Intramolecular π-stacking in isostructural conformational probes depends strongly on charge separation, a proton NMR study

Article abstract of DOI:10.1002/ejoc.200800663

Our solution state conformational methods used previously to study a dicationic molecular template for intramolecular aromatic association were applied to a neutral hydrocarbon analogue to probe the effect of charge on conformation. Conformational analysis of the hydrocarbon revealed modest solvent dependence in largely unfolded molecules. Conformations found in the solid state were unfolded also corroborating the findings of the solution-state study. This study also adds solid-state evidence for three competing solution-state conformers previously predicted by calculations. In the absence of charge, the molecular template does not favor intramolecular association of aromatic substituents. These results agree with the chemical literature and previous reports of neutral hydrocarbon intramolecular association in the solution state. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800663

FULL PAPER
DOI: 10.1002/ejoc.200800663
Intramolecular π-Stacking in Isostructural Conformational Probes Depends
Strongly on Charge Separation, a Proton NMR Study
Pramod Prasad Poudel,[a] Jing Chen,[b] and Arthur Cammers*[a]
Keywords: π-Stacking / Solution state / Crystalline state / Conformation / NMR anisotropy
Our solution state conformational methods used previously
to study a dicationic molecular template for intramolecular
aromatic association were applied to a neutral hydrocarbon
analogue to probe the effect of charge on conformation. Con-
formational analysis of the hydrocarbon revealed modest sol-
vent dependence in largely unfolded molecules. Conforma-
tions found in the solid state were unfolded also corroborat-
ing the findings of the solution-state study. This study also
adds solid-state evidence for three competing solution-state
conformers previously predicted by calculations. In the ab-
sence of charge, the molecular template does not favor intra-
molecular association of aromatic substituents. These results
agree with the chemical literature and previous reports of
neutral hydrocarbon intramolecular association in the solu-
tion state.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
In an approach encapsulated by the early ideas of Kara-
batsos,[1] and in work by Fukazawa,[2–7] and others,[8–12]
a
calculation-based/1H NMR-based, multi-state mathemati-
cal model for the solution-phase conformation of the dicat-
ions 1a–c was devised.[10–12] The steps involved in these con-
formational analyses were: 1) molecular modeling and X-
ray crystallography to locate candidate conformational en-
ergy minima, and grouping these conformations into
classes, 2) ab initio calculations of the effect of anisotropy
on key chemical shifts in these conformations. Figure 1 dis-
plays the calculated anisotropic shielding tensor of benzene
with shielding and deshielding regions at the π-face and
edge respectively. 3) experimentally measuring the chemical
shift difference between key, analogous chemical shifts of
the template molecule and an ideal reference molecule, 4)
solving a system of equations designed to output the con-
formational distribution given the computed chemical
shifts, the experimental chemical shifts and mass balance,
5) checking the stability of the mathematical model by
grouping conformations and omitting the expression for
mass balance under different conditions (temperature and
Figure 1. Above: NMR-assayable π-stacking molecular template. a:
R = Ph; b: R = 2,4,6-trifluorophenyl; c: R = pentafluorophenyl; d:
R = methyl. X = Br or PF6. Below: The numbers are chemical
solvent) to look for negative concentrations of conformers shifts due to shielding in the vicinity of the benzene ring calculated
at rb3lyp/6-311++g(2d,2p) and plotted as a contour slice through
in the output of the algorithm.
C6H6, shown in CPK. The calculation starts at 2 Å on the x axis
and 1.5 Å on the z axis from the benzene centroid.
[a] University of Kentucky, Department of Chemistry,
Chemistry-Physics Building, 505 Rose St., Lexington, KY
40506-0055, USA
Molecular modeling and solid-state studies elucidated
Fax: +1-859-323-1069
four conformations that could compete at room tempera-
ture. Two unfolded, splayed, S, conformational classes and
two folded, C (3-ring cluster) and F (π-face-to-face), confor-
mational classes had different NMR signatures due to the
E-mail: a.cammers@uky.edu
[b] University of Kentucky, College of Pharmacy,
725 Rose Street, Lexington, KY 40536, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. P. Poudel, J. Chen, A. Cammers
FULL PAPER
anisotropy of the phenyl rings attached to the pyridinium
moiety.[13,14] In the development of this conformational
analysis 1b–c were important,[13] but these molecules are
not considered here in any detail. The current study aims
to validate previous conformational studies, and aims to in-
vestigate the condition-dependent conformation of 2a.
