Computationally forecasting the effect of dibenzylammonium substituents on pseudorotaxane formation with dibenzo[24]crown-8

Article abstract of DOI:10.1016/j.tetlet.2015.07.061

The ability to predict the relative stabilities of analogous pseudorotaxanes is essential for the synthetic chemist yet simplified computational forecasting approaches remain scarce. Consequently, ten [2]pseudorotaxanes have been assembled (from a series of para-substituted dibenzylammonium ions and dibenzo[24]crown-8) and their experimentally-determined stabilities correlated with two computational parameters closely related to complexation energy. The strongest relationship was obtained from density functional theory calculation of binding energy (R² = 0.92) while determination of the maximum surface electrostatic potential on the dibenzylammonium ions (a proxy indicator of complex stability) afforded comparable results (R² = 0.88) with great reduction in computational expense.

Full text of DOI:10.1016/j.tetlet.2015.07.061

Tetrahedron Letters 56 (2015) 5175–5179
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Computationally forecasting the effect of dibenzylammonium
substituents on pseudorotaxane formation with dibenzo[24]crown-8
⇑
⇑
Nicholas A. Payne, Luke C. Delmas, Sean A. C. McDowell , Avril R. Williams
Department of Biological and Chemical Sciences, The University of the West Indies, Cave Hill, Barbados
a r t i c l e i n f o
a b s t r a c t
Article history:
The ability to predict the relative stabilities of analogous pseudorotaxanes is essential for the synthetic
chemist yet simplified computational forecasting approaches remain scarce. Consequently, ten [2]pseu-
dorotaxanes have been assembled (from a series of para-substituted dibenzylammonium ions and
dibenzo[24]crown-8) and their experimentally-determined stabilities correlated with two computational
parameters closely related to complexation energy. The strongest relationship was obtained from density
functional theory calculation of binding energy (R2 = 0.92) while determination of the maximum surface
electrostatic potential on the dibenzylammonium ions (a proxy indicator of complex stability) afforded
comparable results (R2 = 0.88) with great reduction in computational expense.
Received 8 May 2015
Revised 16 July 2015
Accepted 18 July 2015
Available online 23 July 2015
Keywords:
Hydrogen bonding
Pseudorotaxanes
Secondary ammonium salt
Crown ether
Ó 2015 Elsevier Ltd. All rights reserved.
Molecular modelling
Surface electrostatic potential
Introduction
design stage—resulting not only in considerable time- and
cost-savings, but also improved control during the final stages of
Since Stoddart’s initial discovery1 of the first threaded
donor/acceptor complex, we have not only seen the assembly of
a myriad of other pseudorotaxanes, but also witnessed their use-
fulness as precursors to a variety of topologically-fascinating
mechanically interlocked molecules (MIMs)2–8 and functional
molecular machinery.9–13 One of the most outstanding templates
which has been developed for MIM synthesis is the hydrogen-
MIM assembly. For instance, stable pseudorotaxane precursors
are desirable for the assembly of non-trivial interlocked molecules
such as suitanes2,6 whereas using components which bind less
strongly has been noted to be beneficial in the preparation of
molecular switches.18
As we continue to pursue supramolecules of increasing com-
plexity, the usefulness of the Hammett constant correlation begins
to diminish since new studies involve more elaborate DBA tem-
plates which bear advanced substituents (such as poly-substituted
aromatic units consisting of bridged/extended dibenzylammonium
bonded
dibenzylammonium
(DBA)/dibenzo-[24]
crown-8
(DB24C8) recognition motif whose remarkable stability14 has
inspired the use of a variety of appropriately-sized crown ethers
for DBA ion recognition in numerous intriguing studies.7,15
Ashton and co-workers published an interesting keynote arti-
cle16 in which they determined the stabilities of several para-
and meta-substituted DBA/DB24C8 pseudorotaxanes and found
good correlation between experimental binding energies and the
structures) for which
r is unknown. We therefore seek to identify
other practical methods for forecasting the relative stabilities of
crown ether/DBA threaded systems acknowledging that these
computational studies must be simple enough to be routinely used
by chemists of all backgrounds and be executable in reasonable
timeframes. This preliminary investigation begins by revisiting
the Ashton study, focusing only on para-substituted DBA ions
(Scheme 1). We have expanded the variety of p-substituents
considered, specifically by including the cyano and iodo analogues
(previously unreported to the best of our knowledge), and devised
Hammett substituent constants17
(r
)
associated with the
para-groups on the DBA phenyl rings. This relationship allows
the relative stability of these analogous complexes to be predicted,
prior to their synthesis, by considering the electronic properties of
the substituted DBA threads—effectively allowing the synthetic
chemist to ‘fine-tune’ the strength of complexation at the initial
a
new synthesis for the bis(4-formylbenzyl)ammonium
hexafluorophosphate thread. We proceed with a discussion of data
from several computational methods and their correlation with
experimental results.
