Oxidative kinetic self-sorting of a dynamic imine library

Article abstract of DOI:10.1021/ja109754t

Dynamic libraries of [n × n] imine components spontaneously simplify during a slow oxidation reaction to produce only n discrete products. The selectivity of this self-sorting process is a consequence of different oxidation rates for various imines, while the dynamic nature of the library enables self-sorting to proceed with high efficiency.

Full text of DOI:10.1021/ja109754t

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Oxidative Kinetic Self-Sorting of a Dynamic Imine Library
ꢀ
Karolina Osowska and Ognjen S. Miljani ꢁc *
Department of Chemistry, University of Houston, 136 Fleming Building, Houston, Texas 77204-5003, United States
S Supporting Information
b
Scheme 1. Response of an Equilibrating [2 Â 2] Mixture to
an Irreversible Removal of One of Its Components
ABSTRACT: Dynamic libraries of [n  n] imine compo-
nents spontaneously simplify during a slow oxidation reac-
tion to produce only n discrete products. The selectivity of
this self-sorting process is a consequence of different oxida-
tion rates for various imines, while the dynamic nature of the
library enables self-sorting to proceed with high efficiency.
ature continues to astonish chemists with its complex
isolated, even though two other compounds with competing
reactivity originally existed in the mixture.
We tested this hypothesis on a well-documented synthesis
N
functional architectures that are constructed with absolute
1
selectivity and without any purification or protecting-group
2
3
manipulation. Such exquisite control of chemoselectivity is
largely enabled by the simultaneous operation of numerous self-
of benzoxazoles and benzimidazoles by oxidative cyclization of
12
aldimines derived from o-hydroxy- and o-aminoanilines, re-
4
sorting processes wherein the components of a metabolic path-
spectively. We chose this reaction because (a) the intermediate
aldimines are formed reversibly, (b) the oxidation step is irrevers-
ible, and (c) the rates of oxidation can be modulated by substitu-
tion. In an exemplary one-pot reaction (Scheme 2, route A), 1,2-
diaminobenzene (3) and benzaldehyde (5) reacted to first form
way selectively recognize each other within a highly complex
cellular environment. Self-sorting spontaneously introduces or-
der into complex systems by reducing them into a set of simpler
subsystems that communicate but do not interfere with each
other. Chemists are increasingly interested in modeling and rep-
licating the behaviors of biological self-sorting systems through
imine 6. Addition of I as the oxidant converted the intermediate
2
imine into benzimidazole 8 in 90% yield. The analogous reaction
of 2-aminophenol (4) gave benzoxazole 9 (86%) without the
need to isolate imine 7.
5
the preparation of their synthetic counterparts.
High-fidelity synthetic self-sorting must have an error-correc-
tion mechanism, which is most commonly based on the rever-
The first imine mixture capable of rudimentary self-sorting
was generated by exposing 3 to imine 10 derived from benzyl-
amine (Scheme 2, route B). Equilibration produced a mixture
4
a-4d,6
sibility of the formation of noncovalent
or dynamically
4
e,4f,7,8
covalent
are thermodynamically driven,
assemblies are the most stable state of the system. Far less
bonds. Most of the reported self-sorting systems
4,6a-6f,7
1
meaning that the resultant
containing 3, 6, 10, and benzylamine (as determined by H NMR
spectroscopic analysis). Addition of I initiated the oxidation of 6
2
6g-6i,9
common are kinetically self-sorting systems,
wherein the
into 8. As 6 was consumed, 3 and 10 re-equilibrated to keep a
steady supply of 6 until all of 3 was exhausted. The final product
mixture contained only benzylamine and 8, which was obtained
in 90% yield after separation. In a separate experiment, 4 and 10
were converted into 9 in 84% yield. In effect, amines 3 and 4,
which can produce oxidizable imines, extracted benzaldehyde
out of its nonoxidizable imine 10. The yields of this indirect
route to 8 and 9 were as high as those obtained in the direct
oxidation.
product formation rates determine the outcome of self-sorting.
Kinetically self-sorting systems are arguably more relevant mod-
10
els for biological processes that operate far from equilibrium.
In this communication, we present kinetic self-sorting of a
8
dynamic library of imines that occurs during a slow irreversible
oxidation. Our work is based on a hypothesis directly derived
11
from the well-known Curtin-Hammett principle, namely that
a quickly equilibrating mixture will spontaneously simplify (self-sort)
if its components react at very different rates in a slow irreversible
reaction. This scenario is illustrated in Scheme 1.
Since imine 10 cannot be oxidized using I as the oxidant,
2
it cannot kinetically compete with 6 and 7. What happens if two
oxidizable imines compete for an oxidant? To answer this
question, 1 equiv of 5 was exposed to a 1:1 mixture of 3 and 4
(1.5 equiv of each). As expected, imines 6 and 7 formed after
overnight heating in PhMe. The Curtin-Hammett principle
stipulates that oxidation of this mixture could have different
outcomes depending on its rate. If imines are oxidized faster than
they exchange with each other, the final 8/9 ratio should be
The four compounds X, Y, 1, and 2 react in a reversible
reaction to establish a mixture of intermediates X1, X2, Y1, and
Y2 (X does not react with Y, and 1 does not react with 2).
If compound X1 reacts fastest in an irreversible reaction, the
mixture responds to its removal by re-equilibrating to produce
more of it. Effectively, X1 is amplified at the expense of its pre-
cursors X2 and Y1; the irreversible removal of X1 eventually
consumes all of X2 and Y1. The nonprecursor compound
Y2 remains unaffected by this process and could react further.
Ultimately, only the products derived from X1 and Y2 are
Received: October 29, 2010
Published: December 20, 2010
r 2010 American Chemical Society
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dx.doi.org/10.1021/ja109754t
|J. Am. Chem. Soc. 2011, 133, 724–727

