Self-sorting of dynamic imine libraries during distillation

Article abstract of DOI:10.1002/anie.201102813

Keep it simple: The reaction of n aldehydes with n amines leads to a dynamic library of [n× n] imines. Slow distillation of the library amplifies the most volatile imine, whereby the most volatile aldehyde and amine are extracted from all other library components. Iterative repetition of the process enabled the self-sorting of the dynamic library into n mechanically separated imines, which were obtained in high yield.

Full text of DOI:10.1002/anie.201102813

DOI: 10.1002/anie.201102813
Dynamic Covalent Chemistry
Self-Sorting of Dynamic Imine Libraries during Distillation**
ˇ
´
Karolina Osowska and Ognjen S. Miljanic*
Dedicated to Professor K. Peter C. Vollhardt on the occasion of his 65th birthday
Nature and chemists approach organic synthesis in very
different ways. Living systems are grand masters of parallel
synthesis: starting with incredibly complex precursor mix-
tures, highly specialized enzymes operate selectively, simulta-
neously, and orthogonally to create many different products
at once. In contrast, laboratory synthesis typically relies on
reagents and catalysts with broad scope and wide functional-
group tolerance; in this case, high-purity starting materials are
required for the sequential preparation of individual products.
Furthermore, undesirable reactivity often has to be blocked
by protecting groups.[1] In recent years, self-sorting[2] has
emerged as a promising preparative method that can enable
the simultaneous synthesis of high-purity products from
complex mixtures of starting materials. Self-sorting can be
defined as the spontaneous reorganization of a disordered
multicomponent system into a set of subsystems with fewer
components and greater order.[2d] In the absence of specific
enzyme catalysis, high fidelity of synthetic self-sorting is
ensured by efficient error-correction mechanisms, which use
the reversible formation of noncovalent and dynamic cova-
lent bonds[3] to continuously recycle side products as the
system heads towards equilibrium. Self-sorting processes can
proceed under thermodynamic[2,4,5] or kinetic[6] control. The
former processes are characterized by a self-sorted equilib-
rium state; the latter are less common and are typically
observed when a system is trapped in a self-sorted local
energetic minimum. We recently reported[7] a hybrid self-
sorting protocol in which components of a dynamic imine
mixture freely equilibrate (thermodynamic control), and sort
on the basis of the rates of their removal from equilibrium
through an irreversible reaction (kinetic control).
that the self-sorting of dynamic mixtures can occur concur-
rently with separation to produce multiple products that are
not only of high purity, but also mechanically separated.
Specifically, we show that vacuum distillation can be used to
sort complex libraries of [n ꢀ n] equilibrating imines (n ꢀ 5)
into n pure compounds simply on the basis of the volatility of
individual imines.
Imines are formed in a reversible reaction of an aldehyde
with an amine. When multiple imines are present in a
solution, they readily exchange their aldehyde and amine
constituents.[8] In any such equilibrating mixture, one imine
has the lowest boiling point. If that compound can be distilled
away selectively, its removal disturbs the equilibrium of the
system and thus forces other imines to reequilibrate and
produce more of the compound just removed—as dictated by
the Le Chꢁtelier principle. Provided that distillation is
sufficiently selective and slower than the imine exchange,[9]
the low-boiling imine will extract its constituent aldehyde and
amine from all other imines that contained them. In the
process, the low-boiling imine is produced in superior yield,
and the remaining equilibrating mixture is reduced in
complexity through the removal of both the low-boiling
imine and all its precursors. If such a sequence is repeated,
multiple species can be produced with a single distillation
setup.