⇑
Corresponding authors.
E-mail addresses: sean.mcdowell@cavehill.uwi.edu (S.A.C. McDowell), avril.
williams@cavehill.uwi.edu (A.R. Williams).
http://dx.doi.org/10.1016/j.tetlet.2015.07.061
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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N. A. Payne et al. / Tetrahedron Letters 56 (2015) 5175–5179
(a)
R
R
R
1. PhMe / Δ
2. NaBH4 / MeOH
3. HCl / CHCl3
4. NH4PF6 / H2O
+
NH2
-
PF6
R
NH2
H
O
1·PF6 - 9·PF6
(b)
OEt
H2N
CHO
EtO
OHC
1. PhMe / Δ
1. HCl / CH3Cl
2. NH4PF6 / H2O
3%
2. NaBH4 /MeOH
+
NH
OEt
NH2
-
PF6
EtO
OEt
EtO
OEt
CHO
OEt
10·PF6
Scheme 1. Protocol used in the synthesis of the para-substituted DBA threads 1ÁPF6–9ÁPF6 (a) and synthetic route utilized in the preparation of the formyl-terminated DBA
ion 10ÁPF6 (b) involving an acetal-substituted dibenzylamine intermediate.
Subsequently, log[Ka(R)/Ka(H)] was plotted against the respec-
tive Hammett substituent constants17 (Fig. 1c), where Ka(R)/Ka(H)
represents the ratio of the association constants of a substituted
DBA thread to that of its protic analogue and thus effectively sets
1ÁPF6 (R = H) at zero. Unsurprisingly, we observed that electron
Synthesis and binding studies
The synthesis of the ten DBA ions was carried out following the
four-step procedure (Scheme 1a) outlined by Ashton and
co-workers,16 with the exception of dialdehyde 10ÁPF6. An equimo-
lar mixture of the corresponding benzylamine and benzaldehyde in
toluene was heated under reflux overnight with the use of a Dean
Stark apparatus. En vacuo concentration of the mixture, followed
by treatment with sodium borohydride in a methanol/THF solvent
afforded the substituted dibenzylamine which was subsequently
protonated using hydrochloric acid. The hydrochloride salt was
converted to the hexafluorophosphate species by treatment with
ammonium hexafluorophosphate in a boiling mixture of water
and methanol. Due to difficulties in reproducing the reported
synthesis of 10ÁPF6,19 we prepared the diethyl acetal-substituted
dibenzylamine (Scheme 1b) and treated it with conc. HCl effecting
simultaneous deprotection and protonation affording 10ÁPF6 after
counterion exchange. Yields were not recorded for the acetal
intermediate since the crude product was immediately taken up
in chloroform and subjected to treatment with HCl.
donating substituents (i.e. those with negative
r values; –OMe
and –Me) caused a reduction in affinity for DB24C8 compared with
1ÁPF6, while electron withdrawing groups (those with positive
r
values; the halogens, –CHO, –NO2 and –CN) enhanced binding.
A good correlation (Fig. 1c) between complex stability and the
corresponding Hammett substituent constant was found
(r)
(R2 = 0.8956) indicating that a linear free energy relationship
(LFER) exists between the two quantities, thereby linking the elec-
tronic properties of the para-substituents to the hydrogen bond
donor ability of the ammonium and benzylic methylene protons.
These results are consistent with those reported in the litera-
ture16—however, as previously mentioned, the applicability of this
prediction method falls off on departure from simple complexes.
Computational studies
Equimolar amounts of the DBA hexafluorophosphate salt and
DB24C8 were combined in deuterated acetonitrile to yield a
10 mM solution (Fig. 1a). The 1H NMR spectra of these solutions
were recorded at 297 K five minutes after mixing and the stability
constants (Ka) for these dynamic systems subsequently determined
via the single point method.20,21 The typical set of signals observed
for systems of this type is illustrated in the 1H NMR spectrum of
the [2]pseudorotaxane assembled from 3ÁPF6 and DB24C8 (Fig. 1b).
Each component of the assembly is assigned two sets of reso-
nances corresponding to signals from protons in the free or uncom-
plexed (uc) state and those in the bound or complexed (c) state.
The equilibrium concentrations of chemical species in these slow22
exchange systems were then determined via the single point
method by comparing integrations of peaks corresponding to the
‘free’ and complexed states of targeted probe protons on each com-
ponent—specifically the DBA benzylic methylene protons (Ha) and
the polyether methylene protons (Hh) which become downfield
and upfield shifted, respectively, on pseudorotaxane formation.
We next turned our attention to computational studies of the
synthesized complexes, in the hope that useful relationships
between the experimentally-determined Gibbs free energies of
complexation and the computational results could be obtained,
allowing us to avoid the limited scope and pitfalls associated with
the Hammett constant correlation approach.
The theoretical work consisted of density functional theory
(DFT) calculations of binding energies and free energies of com-
plexation for the various complexes. The ten substituted DBA ions,
free DB24C8 and the corresponding 1:1 complexes were drawn in
Spartan 14.1.1.423 and the lowest energy conformations were
subjected to geometry optimization and harmonic vibrational
frequency calculations (Fig. 2a). The binding energies for each of
the complexes were then calculated as the difference between
the energy of the 1:1 complex and the total energy of the free com-
ponents. Free energies of complexation were calculated using the
enthalpies and entropies obtained from the frequency calculations.