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Scheme 2. Synthesis of Benzazoles by Oxidative Cyclization
of Directly (Route A) and Indirectly (Route B) Prepared
Imines
Scheme 4. Amine Selects the Most Electron-Rich Aldehyde
would seek the more electron-rich partner. As anticipated, all
four possible imines were formed in appreciable amounts and
could be readily identified in the mixture through the diagnostic
1
14
H NMR chemical shifts of their NdC-H protons. As the
slow oxidation of this mixture commenced, the most electron-
rich imine, 17, was oxidized first, affording benzimidazole 15. In
response to the depletion of 17 in the equilibrium mixture,
imines 16 and 19 started to disproportionate in order to
replenish the lost 17. Eventually, all of 16 and 19 were consumed
by this process, and the only species left in solution was the most
electron-poor imine, 18. Left to itself, 18 was oxidized after
1
3
similar to the equilibrium 6/7 ratio. On the other hand, if
oxidation is much slower than imine exchange, the more rapidly
oxidizing imine (presumably the more electron-rich 6) should
slowly “leak out” of the equilibrium mixture, causing the re-
equilibration to quickly replenish it. In such a situation, 8 should
be obtained in high yield as the product of the faster oxidation,
which was more desirable from a synthetic viewpoint. The use of
prolonged heating with I , generating 20. The final workup of
2
this one-pot reaction isolated only two products: 15 (82%) and
2
0 (76%). In effect, the [2 Â 2] mixture of imines self-sorted
during the oxidation, giving only two products that stemmed
from the oxidation of the most electron-rich and most electron-
poor imines.
1
equiv of I as the weak oxidant and its slow addition (via syringe
2
pump) ensured that the oxidation indeed proceeded more slowly
than imine exchange, and 8 was obtained as the only oxidation
product (70%) along with amine 4, which was recovered un-
Encouraged by the successful self-sorting of a [2Â2] mixture,
we increased the complexity to a [3Â3] mixture (Scheme 6). The
amines 3, 4, and 4-methoxyaniline (21) were combined with the
aldehydes 11, 14, and 2,4-dinitrobenzaldehyde (22). Overnight
heating of these six compounds generated all nine possible imine
combinations. Among these, six imines (those derived from 3
1
changed (Scheme 3). No 9 was detected by H NMR spectroscopy.
Scheme 3. Aldehyde Selects the More Electron-Rich Amine
and 4 but not 21) were oxidizable by I . The first equivalent of
2
iodine oxidized the most electron-rich imine, 17, to give 15. The
second oxidation proceeded at a slightly higher temperature to
provide 23. Finally, the only compound that remained in the
mixture was the nonoxidizable imine 24 composed of 21 and the
most electron-poor aldehyde, 22. Workup of the reaction
mixture isolated only 15 (88%), 23 (76%), and 24 (65%).
The use of I as a weak oxidant was essential in these self-
2
sorting protocols. Analogous reactions with a stronger oxidant
(
bromanil or DDQ) led to much poorer selectivities and partial
oxidation of electron-rich amines 3 and 4. Iodine also has its
limitations, as it cannot oxidize imines that are very electron-poor.
Thus, the oxidative self-sorting operates in the region between the
extremes of fast (and unselective) oxidation and no oxidation at all.
Finally, to establish the preliminary limitations of the selec-
tivity of the self-sorting process, we performed 17 competition
experiments involving different pairs of aldehydes in combina-
tion with amine 3 (Table 1). In general, the benzimidazole
derived from the more electron-rich aldehyde dominated, but the
selectivities were lower than intuitively expected. Most surpris-
ingly, in a competition experiment (marked with a *) involving
13 and 4-methoxybenzaldehyde (25), the major product came
from the more electron-poor aldehyde, 13. Oxidation rates
depend not only on rate constants but also on the relative
An analogous result was obtained in an experiment in which
five aldehydes with various electron densities competed for one
amine. Exposure of a mixture of 5 and 11-14 (1 equiv of each)
to 1 equiv of 3 (Scheme 4) led to the partial formation of five
intermediate imines. The slow oxidation of this mixture exclu-
sively generated (76%) benzimidazole 15 derived from reaction
of 3 with 14, the most electron-rich aldehyde in the mixture.
