Three-Way Chemoselectivity Switching through Coupled Equilibria

Article abstract of DOI:10.1021/acs.orglett.0c02003

Controlling the chemoselectivity of reactions operating on complex mixtures, including those found in biological and petrochemical feedstocks or in the primordial soup from which life emerged, is generally challenging. The selectivity of imine oxidation c

Full text of DOI:10.1021/acs.orglett.0c02003

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Three-Way Chemoselectivity Switching through Coupled Equilibria
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Thamon Puangsamlee and Ognjen S. Miljanic*
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ABSTRACT: Controlling the chemoselectivity of reactions operating on complex mixtures, including those found in biological and
petrochemical feedstocks or in the primordial soup from which life emerged, is generally challenging. The selectivity of imine
oxidation can be controlled in dynamic combinatorial libraries, wherein coupled equilibria of imine exchange and the diaza-Cope
rearrangement determine whether and when the oxidizable precursor is made available to the oxidant. Adjusting the rate of oxidant
addition allows the isolation of three dominant products.
ontrol of chemoselectivity is among the central problems
Curtin−Hammett principle,12 which implies a much faster rate
of the DCL equilibration compared with the irreversible
removal reaction. In such a scenario, relative stabilities of
different imines have no bearing on the final reaction products:
it is only the relative rates of that irreversible reaction that
determine the chemoselectivity. In this study, we manipulated
these relative reaction rates, breaking down the Curtin−
Hammett selectivity but, in turn, revealing a rich reactivity
landscape wherein products can be selected by adjusting the
rate of the irreversible removal.
Imines formed from 1,2-phenylenediamine (3, Scheme 1)
and aromatic aldehydes can be oxidized into corresponding
benzimidazoles using iodine (I2). This oxidation is faster for
imines formed from electron-rich aldehydes than for those
derived from electron-poor precursors. During our studies of
the oxidative self-sorting of imines,13 we noticed that the
product distribution could additionally be influenced by the
rate of oxidant addition. The reaction of equimolar amounts of
4-nitrobenzaldehyde (1), 4-methoxybenzaldehyde (2), and 3
generated a mixture of imines 4 and 5 with some leftover
aldehydes. When this mixture was treated with I2, the imines
were oxidized into benzimidazoles 6 and 7. If I2 was added very
slowly, over 120 h, then the methoxy-substituted 6 constituted
87% of the product mixture. On the contrary, instantaneous
1
Cof synthetic chemistry.
Its ramifications range from
solving the mysteries of prebiotic chemistry2 to improving the
efficiencies of separations and functionalizations of feedstocks
derived from complex petroleum and biomass sources. For a
given set of reactants, the reaction outcome is controlled by
thermodynamic and kinetic factors. Often, they work hand-in-
hand: the most stable reaction products also form the fastest.
Sometimes, they do not, and such reactions can express either
their kinetic (fastest formed) or thermodynamic (most stable)
products. Are these two extremes the only options? In this
Letter,3 we show that they are not: In a complex mixture of
equilibrating precursors, the final reaction product can be
switched at will by changing the rate of reagent addition. The
key to this behavior is the use of coupled equilibria, in which
the products of one reversible reaction act as the substrates for
another. Coupled equilibria phenomena4 have vast relevance
to pollution, climate change,5 ocean acidification,6 and
metabolic pathways.7 Complex coupled equilibria often give
rise to systems-level and emergent phenomena.8
Our studies of irreversible reactions operating on imine
dynamic combinatorial libraries (DCLs)9 have shown that
such “messy” precursor mixtures can still be chemoselectively
functionalized. As one DCL component reacts the fastest in an
irreversible reaction, other library members equilibrate to
produce more of it. The net result is the high-yielding
functionalization of the most reactive DCL member, which is
amplified at the expense of the less reactive members.10
Applied iteratively, such amplification leads to kinetic self-
sorting11 of the DCL into just a handful of fast-reacting
components. Self-sorting hinges on the applicability of the
Received: June 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02003
© XXXX American Chemical Society
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Scheme 1. Oxidation of a Mixture of Imines 4 and 5
Produces 6 and 7 in a Ratio Dependent on the Rate of the I2
Addition
Scheme 3. Selectivity Switching in Imine Oxidation as a
Function of Substitution and I2 Addition Rate
Scheme 2. Oxidation of a Mixture of 3, 8, and 9 Generates
12 and 13 in a Ratio That Is Dependent on the Rate of I2
a
Addition
quick, then it captures this composition of imine precursor
mixture in the ratio of benzimidazole products. However, if the
oxidation is very slow, then the dynamic mixture can
continuously replenish the electron-rich 5 that is being
consumed by its faster oxidation. Slower to oxidize, 4 releases
its 1,2-phenylenediamine component to create more of 5, and
the product distribution switches.