Results and Discussion
Methods
The effects of anisotropic shielding on the chemical shifts
of microstates comprising conformations C, F and S were
calculated by ab initio methods. Experimental differences
between the chemical shifts of 1a and 1d of the three analo-
gous, symmetry-independent protons of the xylene moiety
were used in simultaneous equations. The same model was
used with 2a and 2d. Solving these equations gave the distri-
butions of the conformational classes C, F and S of 1a–c
under various conditions.[13–15] Compound 1d was approxi-
mated to have no connection between conformational
changes and chemical shift. We estimated that 1d corrected
the drift in chemical shifts of Ha–Hc due to bulk solvent
effects and due to changes in ion pairing. Protons Ha and
Hb of the phenylated material had more magnetic disper-
sion and more variable chemical shifts than the methylated
reference compounds. However, the variability in the chemi-
cal shift of Hc was similar in 1a and 1d. Greater apprecia-
tion for this can be seen graphically in the Supporting In-
formation section entitled: Relative Chemical Shift of Ha vs.
Hc as a Function of Solvent Dielectric.
One conformational class, C, found by molecular model-
ing[13] (the global minimum) formed a three-ring aromatic
cluster, which pushed the methine signal of Ha upfield rela-
tive to Hb. The C state allowed three rings to cluster, an
aspect of gas and solution phase aromatic interactions.[16,17]
The C state also accounted for the previous observation
that three phenyl rings gave much evidence for folded con-
formation but two phenyl rings gave little.[18,19] Conforma-
tional class, F, maintained a π-face-to-face relationship be-
tween the xylyl and the phenyl rings, but induced upfield
shifts at Ha and Hb nearly equally. A structural average of
three microstates modeled the F state: one microstate put
the phenyl ring above Ha, another put phenyl above Hb.
Figure 2, structure F, from computational conformation
searching, shows these two conformational contributions
with phenyl proximal to Ha (above) and the other near Hb
Figure 2. Components in an NMR-based solution-state conforma-
tional analysis of 1.
the phenyl is proximal to Ha (S in Figure 2 is Sef, lower
right) or proximal to Hb (structure S in Figure 2, upper
left) produces two related conformational classes, each com-
posed of two microstates.
The conformational analysis took advantage of the fact
that 1 and 2 have dynamic C2v symmetry; the chemical
shifts of half structures were calculated. To calculate and
map the chemical shift anisotropy of the phenyl substitu-
ents on xylyl Ha-Hc in all the conformational microstates,
the model was further simplified. The xylyl ring was erased
and H2 molecules replaced the xylyl C–H bonds at Ha-Hc.
The 2-phenylpyridinium moiety was replaced with fluoro-
benzene. NMR chemical shift calculations were performed
on these simple systems to estimate the magnetic shielding
of the aromatic ring. Equations 1–4 were used to determine
the mol fractions of the conformers present in solution with
chemical shift as the independent variable.[15]
XC + XF + XSee + Xsef = 1
(1)
δ1d(Ha) – δ1a(Ha) = 2CaXC + 2FaXF + 2SeeaXSee
+
2SefaXSef (2)
δ1d(Hb) – δ1a(Hb) = CbXC + FbXF + SeebXSee + SefbXSef (3)
δ1d(Hc) – δ1a(Hc) = 2CcXC + 2FcXF + 2SeecXSee
+
2SefcXSef (4)
Equation (1) is an expression of mass balance; the X val-
(below). The third conformational contribution to the F ues are mol fractions of the conformational classes de-
state put the phenyl ring with respect to Hb in a spatially scribed above, dependent variables to be determined by the
identical manner as the C state with respect to Ha. The solution of these four equations. Equations 2–4 express dif-
magnetic effects of these three conformers were averaged to ferences in chemical shift between 1d and 1a at Ha, Hb and
compose the F state because calculations indicated that Hc, respectively. For 2a, 2d was used as the reference. In
there were minimal energetic differences between them.
the equations, Ca, Fa or Seea etc. are calculated constants
Two splayed (unfolded) conformations derived from two of proportionality relating chemical shift differences [e.g.
low-energy biaryl dihedral angles were found by molecular δ1d(Ha)–δ1a(Ha)] to mol fraction. These coefficients ap-
modeling. Sef or See signify an edge-to-face or an edge-to- pear in Table 1. Because two phenyl rings can affect Ha
edge spatial relationship between phenyl and xylyl. Whether and Hc simultaneously, their corresponding coefficients are
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Intramolecular π-Stacking in Isostructural Conformational Probes
multiplied by 2 in Equations 2 and 4. Equation (3) does not tried. The probe H2 molecule placed at the phenyl perimeter
take this form because there are two symmetrically equiva- produced similar muted effects. Figure 3 shows that the
lent Hb protons which share the effects of the two phenyl chemical shift is more dependent on mono-substitution
rings.
than on the nature of the substituent. Thus, differences be-
tween 1a and 2a should be corrected by the NMR refer-
ences 1d and 2d respectively.