Aldehydes 5 and 11-13 were recovered unreacted, even though
theyall transientlyformedimines duringthe course ofthe reaction.
Next, we constructed a [2Â2] system by combining amines 3
and 4 with aldehydes 13 and 14 (Scheme 5). In this double-
selection mixture, both the amine and aldehyde components
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Scheme 5. Oxidative Self-Sorting of a [2 Â 2] Mixture of
Table 1. Selectivity in Imine Oxidations Evaluated by Pair-
wise Comparisons of Different Aldehydes
1
a
Imines: Shown in the Center Are the Composition and the H
NMR Spectrum of the Intermediate Mixture of Imines before
Oxidation Was Initiated; All Four Possible Imines Were
Evident by Their NdC-H Protons
a
1
The table shows ratios of the relative H NMR yields of the
benzimidazole substituted with R (first number, black) to the benzi-
midazole substituted with R (second number, blue). For each benzi-
1
2
midazole in the table, the number in parentheses indicates the precursor
aldehyde. The * indicates the competition experiment involving 13 and
2
5 that was mentioned in the text.
Scheme 6. Oxidative Self-Sorting of a [3 Â 3] Mixture of
Imines
1
indicated by H NMR spectroscopic analysis), its oxidation
proceeded faster despite the presumably lower rate constant.
1
5
This thermodynamic preference for certain imines and the fact
that imines form and exchange at rates that strongly depend on
their structures add two further levels of complexity to the
phenomenon of oxidative kinetic self-sorting of imines. We are
currently exploring the possibility of sequential self-sorting based
on these additional facets of imine reactivity.
In conclusion, we have demonstrated an example of self-
sorting of a dynamic imine mixture during the course of a slow
irreversible oxidation. The self-sorting is kinetically driven in that
the final product ratios are determined by the corresponding
rates of formation, and it is thermodynamically enabled because
high-yielding formation of individual benzazoles would not have
occurred were it not for the free equilibration of the underlying
mixture of imine precursors. The phenomenon of kinetic self-
sorting should be general for all slow irreversible reactions of
imines as well as other dynamic covalent systems. We are pres-
ently working on demonstrating kinetic self-sorting in imine
reductions and Diels-Alder reactions.
’
ASSOCIATED CONTENT
S
Supporting Information. Synthetic details and charac-
b
concentrations of the two competing imines: as the imine derived
from 13 was favored at equilibrium to the tune of ∼20:1 (as
terization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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’
and Ecology; Bonchev, D., Rouvray, D. H., Eds.; Springer: New York,
2
005.
11) (a) Curtin, D. Y. Rec. Chem. Prog. 1954, 15, 111. (b) Seeman,
J. I. Chem. Rev. 1983, 83, 83. (c) Seeman, J. I. J. Chem. Educ. 1986, 63, 42.
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Corresponding Author
miljanic@uh.edu
(
(
2
006, 35, 460. (b) Ponnala, S.; Sahu, D. P. Synth. Commun. 2006, 36,
’
ACKNOWLEDGMENT
2189.
(
13) In fact, a fast irreversible reaction is often used to “trap” an
We thank Ms. Jovana Mili ꢁc for insightful discussions. This
equilibrating mixture before analysis without disturbing the component
ratios.
(
NMR spectrum in Scheme 5. Amine 3 is capable of forming double
imines with either of the aldehydes, and some imines exist in their closed
benzimidazoline and benzoxazoline forms (not shown).
research was financially supported by the donors of the American
Chemical Society Petroleum Research Fund (ACS-PRF), the
University of Houston (UH) and its Grant to Advance and
Enhance Research, the Texas Center for Superconductivity at
UH, and the Institute for Space Systems Operations. K.O.
acknowledges Drs. Joan and Herman Suit for the Eby Nell
McElrath Postdoctoral Fellowship.
1
14) The situation is slightly more complex than suggested by the H
(15) The opposing influences of imine stability (which favors
donor-acceptor combinations of constituent amines and aldehydes)
and rate of oxidation (which favors donor-donor combinations)
suggest that the outcome of oxidation should depend on the rate of
addition of I . Indeed, when I was added very slowly (over 120 h), the
’
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