity with these cages remains some-
containing furfural. With these assumptions, a literature
what underexplored, with only a few examples reported to
method26 was used to determine the binding constant of
date.6r,24 Hence a study of the encapsulation and reactivity of
furfural inside the cage as Ka ¼ 1.0 ꢁ 103 M.
furfural within these cages appeared to be warranted.
To conrm that furfural can indeed reside within the cage,
Herein, we show that the FeI4IL6 cage does indeed bind
we next explored the energetics of furfural encapsulation by
computational methods (see also ESI†).27 The resulting opti-
mised structure shows that there is ample room for furfural to
bind within the cage, and that when it does so it is anchored
furfural, and that (simply as a function of this binding) the
reactivity of the encapsulated furfural is dramatically altered.
Specically, we demonstrate that the FeI4IL6 cage is in fact
a general catalyst for the (non-electrochemical) reduction of
primarily by CH/p hydrogen bonds from the hydrogens on the
a range of aromatic aldehydes to their corresponding alcohols
furan ring to the aromatic rings of the cage ligands (Fig. 2).28
using the weak hydride donor sodium cyanoborohydride (see
Several interactions can be identied, ranging between 3.1 and
Scheme 1). Using a range of control and competition reactions,
˚
3.3 A. In addition, there are three close contacts between the
we show that the FeI4IL6 cage architecture is essential for this
carbonyl oxygen and protons lining one of the triangular
enhanced conversion and that the cage is a genuine catalyst for
openings of the tetrahedral cage. This combination of non-
the reduction of these carbonyls to their corresponding alcohols
covalent interactions orientates the substrate within the cage
under our very mild conditions. To the best of our knowledge,
as shown in Fig. 2.
Fig. 1 The 1H NMR spectrum of the Fe4L6 cage in D2O in the presence
of 10 equivalents of furfural after heating to 50 ꢃC for 1 h. Peaks
labelled with blue filled stars indicate free cage, peaks with black open
Scheme 1 An illustration of the general class of reactions explored in circles indicate free furfural and peaks denoted with red triangles
this work, using the example of furfural reduction to furfuryl alcohol constitute a new set of cage-like peaks that all show exchange cross-
using sodium cyanoborohydride (NaCNBH3) as the reducing agent. peaks to corresponding free cage peaks (see Fig. S1†). COSY and
Only one of the six identical edges of the anionic FeI4IL6 cage is shown NOESY NMR data indicate that the peak at 7.4 ppm consists of signals
for clarity.
emanating from both free cage and free furfural that are coincident.
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Fig. 2 Calculated orientation of the furfural substrate within the Fe4L6
cage. Dashed lines depict the two hydrogen bond types that anchor
the substrate in the cage: CH/p interactions with the aromatic rings
of the cage ligands (blue); and O/H–C interactions with the carbonyl
group projected towards a triangular opening in the wall of the cage
(magenta).
Fig. 3 Calculated HOMO and LUMO energies (eV) for furfural (left) and
the protonated furfuralium form (right), outside (exo) and inside (endo)
the Fe4L6 cage.
alcohols by the mild reducing agent sodium cyanoborohydride
are generally held to work effectively only in acidic solutions.29
This suggested to us that if the aldehyde was indeed encapsu-
lated by the anionic Fe4L6 cage, and if such cages were indeed
capable of stabilising protonated substrates (which might nor-
mally only form to a signicant degree in acid solution), then
Quantum mechanical calculations on the optimised struc-
ture at the BP86 level of theory showed that encapsulated
furfural is 81.5 kcal molꢂ1 more stable than exohedral (i.e. free)
furfural. The hydrogen-bonds to the carbonyl moiety are weak
and are a product of its position (projected towards the trian- reactions that would otherwise require acidic conditions might
gular face). The orientation is therefore dictated by the CH/p occur in the presence of cage, even though the medium outside
hydrogen bonds between C–H bonds (from the aromatic R- the cage might be neutral (or even basic).
group of the aldehyde) and the cage ligands. Moreover, the
calculations suggest that the lowest unoccupied orbital (LUMO)
of furfural is stabilised relative to the highest occupied orbital
(HOMO) upon encapsulation: furfural inside the Fe4L6 cage
experiences a 9.5 kcal molꢂ1 stabilisation of the LUMO
To explore this hypothesis, we therefore studied the reduc-
tion of furfural to furfuryl alcohol using the mild reducing agent
NaCNBH3 both in the presence and absence of cage. A typical
procedure is given in the Experimental section. The cage was
prepared as the tetramethylammonium salt as described by
compared to the substrate outside the cage (Fig. 3). Such Nitschke and co-workers,21 and was isolated in a pure form prior
a lowering of the LUMO energy is most intriguing, as it suggests to use for the following experiments. The results (see Table 1,
that nucleophilic attack at the carbonyl carbon will be facili- entry 1), indicate that aer extraction of the reaction mixture
tated upon encapsulation, relative to the situation for furfural in
free solution.