N. A. Payne et al. / Tetrahedron Letters 56 (2015) 5175–5179
5177
Figure 1. (a) Schematic of the complexation of a para-substituted DBA ion with DB24C8 and table of the substituents considered in this study, (b) Sample 1H NMR spectrum
of [3ÁPF6][DB24C8] with peak assignments where (c) and (uc) correspond to protons in the complexed and uncomplexed species, respectively, and (c) Correlation of stability
constants determined experimentally via the single point method with known Hammett substituent constants (r).
Figure 2. (a) Optimized structures of 9ÁPF6, DB24C8 and [9ÁPF6][DB24C8] (H atoms except R2NH+2 omitted for clarity) and (b) Correlation of computational binding energy and
free energy with experimentally-determined free energies of complexation (DGexp) for the [2]pseudorotaxanes prepared.
DFT calculations were carried out at the B3LYP level with the
6-31G⁄ basis set. In the case of 5ÁPF6 and [5ÁPF6][DB24C8],
the LANL2DZ basis set was applied to the iodine atoms while the
6-31G⁄ basis set was applied to all other atoms.
Contrastingly, we have considerable flexibility in making signifi-
cant modifications to the dibenzylammonium threads allowing
us to fine-tune their binding to crown ethers. To this end, we
decided to move forward by assessing the cationic threads in
isolation, resulting in a significant reduction in computational
effort thereby facilitating the possibility of improved accuracy
through calculations at higher levels of theory or larger basis sets.
We subsequently focused on the response of the maximum of
the molecular electrostatic potential on the thread’s surface
(Vs,max) to changes in the electron-withdrawing/-donating nature
of the DBA p-substituents. The ammonium centre binds to crown
ethers through intermolecular hydrogen bonding and Coulombic
interactions with the crown’s electron-rich (negative) ligating
atoms; both of these binding mechanisms being dependent on
the degree of positive charge at the ammonium centre, easily
Although these theoretical calculations of binding energy
(R2 = 0.9161) and free energy of complexation (R2 = 0.8985) were
well-correlated with experimental data (Fig. 2b), we found it nec-
essary to explore other theoretical methods that would better fit
the criteria for speed, high accuracy and ease of use. We noted that
reducing the overall system size being considered greatly reduced
the timeframe in which these calculations could be executed. In
reality, the design of new pseudorotaxanes is greatly restricted
by the small window of opportunity for modification of the macro-
cycle cavity size since interrupting the –O–C–C–O– repeating units
hinders the affinity of crown ethers for DBA ions.24,25