We assessed the synthetic viability of this proposition in
an experiment which examined the behavior of a mixture
prepared from two aromatic aldehydes 1 and 2 and two
anilines A and B (Scheme 1). To ensure that the resulting
imines had significantly different boiling points, we chose
aldehydes and anilines of different molecular masses and
assumed that a higher mass would lead to a higher boiling
point. The heating of these four reactants under dehydrative
conditions produced a mixture of all possible imines: 1A, 2A,
1B, and 2B.[10] The most volatile of the four was 1A—the
product of the reaction of the lighter aldehyde with the lighter
aniline; conversely, the least volatile imine was the product
2B of the heavy–heavy combination. Vacuum distillation (90–
1158C, 0.10 mmHg) of this mixture began with the selective
removal of low-boiling 1A.[11] With the depletion of 1A, 2A
and 1B started decomposing to produce more of 1A;
eventually, these two compounds were completely consumed
in the process, and the only imine remaining in the distillation
flask was 2B. Compounds 1A (most volatile, light distillation
fraction) and 2B (least volatile, heavy distillation fraction)
were isolated in virtually quantitative yield (96 and 98%,
respectively) and in very high purities, as evidenced by
1H NMR spectroscopy (98 and 99%, respectively; see the
Supporting Information for details).[12] Three additional
higher-boiling [2 ꢀ 2] combinations (see the Supporting Infor-
The synthetic applicability of self-sorting is frequently
limited by the fact that all self-sorted species remain in the
same solution. The isolation of individual components
requires separation, which can be problematic in the case of
fragile supramolecular complexes. Herein, we demonstrate
ˇ
´
[*] Dr. K. Osowska, Prof. O. S. Miljanic
Department of Chemistry, University of Houston
Houston, TX 77204-5003 (USA)
E-mail: miljanic@uh.edu
Homepage: http://www.miljanicgroup.com
[**] This research was financially supported by the donors of the
American Chemical Society Petroleum Research Fund (ACS-PRF),
the Welch Foundation (grant no. E-1768), 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 Dr. Joan Suit and Dr.
Herman Suit for an Eby Nell McElrath Postdoctoral Fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102813.
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Scheme 1. Simplification of a [2ꢀ2] mixture of imines during the
course of a vacuum distillation.
Scheme 2. Simplification of a [3ꢀ3] mixture of imines during the
course of a vacuum distillation. For simplicity, imine structures are not
shown. Imine designators are a combination of the corresponding
designators for the constituent aldehyde and aniline; for example,
imine 2B is formed by the dehydrative coupling of 2 and B.
mation) were subjected to similar distillation conditions with
analogous results: the high-yielding production of the most
volatile and least volatile fractions, with virtually no evidence
of “crossed” products.
These encouraging results suggested to us that a more
complex mixture could be sorted in an analogous manner
during a distillation. A [3 ꢀ 3] imine mixture (Scheme 2) was
created from aldehydes 1–3 and anilines A–C. The most
volatile of the nine imines formed was 1A—the combination
of the lightest aldehyde and the lightest aniline. Its prefer-
ential removal from the mixture by distillation (110–1208C,
0.10 mmHg) caused the decomposition of its precursors 2A,
3A, 1B, and 1C. Once all of 1A had been distilled off (90%
yield, 98% purity), five imines—1A, 2A, 3A, 1B, and 1C—
had been removed from the mixture. In essence, the selective
distillation of 1A extracted the most volatile aldehyde 1 and
the most volatile aniline A out of all other imines that
contained them. Of the four imines that remained (2B, 3B,
2C, and 3C), compound 2B was the next most volatile. An
increased distillation temperature (1508C, 0.10 mmHg) ena-
bled its isolation in very high yield (94%, 100% purity) with
the concurrent elimination of 3B and 2C from the equilib-
rium mixture. Ultimately, the only compound remaining in
the distillation flask was the least volatile imine 3C, which was
isolated in 99% yield (89% purity). Two additional [3 ꢀ 3]
experiments were performed (see the Supporting Informa-
tion).
Next, we examined a [4 ꢀ 4] mixture (Scheme 3) produced
from aldehydes 2–5 and anilines B–E. 1H NMR spectroscopy
revealed the presence of at least 12 imines; overlapping peaks
probably obscured the presence of an even larger number of
species. According to the logic of the [2 ꢀ 2] and [3 ꢀ 3]
experiments, the distillation of this mixture produced, in this
order, 2B (88%), 3C (91%), 4D (77%), and 5E (85%). A
Scheme 3. Simplification of a [4ꢀ4] mixture of imines during the
course of a vacuum distillation. Imine designators are a combination
of the corresponding designators for the constituent aldehyde and
aniline.
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Scheme 4. Simplification of a [5ꢀ5] mixture of imines during the
course of a vacuum distillation. Imine designators are a combination
of the corresponding designators for the constituent aldehyde and
aniline.
second [4 ꢀ 4] experiment is described in the Supporting
Information.