In their study of monoterpene-like cyclisation reactions
using analogous M4L6 cages to those that are employed here,
Toste, Bergmann, Raymond and co-workers postulated that the
into organic solvent and purication by column chromatog-
raphy, a 65% isolated yield of furfuryl alcohol is achieved aer
a reaction time of 6 h at 50 ꢃC in the presence of 9 mol% of the
cage at pH 7 (pH of bulk solution), whereas the yield under
otherwise identical conditions but in the absence of cage gives
M4L6 cage was acting to stabilise the protonated aldehyde only 4% furfuryl alcohol (no conversion to the alcohol is
oxocarbenium ions in their substrates, leading to enhanced observed in the absence of a hydride source). This suggests that
reactivity for cyclisation.14 As shown in Fig. 3 (see also ESI†), the cage is turning over between 6 and 7 times during the course
calculations suggest that the protonated oxocarbenium ion of
furfural (“furfuralium”) can also be accommodated by the cage.
The effect of protonation of the furfural in this way is also to
lower the LUMO (right hand side of Fig. 3) and hence render the
carbonyl moiety easier to reduce. There are distinct parallels
of this reaction. Between 10 and 15% of the furfural starting
material could be recovered aer 6 h of reaction in the presence
of cage. The remaining 20% or so of furfural that was neither
converted to furfuryl alcohol nor recovered unchanged is
probably consumed in reaction with the imine ligands of the
here with acid catalysis of carbonyl reduction in bulk solution, cage, as suggested by LCMS analysis of the aqueous (cage-
where the effect of protonation is to withdraw electron density containing) phase aer reaction (see ESI, Fig. S9†). Competi-
from the carbonyl moiety, rendering nucleophilic attack more tive inhibition by the furfuryl alcohol product does not appear
facile. Indeed, reductions of aldehydes to the corresponding
to be a contributor to the less than quantitative conversion of
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Table 1 Isolated yields of various alcohols obtained by the reduction of their corresponding aldehydes with NaCNBH3 in the presence and
absence of 9 mol% cage
Yield (9 mol%
cage)
Yield (no
cage)
Entry
Substrate
Product
1
2
65 ꢀ 1%
51 ꢀ 2%
4 ꢀ 1%
3 ꢀ 1%
3
4
62 ꢀ 4%
51 ꢀ 1%
7 ꢀ 2%
4 ꢀ 1%
5
6
7
8
9
60 ꢀ 5%
43 ꢀ 3%
52 ꢀ 5%
39 ꢀ 3%
60 ꢀ 2%
24 ꢀ 2%
6 ꢀ 1%
7 ꢀ 1%
2 ꢀ 1%
10 ꢀ 2%
10
11
63 ꢀ 2%
66 ꢀ 2%
12 ꢀ 1%
6 ꢀ 1%
12
27 ꢀ 1%
7 ꢀ 1%
furfural in this case: Fig. S10 (ESI†) suggests that furfuryl 9 mol% of the cage). These data can be compared to those ob-
alcohol binds very weakly inside the cage under these condi- tained under otherwise identical conditions but in the absence
tions, and so should be readily displaced by furfural.
of cage (red line and circles), and a comparison of the initial
Fig. 4 (black line) shows how the isolated yield of furfuryl rates of reaction suggests a 10-fold acceleration of the rate of
alcohol varies with reaction time (again in the presence of 1 reaction in the presence of cage. The data in Fig. 4 were ob-
ꢃ
equivalent of NaCNBH3 relative to furfural at 50 C, and using tained by stopping
a
standard reaction procedure (see
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and the reaction stirred at 50 ꢃC for 2 hours. The yield of furfuryl
alcohol from this reaction was found to be only 25–30%,
whereas an experiment run under otherwise identical condi-
tions but without an initial incubation of the cage with benzene
typically yielded ꢄ50% furfuryl alcohol over the same time
period (Fig. 4). Hence the presence of a competing guest for the
cage does indeed seem to retard the reduction of furfural,
further suggesting that the catalysis is occurring inside the cage.