Intrigued by this result, we set out to determine whether
such selectivity switching could be further controlled. To do
so, we devised a dynamic system that operates using two
reversible reactions: imine exchange and the diaza-Cope
rearrangement of diimines of the general structural type 8
14
(Scheme 2). Vogtle and others15 have shown that the diaza-
̈
Cope equilibrium favors imines derived from salicylaldehyde
(such as 8) over their rearranged isomers (such as 9) on
account of their greater stabilization by [N···H−O] hydrogen
bonding. This equilibrium position means that the salicylalde-
hyde component (highlighted in red, Scheme 2) can be
directly exchanged from its imine 8 by a reaction with 3 to
produce the oxidizable imine 10. The more electron-rich 2,4-
dimethoxybenzaldehyde (highlighted in blue) cannot directly
engage in an oxidation. Instead, 8 must first undergo diaza-
Cope rearrangement into the less favored isomer 9, and only
then can 9 exchange with 3 to produce the oxidizable imine 11.
a
In the top part, the horizontal arrows show the diaza-Cope
rearrangement, and the vertical arrows show the imine exchange.
(<2 min) I2 addition resulted in 7 as the dominant product
(76%). This selectivity switching could be explained as follows.
The intermediate imine mixture has more of the nitro-
substituted 4: its push−pull electronic nature means it is both
more stable and more quickly formed than 5. If the oxidation is
B
https://dx.doi.org/10.1021/acs.orglett.0c02003
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Scheme 4. Three-Way Switching of Chemoselectivity in Imine Oxidation as a Function of I2 Addition Rate
Thus being once-removed from the immediate exchange, the
2,4-dimethoxybenzaldehyde component must traverse a longer
reaction pathway to engage in an oxidation and may not have
enough time to do so if the oxidation is too fast. Indeed, I2 (2
equiv vs 8) addition in 1 min effectively generated only the
benzimidazole 12 derived from salicylaldehyde (98:2 selectiv-
ity over 13 based on NMR yields determined using 1,3,5-
trimethoxybenzene as the internal standard). As the I2 addition
was slowed down, 2,4-dimethoxybenzaldehyde had enough
time to travel across the shallow energy landscape, and the
molar fraction of its oxidation product 13 in the final product
mixture increased to 25, 59, and finally 76% if I2 was added
over 2, 6, or 120 h, respectively.
To establish whether this selectivity switching is general, we
examined several other diimines analogous to 8 and 9, which
related to each other through diaza-Cope rearrangement
(Scheme 3).16 Salicylaldimines 14a−e were preferred over
their rearranged isomers 15a−e regardless of the substituents
R. The addition of 3 once again initiated the increase in the
complexity of this dynamic mixture, as imines 10 and 16a−d/4
could now be formed, along with partially exchanged species
not shown in Scheme 3. Iodine addition then began (2 equiv
relative to 14a−e). As in the previous experiment, the
outcomes of these reactions were dependent on the rate of
I2 addition, but this dependence varied based on the
substitution in the starting imines 14/15. In the parent system
14a/15a (R = H), slower addition mildly increased the ratio of
product 17a to product 12, switching from a relative ratio of
1:4.47 to 1:3.29. Selectivity switching observed in Scheme 2
was replicated with the 14b/15b (R = Me) couple; the
benzimidazole obtained from the electron-rich 16b dominated
the product mixture under slow addition conditions, whereas
12 was the main product if I2 was added instantaneously. In
compounds 14c/15c, the result was puzzling: the significantly
more electron-rich para-N,N-dimethylamino substituted pre-
cursor failed to yield 17c as the dominant product even at long
addition times. A possible explanation for this aberration can
be found in the slowdown of the diaza-Cope rearrangement in
systems with electron-rich substituents.15a This slowing may
have effectively shut down the pre-equilibration, making the
imine library not dynamic anymore and making the product
ratio independent of the I2 addition rate. The example of 14d/
15d (R = Cl) offered another interesting conclusion. As
expected, 12 dominated under fast addition conditions, but the
switch to 17d as the major product with slower I2 addition was
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surprising at first glance. Tentatively, this behavior can be
rationalized as follows.
other simple reaction parameters: concentration, pressure, and
temperature. We believe that the use of coupled equilibria can
allow the virtual dialing-in of reactivity in highly complex
libraries.