In our most complex experiment, we constructed a [5 ꢀ 5]
library of presumably 25 imines (Scheme 4; the exact number
1
of imines could not be confirmed by H NMR spectroscopy
because of overlapping peaks) from aldehydes 1–5 and
anilines A–E. Again, imine 1A was distilled first (77%
yield, 96% purity as determined by NMR spectroscopy); in
the process, imines 2A, 3A, 4A, 5A, and 1B–E were all
eliminated from the equilibrium mixture. The second step of
the distillation saw the isolation of 2B (80% yield, 96%
purity) at the expense of 3B, 4B, 5B, and 2C–E. Imine 3C was
isolated third (80% yield, 99% purity), with the removal of
4C, 5C, 3D, and 3E. In the final step of the distillation, imine
4D (73% yield, 99% purity) was formed and distilled at the
expense of 5D and 4E. The residue in the distillation flask
was identified as 5E (80% yield, 83% purity). Effectively,
one reaction enabled us to access five compounds simulta-
neously, all in yields greater than 70%!
Figure 1 illustrates the typical purities of products
obtained from the distillative self-sorting of an exemplary
[4 ꢀ 4] mixture (discussed in Scheme 3): four isolated fractions
are essentially pure compounds, as evidenced by the segments
of their 1H NMR spectra in the bottom panel of Figure 1. As
could be expected, the final distillation residue (lowermost
spectrum, compound 5E) is the least pure fraction.
Figure 1. Top: Imine-diagnostic segment of the 1H NMR spectrum of
the crude mixture of imines obtained by the dehydrative heating of
aldehydes 2–5 with anilines B–E (Scheme 3). Bottom: The same
segment of the 1H NMR spectra of individual distillation fractions;
each spectrum indicates almost the exclusive presence of a single
In this hybrid self-sorting protocol, both kinetic and
thermodynamic factors play a role in the outcome of self-
sorting. Although evaporation rates determine which imines
will be isolated as the exclusive products, the underlying
thermodynamic equilibration is required to maximize the
yields of these products. In that respect, this distillative self-
sorting is conceptually similar to our recently reported self-
sorting of an imine mixture through an irreversible oxida-
tion.[7] The chief difference is in the method used to
irreversibly disturb the equilibrium and initiate a self-sorting
sequence: in the current study, a physical transformation
^
imine. “ ” denotes minor imine impurities.
(evaporation) is used, whereas we used a chemical stimulus
(oxidation) in our previous study. Taken together, these
results suggest that hybrid self-sorting should be very broadly
applicable.
The success of this self-sorting method sounds a cau-
tionary note about the use of separation techniques in the
analysis of dynamic combinatorial libraries (DCLs). Distil-
lation is clearly able to profoundly affect the composition of a
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dynamic library.[13] Our experiments were designed to max-
Wu, J. C. Fettinger, P. Y. Zavalij, L. Isaacs, J. Org. Chem. 2008,
73, 5915 – 5925; b) S. Liu, C. Ruspic, P. Mukhopadhyay, S.
Chakrabarti, P. Y. Zavalij, L. Isaacs, J. Am. Chem. Soc. 2005, 127,
15959 – 15967; c) A. Wu, L. Isaacs, J. Am. Chem. Soc. 2003, 125,
4831 – 4835; d) W. Jiang, Q. Wang, I. Linder, F. Klautzsch, C. A.
Schalley, Chem. Eur. J. 2011, 17, 2344 – 2348; e) W. Jiang, A.
Schꢂfer, P. C. Mohr, C. A. Schalley, J. Am. Chem. Soc. 2010, 132,
2309 – 2320, and references therein; f) M. Chas, G. Gil-Ramꢃrez,
E. C. Escudero-Adꢄn, J. Benet-Buchholz, P. Ballester, Org. Lett.
2010, 12, 1740 – 1743; g) N. Tomimasu, A. Kanaya, Y. Takashima,
H. Yamaguchi, A. Harada, J. Am. Chem. Soc. 2009, 131, 12339 –
12343; h) G. Celtek, M. Artar, O. A. Scherman, D. Tuncel,
Chem. Eur. J. 2009, 15, 10360 – 10363; i) D. Ajami, J.-L. Hou, T. J.
Dale, E. Barrett, J. Rebek, Jr., Proc. Natl. Acad. Sci. USA 2009,
106, 10430 – 10434; j) D. Braekers, C. Peters, A. Bogdan, Y.
Rudzevich, V. Bçhmer, J. F. Desreux, J. Org. Chem. 2008, 73,
701 – 706; k) F. Wang, C. Han, C. He, Q. Zhou, J. Zhang, C.
Wang, N. Li, F. Huang, J. Am. Chem. Soc. 2008, 130, 11254 –
11255; l) C. Burd, M. Weck, Macromolecules 2005, 38, 7225 –
7230.
imize these effects, but changes in composition probably
occur during all separations of DCLs, as any separation
creates an open system that begins to move away from the
established equilibrium. Thus, the use of HPLC, GC/MS, and
other separation-coupled analysis techniques should be
accompanied by the independent verification of library
composition through, for example, purely spectroscopic
techniques, which are unlikely to significantly affect product
distribution.