Table 1 then shows that catalysis of aromatic aldehyde
hydrogenation with this cage appears to be a general phenom-
enon; eleven further aldehydes as listed convert to their corre-
sponding alcohols signicantly more rapidly when using the
cage as a catalyst compared to when no cage is present. The data
in Table 1 suggest that increased steric bulk leads to poorer
conversion of the aldehyde to its corresponding alcohol
(compare entries 1 and 2, and entries 3, 6 and 8), which is
consistent with increased sterics disfavouring encapsulation
within the cage. Indeed, the length of p-tert-butylbenzaldehyde
(entry 12) exceeds the interior dimension of the cage and shows
considerably lower yields compared to the other aldehydes
employed. DFT calculations (ESI, Fig. S8†), suggest that
although an entire molecule of p-tert-butylbenzaldehyde cannot
t inside the cage, it is possible for the aldehyde group on this
molecule to poke into the cage cavity through one of the
triangular openings in the wall of the cage. This would account
for the fact that conversion of p-tert-butylbenzaldehyde to its
corresponding alcohol is enhanced by the cage, but to a much
lesser extent than for the smaller aldehydes that are a better t
within the cage cavity. It is also noteworthy that conversions of
all the aldehydes mentioned in Table 1 occur much faster at
slightly elevated temperatures (50 ꢃC) than they do at room
temperature. For example, under identical conditions to those
reported in Table 1, but at room temperature (298 K), the yield
of 4-methylbenzyl alcohol (from the reduction of p-tolualde-
hyde) was 2% (ꢀ1%), whilst the yield of methyl 4-tert-butyl-
benzyl alcohol (from p-tert-butylbenzaldehyde) was 7% (ꢀ1%).
This fact is also consistent with a mechanism whereby the
improved exibility (and perhaps also uxionality) of the cage at
elevated temperatures allows some of the bulkier compounds
listed in Table 1 to encapsulate (or partially encapsulate) inside
the cage, and hence convert more readily to their corresponding
aldehydes. Experimental evidence for the interaction of p-tert-
butylbenzaldehyde (the largest entry in Table 1 by volume) and
p-tolualdehyde (entry 8, of intermediate volume between
furfural and p-tert-butylbenzaldehyde) with the cage is provided
Fig. 4 Yields of furfuryl alcohol vs. time in the presence of 9 mol%
cage (black line and squares) or in the absence of cage (red line and
circles). Yields in the presence of cage are isolated yields. Yields in the
absence of cage were determined by 1H NMR and are likely to be slight
overestimates of the amount of furfuryl alcohol produced.
Experimental section) aer the time periods indicated and
extracting the reaction mixture as per the standard procedure.
1
In situ monitoring of reaction progress by H NMR tended to
give less reliable data, as certain cage peaks overlap with those
of the products. Moreover, Fig. S11 (ESI†) shows that adding
a further equivalent of both furfural and NaCNBH3 to an
ongoing catalytic reaction at t ¼ 6 h leads to an additional two
catalytic turnovers of the cage. As competitive inhibition by the
product is minimal in this case (see above), we attribute the
drop-off in yields during this second cycle to cage decomposi-
tion through the pathways suggested in Fig. S9.† Alternatively,
the Fe4L6 cage can be recovered from the aqueous phase aer
a single catalytic run (see Fig. S11 and associated discussion in
the ESI†) and can then be re-used in catalytic experiments
(albeit delivering lower conversion rates compared to fresh
cage, most probably due to some decomposition of the cage).
Taken together, these data suggest that the cage can, at least to
some extent, be recycled and re-used for more than one catalytic
reaction, preforming multiple turnovers in each experiment.