Table 1. Values of the coefficients used in the equations above.
Coefficient[a]
Ha
Hb
Hc
C
1.70
0.52
–0.80
0.14
0.19
1.26
–0.67
0.22
0.07
0.40
0.13
0.00
F
See
Sef
[a] Coefficients were calculated at the rb3lyp/6-311++g(2d,2p) level.
The model is not perfect. One approximation in the
model is the way that the F states and the S states are
binned to comprise the distribution. Better math would tell
us if the phenyl prefers the Ha or the Hb side of the ring
in the S states for example. However there is not enough
information in the spectra for this level of analysis. Another
approximation in this conformational analysis labels S
states unfolded and C and F states folded; there is perhaps
some residual intramolecular aryl–aryl contact in the S
Figure 3. The effect of anisotropy on the chemical shift of H2 at H
as a function of σ-para of X. In this study the fluoro substituent
states. An analysis of the solvent accessible surface area of (✧) modeled monosubstitution. The benzene ring (᭺) deviated the
most from the trend. Low R2 indicates poor linear relationship.
the conformations was presented previously as an argument
for classifying the conformations in this manner.[14] Calcu-
lations in the gas phase overestimate the effect of chemical
shift anisotropy when distances allow solvent to fit between
Solid State
the phenyl ring and the proton of interest. In the mathemat-
ical model these go from small to zero to correct for shield- as supplementary data. Previous studies[13–15] only pre-
ing by solvent (coefficient for Sef, Hc in Table 1).[15]
sented solid-state evidence for the F state with the phenyl
The crystallographic information files (CIF) are available
Preoccupation about these issues instigated checks of ring positioned proximal to Ha in the dibromide salts of
Equations 2–4 for molecules 1a–c by averaging the S state 1a–c. The other conformational microstates comprising
expressions and excluding the hard-wired mass balance of conformations C, F and S represented low-energy states
Equation (1); the mass balanced in these systems of equa- from calculations: conformational searches with Amber* as
tions within ca. 10%. Descriptions of these checks are avail- implemented in Macromodel.[22] The crystal structure (Fig-
able in greater detail.[15]
ure 4, middle) of the 1a-2PF6 salt belongs to the F confor-
The mathematical model that connected experimental mational group with the phenyl rings above Hb. This con-
chemical shift differences to the conformation of 1a should formational microstate was previously used to construct the
perform as well for 2a once the ideal chemical shift refer- mathematical model of the F state, but was only supported
ence is changed to 2d. Successful application requires near on the basis of calculation. The carbon atom and nitrogen
equivalent NMR anisotropy of monosubstituted phenyl atomic positions of the solid state of 1a-2PF6 and the F
rings so that the substituents: N-xylylpyridinium-2-yl of 1a, state with the phenyl over Hb used previously overlapped
2-xylylphen-1-yl of 2a and the F atom substituent in the with a root mean square (RMS) difference of 0.2 Å. These
model exert similar magnetic effects on the chemical shifts calculations are described further in the Supporting Infor-
of proximal atoms. This was found not to be the case for mation under the heading root mean square positional simi-
1a, 1b and 1c. The constants in Equations 2–4 had to be larity.
calculated for each of these separately.[15]
Solid state evidence that 1 and 2 model π-stacking comes
To probe the applicability of the chemical shift constants from the fact that the di-PF6 methyl derivative 1d-2PF6
used for 1a to the conformational analysis of 2a, chemical crystallized in an S state (not shown). If it were phenyl and
shift calculations of a series of monosubstituted benzene not methyl, the phenyl rings in this conformation would not
rings that spanned the usual linear free energy relationship intramolecularly associate with the xylyl ring. These two
were run and the results were plotted against sigma- crystal structures (1a-2PF6 and 1d-2PF6) in the absence of
para.[20,21] An H atom in H2 was put at (x, y, z: 0.49, 0.49, other data might have led one tentatively to the hypothesis
2.6 Å) with respect to a phenyl ring positioned with C1, that the phenyl rings provide the cohesive force to favor the
and C4 along the horizontal axis; all C atoms were in the folded states.