We believe that our study may have industrial relevance.
Within the past two decades, some of the most significant
reductions in construction and energy costs in the chemical
industry have been achieved through reactive distillation
plants,[14] which use distillation both as a separation technique
and as an equilibrium-driving force that ensures full con-
version of precursors. Esters are among the hundreds of
chemicals produced by this method;[14b] reactive distillation
drives their formation from carboxylic acid and alcohol
precursors. Since transesterification is a dynamic reaction,[5k]
largely parallel to imine exchange, our protocol should enable
the equilibration and distillative self-sorting of a mixture of
esters. Could a mixture of several carboxylic acids and
alcohols be used for the production of many different esters
in a single reactor and their self-sorting by distillation into a
handful of high-purity products? Current studies in our group
are focused on answering this question and on the combina-
tion of chemical and physical self-sorting methods into
sequences which could exponentially simplify complex pre-
cursor mixtures.
[5] For selected examples of thermodynamically controlled self-
sorting based on dynamic covalent and metal–ligand bonds, see:
a) R. J. Sarma, J. R. Nitschke, Angew. Chem. 2008, 120, 383 –
386; Angew. Chem. Int. Ed. 2008, 47, 377 – 380; b) D. Schultz,
J. R. Nitschke, Proc. Natl. Acad. Sci. USA 2005, 102, 11191 –
11195; c) M. Hutin, C. J. Cramer, L. Gagliardi, A. R. M. Shahi,
G. Bernardinelli, R. Cerny, J. R. Nitschke, J. Am. Chem. Soc.
2007, 129, 8774 – 8780; d) K. Mahata, M. L. Saha, M. Schmittel,
J. Am. Chem. Soc. 2010, 132, 15933 – 15935, and references
therein; e) B. Brusilowskij, E. V. Dzuyba, R. W. Troff, C. A.
Schalley, Chem. Commun. 2011, 47, 1830 – 1832; f) J.-M. Han, J.-
L. Pan, T. Lei, C. Liu, J. Pei, Chem. Eur. J. 2010, 16, 13850 –
13861; g) F. Dumitru, Y.-M. Legrand, A. van der Lee, M.
Barboiu, Chem. Commun. 2009, 2667 – 2669; h) J.-B. Lin, X.-N.
Xu, X.-K. Jiang, Z.-T. Li, J. Org. Chem. 2008, 73, 9403 – 9410; i) I.
Saur, R. Scopelliti, K. Severin, Chem. Eur. J. 2006, 12, 1058 –
1066; j) R. Krꢂmer, J.-M. Lehn, A. Marquis-Rigault, Proc. Natl.
Acad. Sci. USA 1993, 90, 5394 – 5398; k) S. J. Rowan, D. G.
Hamilton, P. A. Brady, J. K. M. Sanders, J. Am. Chem. Soc. 1997,
119, 2578 – 2579.
Received: April 22, 2011
Published online: July 15, 2011
Keywords: aldehydes · amines · chemoselectivity ·
.
dynamic covalent chemistry · equilibria
[6] For examples of kinetic self-sorting, see: a) E. Masson, X. Lu, X.
Ling, D. L. Patchell, Org. Lett. 2009, 11, 3798 – 3801; b) P.
Mukhopadhyay, P. Y. Zavalij, L. Isaacs, J. Am. Chem. Soc. 2006,
128, 14093 – 14102; c) X. Shi, J. C. Fettinger, M. Cai, J. T. Davis,
Angew. Chem. 2000, 112, 3254 – 3257; Angew. Chem. Int. Ed.
2000, 39, 3124 – 3127; d) L. J. Prins, F. de Jong, P. Timmerman,
D. N. Reinhoudt, Nature 2000, 408, 181 – 184; e) L. J. Prins, J.
Huskens, F. de Jong, P. Timmerman, D. N. Reinhoudt, Nature
1999, 398, 498 – 502; f) E. Kassianidis, R. J. Pearson, E. A. Wood,
D. Philp, Faraday Discuss. 2010, 145, 235 – 254; g) R. Issac, J.
Chmielewski, J. Am. Chem. Soc. 2002, 124, 6808 – 6809; h) A.