A further set of controls was undertaken in order to show
that the specic supramolecular architecture of the cage is
essential for aldehyde reduction, and that the catalysis is not
mediated by the subcomponents of the cage. Hence, when the
simple salt FeSO4 (0.36 equiv. relative to furfural) was used in
place of the cage, the conversion of furfural to furfuryl alcohol
was only ꢄ5% (the same as for the reaction in the absence of
cage; Table 1, entry 1). Meanwhile, if a complex mimicking
1
ꢃ
by H NMR spectroscopy at 50 C (ESI, Fig. S24 and S25†). In
both cases, addition of the guest aldehyde to the cage leads to
signicant broadening of the 1H NMR signals corresponding to
both the cage and the guest, consistent with an intermediate
rate of exchange of the guest in and out of the cage on the NMR
timescale as previously reported by Nitschke and co-workers for
the binding of guests within a range of FeI4IL6 cages.30
a single vertex of the cage (reported previously by Salles et al.24a
)
was used in place of the cage, then the yield of furfural alcohol
aer 6 h at 50 ꢃC was only 10%, even in the presence of 40 mol%
of this vertex complex. A competitive inhibition study was also
undertaken using benzene, which Nitschke and co-workers
have previously shown to be an excellent guest for this cage.5c
Hence, 0.09 equivalents of cage were incubated in D2O for an
hour with 1 equivalent of benzene. Aer this time, 1 equivalent
of furfural was added and the incubation continued for
a further hour. Finally, one equivalent of NaCNBH3 was added
Attempts at using still more bulky aldehydes (namely 9-
anthracenecarboxaldehyde, 3,5-di-tert-butylbenzaldehyde, 4-
(diphenylamino)benzaldehyde
and
3,5-di-tert-butyl-2-
hydroxybenzaldehyde, all which might have been expected to
be completely excluded from the cage on steric grounds) were
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unsuccessful, as none of these aldehydes are water-soluble to
any signicant degree. Therefore, there was no conversion of
these aldehydes in either the presence or absence of cage. In
contrast, all the aldehydes shown in Table 1 exhibit at least
partial water solubility, allowing these species to dissolve in
bulk solution and thus gain access to the cage cavity. Electron-
withdrawing substituents (entries 5, 9 and 10) tend to give rise
to greater conversion to the alcohol than is evident with
electron-donating substituents (entries 2, 4, 7 and 8). These
results are consistent with nucleophilic hydride attack at the
carbonyl carbon, and the same trend can be observed both with
and without cage. However, the extent of conversion is always
signicantly better when cage is present.
In order to probe the selectivity of the cage further, a series of
reactions were performed involving other potentially reducible
chemical moieties, as well as mixtures of aldehydes. Hence,
entries 9 and 10 in Table 1 show that when only one equivalent
of NaCNBH3 is used, only the aldehyde is reduced and that
there is no detectable competitive reduction of the ketone or
ester moieties under these conditions. Meanwhile, a competi-
tion experiment between one equivalent of p-chlor-
obenzaldehyde and (much bulkier) p-tert-butylbenzaldehyde in
the presence of only one equivalent of NaCNBH3 and 9 mol%
cage leads to a 60% yield of p-chlorobenzyl alcohol and only
a 13% yield of p-tert-butylbenzyl alcohol. This compares to a 7%
yield of both alcohol products aer 6 h when the same
competition experiment is run in the absence of cage. These
Fig. 5 Yields of 4-methylbenzyl alcohol vs. pH in the presence of
9 mol% cage (orange points and line) or in the absence of cage (blue
points and line). All yields are isolated yields after 6 h of reaction under
the conditions reported in the Experimental section.
effectively increasing the basicity of the encapsulated substrate
by around 5 pKa units under neutral conditions (compare the
yields obtained with and without cage at pH 7 and pH 2
respectively). Again, alteration of substrate basicities as a func-
tion of binding in order to enhance a reaction that would
otherwise not take place in bulk solution is a strategy oen
employed by enzymes.
results suggest that the cage cavity provides a microenviron- Conclusions
ment that can bias relative product distributions away from
In summary, we have shown that a variety of aromatic aldehyde
those observed in the absence of cage. Moreover, the yield of p-
tert-butylbenzyl alcohol is halved in this cage-containing
competition reaction, relative to its value when p-tert-butyl-
benzaldehyde is reduced in the presence of cage but without any
competitor substrate. The implication is that the cage not only
enhances the extent of aldehyde reduction, but that it can also
impose some selection on the reaction outcome by preferen-
tially catalysing the reduction of those aldehydes that t more
easily inside the cage. Such size-selective catalysis is reminis-
cent of the mode of action of natural enzymes.
substrates can be reduced to their corresponding alcohols in
good yields using the mild reducing agent NaCNBH3 as
a hydride source and using Nitschke's Fe4L6 cage as an enzyme-
like catalyst. In the absence of cage, reduction of the aldehydes
is limited. 1H and NOESY NMR spectroscopy, DFT calculations,
control reactions with sub-components of the cage and
competition reactions all suggest that catalysis occurs inside
the cage. Complete selectivity for aldehyde reduction (over the
reduction of ketones and esters) is observed. Meanwhile,
computational analysis and pH-dependency studies suggest
that the reason for the enhanced reactivity in the presence of
cage is the stabilisation of protonated oxocarbenium ions inside
the cage, which activates the encapsulated species to nucleo-
philic attack. Work to expand the scope of these studies (in
particular, target reactions, type of cage catalyst and alternative
reaction conditions) is currently ongoing in our laboratories.