xy plane and the phenyl centroid was at 0, 0, 0. The results
Another switch in solid-state conformation occurred
are summarized in Figure 3. There are three points for when the N atoms in 1a were substituted with C atoms to
phenyl because the most popular biphenyl dihedrals were produce the neutral all hydrocarbon derivative 2a. Inspec-
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P. P. Poudel, J. Chen, A. Cammers
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Figure 5. The mol fraction folded (F+C) [circles] and unfolded S
[squares] are plotted as a function of solvent dielectric for 1a-2PF6
[grey], 1a-2Br [black] and 2a [white]. Solvents: (1) C6D6 (2) [D8]Tol
(3) CDCl3 (4) [D6]acetone (5) CD3OD (6) [D7]DMF (7) CD3CN
(8) [D6]DMSO (9) D2O.
From the solvent-dependent conformation of 1a and 2a
in Figure 5 the initial purpose of this study was fulfilled.
Molecule 2a and 2d were synthesized to test 1a as a model
for π-stacking. If the conformations of 2a had not changed
with the solvent in a similar manner to 1a we would have
to ascribe something other than the native attraction of the
rings to one another as the major factor in control of con-
formation. Figure 5 shows that increasing solvent polarity
tends to fold both molecules and the trend appears to be
modestly solvophobic.[23] The conformational aspects of
both molecules being a function of π-stacking, as stated
above, was corroborated by the fact that 1a-2PF6 crys-
tallized in an F conformation and 1d-2PF6 crystallized in a
splayed open conformation. The fact that 1a-2Br and 1a-
2PF6 behave similarly also corroborates the notion that in-
tramolecular interactions in the cation and changes in sol-
vent contact govern conformation. This justifies the origi-
nal control experiments for this issue which compared the
conformational behavior of 1a-2Br to 1a-2Cl.[13]
The other salient feature of the graph in Figure 5 is that
neutral 2a is less folded than charged 1a. This result agrees
with the conformations found in the solid states in that 1a-
2PF6 and 1a–c-2Br crystallized in two distinct F conforma-
tions from polar solvent, but 2a crystallized in a mixed S
conformation from a non-polar solvent mixture (10:1 hex-
ane/EtOAc) in which the fraction unfolded conformation
was likely ca. 90%.
Figure 4. ORTEP stereoviews of X-ray structures of 1a 2Br + H2O,
1a 2PF6, F atoms not shown, and 2a.
tion of the crystal structure of 2a revealed a conformer that
possessed two symmetry-unrelated S conformations at
either end of the molecule. To quantify how closely the solid
state of 2a resembled any of the four microstates used to
model the magnetic behavior of the S conformation in the
previous analyses of 1, RMS differences in analogous
atomic positions were calculated between the two ends of
the solid state conformer of 2a and the previously calcu-
lated S states of 1a. These RMS differences were compared
to RMS differences in atomic coordinates between the solid
state of 2a and previous C and F states of 1. The atomic
coordinates of the conformer in the solid state of 2a over-
lapped well with two S states used previously. The descrip-
tion of this analysis is available in the Supporting Infor-
mation under the heading Root Mean Square Atomic Posi-
tional Similarity.
Solution State
Figure 5 graphically shows the solvent dependence of the
In the previous study of this system 1b and 1c progress-
conformations of 1a-2PF6, 1a-2Br and neutral 2a from si- ively promoted unfolding.[15] The disposition of the aro-
multaneous solutions of Equations 1–4 with NMR chemi- matic rings in the general structure of 1a promote face-to-
cal shifts of Ha, Hb and Hc as input. Missing points are face, edge-to-center association between the xylyl and
due to insolubility. Grossly, the conformations in the mole- phenyl rings.[18,24] Putative quadrupolar enhancement of
cules change as a function of solvent dielectric although aromatic association by progressive substitution with F
one would expect microscopic solvent properties to be in- atoms would depend on a face-to-face, center-to-center as-
fluential. These microscopic effects might be manifest in the sociation.[25,26] However, such an interaction is inhibited by
solvent-dependent mol fraction in the four curves at point torsional strain in the general structure of 1 and 2. In the
7, CD3CN. However, microscopic solvent effects are beyond current study, N-to-C substitution promoted unfolding of
the current analysis.
similar magnitude to that observed for 1c with the caveat
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Intramolecular π-Stacking in Isostructural Conformational Probes
that 1c-2Br did not unfold to the extent that 2a unfolded pared to heteroatom analogues.[36–39] The aromatic interac-
due to limitations in solubility with nonpolar solvents.
