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Research Article
Received: 17 November 2011 Revised: 16 February 2012 Accepted: 16 February 2012 Published online in Wiley Online Library
Rapid Commun. Mass Spectrom. 2012, 26, 1070–1080
(wileyonlinelibrary.com) DOI: 10.1002/rcm.6203
Probing the mechanism and dynamic reversibility of
trianglimine formation using real-time electrospray ionization
time-of-flight mass spectrometry
Hany F. Nour 1 , Ana M. Lopez-Periago 2 and Nikolai Kuhnert 1,2 *
1 School of Engineering and Science, Organic and Analytical Chemistry Laboratory, Jacobs University, 28759 Bremen, Germany
2 Synthetic and Biological Organic Chemistry Laboratory, School of Biomolecular and Medical Science, The University of Surrey,
Guildford GU2 7XH, UK
RATIONALE: The [3+3]-cyclocondensation reactions of chiral (1R,2R)-1,2-diaminocyclohexane with aromatic or
aliphatic bis-aldehydes to form trianglimine macrocycles were reported a decade ago and were believed to
proceed through a stepwise mechanistic pathway; however, no intermediates were ever isolated or detected
and characterized.
METHODS: We investigated the mechanism of the [3+3]-cyclocondensation reaction using a selection of dialdehyde
starting materials using real-time electrospray ionization time-of-flight mass spectrometry.
RESULTS: We observed up to a maximum of 16 reaction intermediates along the reaction pathway, more than
for any other multistep reaction reported. We also probed the dynamic reversibility of trianglimines using
selected small dynamic combinatorial libraries and showed that trianglimine formation is indeed fully
reversible.
CONCLUSIONS: This study represents a significant contribution towards understanding the mechanism of trianglimine
formation and its potential applicability can be extended to include other cascade reactions. Copyright © 2012 John Wiley
& Sons, Ltd.
1070
The synthesis of imine macrocycles relies in numerous cases
on [n+n]-cyclocondensation reactions of diamines and dialdehydes.
[1–4] In most cases, it involves preorganization of the
building blocks with the aid of a template or non-covalent
interactions to a predictable geometry. [5–8] [3+3]-Cyclocondensation
reactions have only been discovered in the last
decade and promise a new approach for the synthesis of
architecturally unique and exciting macrocyclic structures
with potential applications.
Gawroński et al. have introduced an efficient synthetic
strategy for the synthesis of large poly-imine meta- and
para-cyclophane type macrocycles which were named trianglimines
by our group due to their unique triangular
structure. [9,10]
Trianglimines form in quantitative yields without using
a template and the reaction takes place under the influence
of conformational bias imposed on the reactive
intermediates. [9] Hexaamine macrocycles are referred to
as trianglamines and they constitute reduced version of
trianglimines. [9,10] Trianglamines are readily synthesized
in quantitative yields by reducing trianglimines with
* Correspondence to: N. Kuhnert, School of Engineering and
Science, Jacobs University, P.O. Box 750 561, 28725 Bremen,
Germany.
E-mail: n.kuhnert@jacobs-university.de
Rapid Commun. Mass Spectrom. 2012, 26, 1070–1080
sodium borohydride. [9,10] We have shown that trianglimines
can be obtained from almost any synthetically accessible
aromatic dialdehyde with complete control of the size of
the macrocycle and functionalities incorporated into the
aromatic moiety. [10–14] More importantly, we have demonstrated
that trianglimines can be incorporated into more
sophisticated structures such as catenanes and shown
their promise in chiral recognition. [15,16] Trianglimines
are characterized by their structural diversity, ease of
synthesis in quantitative yields and most importantly by
their chirality, where both enantiomers of any derivative
are readily available in a pure form. [9–17] Recently, we
reported a novel functionalization approach for the synthesis
of regioisomeric C 3 -symmetrical and non-symmetrical
trianglimines. [18] We showed also that ESI-TOF (electrospray
ionization time-of-flight) mass spectrometry (MS) could
be used as a sophisticated technique for monitoring the progress
of the [3+3]-cyclocondensation reactions. [18] ESI-MS
has been used recently as a sophisticated tool for studying
complex reaction mechanisms in real time in solution. [19–22]
Examples of such mechanistic work include the investigation
of enzymatic reactions such as proteases, glycosidases or
nucleases or cascade reactions in organocatalysis. [23–27] In
this contribution, we describe our efforts to utilize ESI-TOF
MS to detect and to characterize the reactive intermediates
participating in the formation of trianglimine macrocycles.
We also studied dynamic reversibility of trianglimines in
solution by ESI-TOF MS.
Copyright © 2012 John Wiley & Sons, Ltd.