The chlorine substituent in the para position is weakly
electron-withdrawing, with a Hammett parameter of +0.23.
Ortho substituents are generally not used in Hammett
correlations because of steric effects, but an OH group in a
meta position has a Hammett value close to that of para-Cl:
+0.12.17 Stated differently, the OH group influences the
electronics of precursor imines by its electron-donating
resonance effect but also as an electron-withdrawing inductive
acceptor. Finally, the electron-withdrawing NO2 group in 14e/
15e led to identical product mixtures regardless of the I2
addition rate: 12 was the only product, with no 6 observed in
either case. Nitro-substituted 4 oxidizes so much slower than
10 that allowing extra time for pre-equilibration did change the
amount of 6 produced.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02003.
Experimental procedures and copies of 1H NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
̌
Encouraged by the apparent ability to switch the product of
oxidation, we speculated that a three-way selectivity switching
may be possible as well. The experiments aimed at testing this
hypothesis exposed the diaza-Cope precursor 8 not to 1,2-
phenylenediamine (3) but instead to its imine with 4-
nitrobenzaldehyde (4). Three oxidation products could be
obtained from such a DCL (Scheme 4). With very fast oxidant
addition, imine 4 had no time to exchange with 8 or with the
minor amount of 9 formed by the diaza-Cope rearrangement
of 8 and simply oxidized into 6 (top two panels in Scheme 4).
If oxidation was slower (1−5 h), then the exchange between 8
and 4 initially generated 10, 18, and 19; imine 10 could then
be oxidized into 12 faster than the electron-poor imine 4 (third
panel in Scheme 4). The amounts of imines 11, 20, and 21
formed under these conditions were still quite small because of
the low initial concentration of their precursor 9, and 12
dominated the product mixture. No 6 was observed under
these conditions. Finally, if oxidant addition was slowed down
even further (6−120 h), then diaza-Cope rearrangement and
imine exchange had enough time to lead to a complete
explosion of complexity in this DCL. Starting with just 8 and 4
as starting materials, as many as 45 diaza-Cope rearranged
products could be formed, including completely scrambled
species such as 22 (bottom panel in Scheme 4). The most
electron-rich imine 11 was present in appreciable amounts
under these conditions, and its fast oxidation produced the
third possible product, benzimidazole 13. With the oxidant
added over 120 h, 13 was the major product, with 12
eventually forming just 7% of the product mixture (graph in
Scheme 4, table of yields given in the Supporting Information).
In conclusion, we have shown that the tuning of relative
rates of irreversible and reversible transformations in a DCL
can express a variety of its members, ranging from electron-rich
to electron-poor. This product selection was accomplished in
the absence of any enzyme or synthetic catalysts that could
impart selectivity, and the only parameter that changed was the
rate of oxidant addition. These results may offer insights into
processes in prebiotic chemistry: multiple components of the
“primordial soup” could have selectively reacted under
differing spatiotemporal conditions. We have also shown that
the diaza-Cope rearrangement can be used as a well-behaved
dynamic reaction, thus expanding the arsenal of dynamic
combinatorial chemistry.18 Our results suggest that in
sufficiently complex mixtures there may, in fact, exist a
continuum of products ranging from absolute thermodynamic
minima to a number of local minima, which can all be
addressed by fine-tuning the rates of reagent addition as well as
́
Ognjen S. Miljanic − Department of Chemistry, University of
Houston, Houston, Texas 77204-5003, United States;
orcid.org/0000-0002-7876-9034; Email: miljanic@uh.edu
Author
Thamon Puangsamlee − Department of Chemistry, University
of Houston, Houston, Texas 77204-5003, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02003
Author Contributions
T.P. performed all experiments and analyzed the results
̌
together with O.S.M. Both authors wrote the manuscript and
have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the support from the Welch Foundation
(award E-1768), the donors of the American Chemical Society
Petroleum Research Fund (award ND-58919), and the
̌
University of Houston. O.S.M. thanks the Alexander von
Humboldt Stiftung for supporting his summer stay at the
̈
Ruprecht-Karls-Universitat in Heidelberg (Germany), where
the ideas on which this manuscript is based were developed.
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