Finally, some direct evidence in support of stabilisation of
protonated intermediates as the mechanism for the enhanced
reactivity for aldehyde reduction in the presence of the anionic
Fe4L6 cage was obtained. Fig. 5 shows the effect that altering the
pH of the bulk solution has on the yield of 4-methylbenzyl
alcohol (from tolualdehyde, both of which have methyl groups
1
which are readily-discernable by H NMR spectroscopy, aiding
analysis) under the standard reaction conditions reported in the
Experimental section in the presence and absence of cage.
When cage is present, a clear trend is observed whereby the
yield increases in a linear fashion as the pH of the bulk solution
Experimental section
Typical procedure
is varied between 12 and 4 (pH lower than 4 was not probed as 100 mg (0.027 mmol, 0.09 equiv.) of the [Fe4L6] cage21 (as the
the cage is known to be unstable under acidic conditions21). tetramethylammonium salt) was weighed into a 14 mL vial with
This stands in contrast to the reaction yields in the absence of a small magnetic stir-bar. The vial was closed with a rubber
cage, which are essentially basal until pH 4, aer which there is septum and kept under nitrogen using Schlenk techniques.
a marked increase in yield with each successive reduction in Aldehyde (0.3 mmol, 1 equiv.) was added to the same vial (using
pH. The implication is that the cage is stabilising the proton- a micro-syringe for liquids) under a nitrogen atmosphere. 3 mL
ated form of the aldehyde in the basic and near-neutral regime, of degassed distilled water was then injected into the same vial
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under nitrogen, and the reaction mixture stirred for 1 h at 50 ꢃC.
Meanwhile, NaCNBH3 (0.3 mmol, 19 mg, 1 equiv.) was weighed
out inside a glove-box into a separate vial sealed with a rubber
septum. 2 mL of degassed distilled water was then injected into
this vial containing the NaCNBH3 under nitrogen. The aqueous
solution of NaCNBH3 was then transferred to the main reaction
vial under nitrogen. The reaction mixture was then kept stirring
for another 6 hours at 50 ꢃC inside the sealed vial. Aer this
time, the reaction mixture was allowed to cool down to room
temperature before extraction of the products with dichloro-
methane (4 ꢁ 20 mL). The organic layers were combined and
dried over MgSO4. The solvent was removed under reduced
pressure and the products were isolated by column chroma-
tography using diethyl ether/hexane mixtures as the eluents (the
ratio varied with the Rf values of the product; typically, 20–40%
diethyl ether in hexane was used). The solvents were then
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ꢃ
carefully removed under reduced pressure at 25 C and nally
the product was dried under high-vacuum with cooling (in
order to prevent any evaporation of the products). Character-
isation of all alcohol products is given in the ESI.† Control
reactions without cage were conducted in an entirely analogous
manner, save for the addition of cage. Under these standard
conditions, the pH of the reaction medium was 7. The pH could
be adjusted to other values by using sodium bicarbonate and/or
NaOH (to move more basic), or HCl or phosphoric acid (to move
to more acidic pH).
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Author contributions
AP, MAS and DYO performed the experiments and analysed the
data. SS performed the calculations. MDS conceived the project
and analysed experimental data. All authors contributed to the
writing of the manuscript.
Conflicts of interest
There are no conicts of interest to declare.
3 For selected reviews of this topic, see: (a) D. Zhang,
A. Martinez and J.-P. Dutasta, Chem. Rev., 2017, 117, 4900–
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Acknowledgements
This project was supported by the EPSRC (EP/R020914/1). MDS
thanks the Royal Society for a University Research Fellowship
(UF150104) and DYO thanks the University of Glasgow and
EPSRC for a summer internship. The authors thank Diana
Castro and Jennifer Mathieson (University of Glasgow) for LC-
MS measurements, Andrew Monaghan (University of Glasgow)
for ESI-MS measurements, David Adam (University of Glasgow)
for assistance with the NOESY NMR experiments and Prof.
Graeme Cooke (University of Glasgow) for the use of the Cooke
group glovebox for the storage of starting materials. The data
which underpin this work are available at DOI: 10.5525/
gla.researchdata.1124 and are licensed CC BY 4.0.
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