Saghatelian, Y. Yokobayashi, K. Soltani, M. R. Ghadiri, Nature
2001, 409, 797 – 801; i) E. A. Wintner, M. M. Conn, J. Rebek, Jr.,
Acc. Chem. Res. 1994, 27, 198 – 203; j) L. E. Orgel, Nature 1992,
358, 203 – 209.
[1] a) T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
Synthesis, Wiley, New York, 2007; for recent examples of
syntheses of complex molecules without protecting groups, see:
b) I. S. Young, P. S. Baran, Nat. Chem. 2009, 1, 193 – 205; c) P. S.
Baran, T. J. Maimone, J. M. Richter, Nature 2007, 446, 404 – 408.
[2] a) S. Ghosh, L. Isaacs in Dynamic Combinatorial Chemistry in
Drug Discovery, Bioorganic Chemistry, and Materials Science
(Ed.: B. L. Miller), Wiley, New York, 2010, pp. 155 – 168;
b) B. H. Northrop, Y.-R. Zheng, K.-W. Chi, P. J. Stang, Acc.
Chem. Res. 2009, 42, 1554 – 1563; c) J. R. Nitschke, Acc. Chem.
ˇ
´
Res. 2007, 40, 103 – 112; d) K. Osowska, O. S. Miljanic, Synlett,
2011, 12, 1643 – 1648.
[3] a) J. N. H. Reek, S. Otto, Dynamic Combinatorial Chemistry,
Wiley-VCH, Weinheim, 2010; b) Dynamic Combinatorial
Chemistry in Drug Discovery, Bioorganic Chemistry, and Mate-
rials Science (Ed: B. L. Miller), Wiley, New York, 2010; c) P. T.
Corbett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor, J. K. M.
Sanders, S. Otto, Chem. Rev. 2006, 106, 3652 – 3711; d) S. J.
Rowan, S. J. Cantrill, G. R. L. Cousins, J. K. M. Sanders, J. F.
Stoddart, Angew. Chem. 2002, 114, 938 – 993; Angew. Chem. Int.
Ed. 2002, 41, 898 – 952; e) R. F. Ludlow, S. Otto, Chem. Soc. Rev.
2008, 37, 101 – 108.
ˇ
´
[7] K. Osowska, O. S. Miljanic, J. Am. Chem. Soc. 2011, 133, 724 –
727.
[8] G. Tꢅth, I. Pintꢆr, A. Messmer, Tetrahedron Lett. 1974, 15, 735 –
738.
[9] a) D. Y. Curtin, Rec. Chem. Prog. 1954, 15, 111 – 128; b) J. I.
Seeman, Chem. Rev. 1983, 83, 83 – 134.
[10] Imine mixtures were preformed in toluene at reflux. Water
removal (with a Dean–Stark trap) is critical, because it prevents
the hydrolysis of imines into an aniline and an aldehyde—both of
which would be more volatile than the corresponding imine.
After dehydration, the only dynamic reaction is imine exchange.
[4] For selected examples of thermodynamically controlled self-
sorting based on noncovalent interactions, see: a) S. Ghosh, A.
8348
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[11] Imine distillation should be understood conditionally. Virtually
all imines investigated in this study are solids. Upon heating, they
melt and then evaporate, and solidify at various points along the
distillation apparatus, from where they can be extracted by
careful scratching and washing. See the Supporting Information
for details.
[12] In all distillation experiments, the major impurities were other
imines—typically the “crossed” light–heavy combinations; no
NMR spectroscopic evidence of other side products was found.
[13] a) B. Buchs, W. Fieber, F. Vigouroux-Elie, N. Sreenivasachary, J.-
M. Lehn, A. Herrmann, Org. Biomol. Chem. 2011, 9, 2906 –
2919, and references therein; b) B. Buchs, G. Godin, A. Trachsel,
J.-Y. de Saint Laumer, J.-M. Lehn, A. Herrmann, Eur. J. Org.
Chem. 2011, 681 – 695, and references therein.
[14] a) Reactive Distillation: Status and Future Directions (Eds.: K.
Sundmacher, A. Kienle), Wiley-VCH, Weinheim, 2003; b) G. J.
Harmsen, Chem. Eng. Process. 2007, 46, 774 – 780; c) C. P.
Almeida-Rivera, P. L. J. Swinkels, J. Grievink, Comput. Chem.
Eng. 2004, 28, 1997 – 2020.
= À
Purity was thus estimated by comparing the integral of the N C
H peak of the desired imine to the sum of the integrals of the
corresponding peak for all other imines.
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