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N. A. Payne et al. / Tetrahedron Letters 56 (2015) 5175–5179
Figure 4. Schematic of pH-switchable rotaxane26 beside the corresponding indi-
vidual threads showing the computed surface electrostatic potentials.
locations for DB24C8). In the protonated thread, the positive
potential is concentrated mostly over the ammonium with the
bipyridinium site also showing positive potential, albeit to a lesser
extent. Upon deprotonation, the map shows that there is a shift in
the location of the maximum positive potential from the ammo-
nium to the bipyridinium, an observation in line with the move-
ment of the crown ether with change in pH. Furthermore, in the
protonated thread, the region of positive potential over the bipyri-
dinium would indicate partial occupancy, which is in agreement
with the 1H NMR experiments performed on the rotaxane.26
While the method can highlight potential binding regions, it must
be noted that prediction for the binding affinities in multiply
charged species is currently only qualitative as the range of the
surface potentials on the molecule is influenced by the charge.
Figure 3. (a) Molecular electrostatic potential map of the nitro-substituted DBA
thread, 9ÁPF6, illustrating the positive potential (blue) concentrated at the R2NH2+
portion of the molecule and (b) Correlation of Vs,max values with experimental data.
determined by molecular electrostatic potential (MEP) studies.
Electrostatic potential maps were consequently generated for the
ten previously optimized DBA ions with an example of the map
for 9ÁPF6 illustrated in Figure 3a.
We expected that electron-withdrawing substituents would
enhance the electron deficiency of the ammonium centre, which
would be reflected in the magnitude of the positive potential
observed on the MEP map. Thus, it follows that the magnitude of
the maximum surface potential (Vs,max) at the ammonium centre
should be proportional to the binding affinity of these DBA ions
for crown ethers. Indeed a good correlation between Vs,max at the
R2NH+2 binding sites and experimentally-determined free energies
of complexation was obtained (R2 = 0.8804, Fig. 3b). While the
binding and free energy data gave slightly stronger correlations
with experimental data, the tremendous reduction in computa-
tional expense due to the dramatic reduction in system size ren-
ders the MEP method far more practical as we pursue higher
order supramolecular assemblies, especially for applications in
planning the synthesis of mechanically interlocked molecules.
In order to test the viability of the method, we sought a simple
model system, namely a pH-sensitive molecular switch reported
by Eizarov.26 On the thread, there is competition for binding of
DB24C8 between bipyridinium and pH-dependent dialkylamine/-
dialkylammonium sites. Under acidic conditions, the ammonium
site shows higher affinity towards DB24C8 and therefore is the
preferential binding site (Fig. 4). Deprotonation from treatment
with base shifts the equilibrium towards docking on the bipyri-
dinium thus effectively creating a molecular switch.
Conclusion
Noting the limitations of using the LFER (which correlates the
Hammett substituent constants and DBA/crown association con-
stants) to predict the stability of pseudorotaxanes, we have inves-
tigated computational methods to predict the binding affinity of a
variety of p-substituted dibenzylammonium ions to crown ethers.
Calculation of binding energies and free energies by DFT provided
data well-correlated with experimental results. Owing to the com-
putational expense of optimizing the assembled pseudorotaxanes
by DFT, we proceeded with determination of the maximum surface
molecular electrostatic potential at the ammonium centres of the
DBA threads. We found that Vs,max afforded a strong correlation
with experimental data—comparable to that of the binding and
free energy results but with a significant reduction in computer
time and the surface potential maps can also be used to highlight
preferential binding sites in a rotaxane molecular switch. These,
coupled with the visually stimulating maps obtained from the
MEP computations, leads us to believe that Vs,max computation is
a fitting tool for the non-theoretical chemist to predict relative sta-
bilities of DBA/Crown supramolecular complexes.
Using the method for calculating and plotting the surface elec-
trostatic potentials, we modelled the threads of the rotaxanes
shown in Figure 4. The colour thresholds have been modified to
highlight the regions of high surface potential (i.e., possible binding

N. A. Payne et al. / Tetrahedron Letters 56 (2015) 5175–5179
5179
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The Authors wish to thank The University of the West Indies
and the Government of Barbados for their financial support.
Special thanks to Crystal Best who assisted in the synthesis of
9ÁPF6.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.
061. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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