tions increase when substituents perturb the electronic na-
The conformational behavior of the all-carbon analogue ture of the rings.[40,41]
brings our π-stacking model in line with previous reports in
Incisive calculations of intermolecular interactions of
the chemical literature. Even though solvent is an important small arene derivatives gave similar dependences on the
factor in the global conformation of biological polymers electronic nature of aryl substituents.[42,43] In related studies
due to synergism in many modest interactions toward a of intermolecular aromatic association in large π-systems,
native state, generally solvent-sensitive conformation in again, one or more electron-deficient aromatic component
small organic molecules is rare and not very dramatic.[27,28] exalts cohesion at the molecular level.[44–47] When at least
When observed, solvent-dependent conformation relies on one component in the aromatic interactions is electron-
strong interactions between dipoles or changes in the sol- poor, attractions between aromatic groups neatly explain
vent’s ability to hydrogen bond with a group upon confor- synthetic[48–50] and computational results.[51] As assayed by
mational change.
many solution-phase methods, neutral hydrocarbon aro-
The chemical literature indicates that 1a should favor matic interactions have been found to be very weak; they
folded conformations and 2a should not. Studies of deriva- are certainly weak relative to the amount of attention that
tives of monocation half structures of 1a indicate that elec- they routinely receive in the chemical literature. By default,
trostatic effects increase the rotational barrier of the C–N in the chemical literature π-stacking more often than not
bond.[24] In studies of a wide variety of template molecules refers to cohesive forces based on weak electrostatic interac-
(Figure 6) aimed toward the measurement of intramolecu- tions instead of the canonical dispersive interaction be-
lar aromatic interactions,[26,29] more favorable interactions tween aromatic moieties; however, the latter is the usual
were found when at least one electron-poor aromatic group mental picture invoked by π-stacking.
was involved.[26] Favorable interactions were not detected
or interactions were found to be repulsive between electron-
rich, or between all hydrocarbon, aromatic rings (3 and
Conclusions
4).[9,30–32] In Wilcox’ ingenious template 5, the aromatic in-
While the conformation of the solid state might not gen-
erally be assumed to be the preferred conformation in the
solution state, this study found the preferred conformations
in solution and in the solid state to be similar. The three
ortho-aryl derivatives, 1a–c, crystallized in folded, stacked
conformations and favored the folded solution state,
whereas 2a crystallized in an unfolded conformation and
was found to prefer an unfolded conformational state in
solution.
teractions were not as cohesive as the alkyl/aromatic inter-
actions.[33] Other studies show that aromatic hydrocarbon
interactions are very weak even when structural analysis
puts these groups within interaction distances, 6[8,34,35] com-
Previous conclusions that interactions between the aryl
substituents folded this molecular family were corroborated
by the current study in that the conformational effects were
found to be governed by the very modest attraction between
aromatic groups. Consonant with other reports in the
chemical literature, interactions between hydrocarbon aro-
matic groups of organic molecules in solution phase are un-
remarkable in the control of conformation. This report is
the sixth and most likely the last of our studies of the con-
formation of this molecular family.
Experimental Section
General: Melting points are uncorrected. Solid-state data on all the
compounds were collected with
a Nonius kappaCCD dif-
fractometer; cell refinement and data reduction were done using
SCALEPACK and DENZO-SMN.[52] Structure solution and re-
finement were carried out using the SHELXS97 and SHELXL97
program, respectively.[53]
CCDC-697018 (for 1a-2PF6), -697019 (for 1d-2PF6) and -697020
(for 2a) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Figure 6. Some conformational templates of aromatic interactions
in the chemical literature.
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P. P. Poudel, J. Chen, A. Cammers
FULL PAPER
1H NMR Studies: Conformation of 1a and 2a were studied using
two NMR tubes; one tube contained the phenyl analog and the
other contained the reference compound 1d or 2d in the identical
solvent. Temperature-controlled measurements were recorded to
three digits past the decimal after the lack of drift in chemical shifts
indicated thermal equilibrium. See previous studies for more de-
tails.[14,15]
shifts of 1a-2Br, 1d-2Br, 1a-2PF6, 1d-2PF6, 2a and 2d in the sol-
vents used in Figure 5. Graphs comparing the conditional chemical
shifts of 1a, 2a, 1d and 2d. RMS differences in the comparison of
the solid state of 2a and the conformations used previously, demon-
1
strating that the solid state of 2a is an S state. Sample 13C and H
NMR spectra are available for 2a and 2d.
Synthesis: Counter ion exchange to synthesize 1a-2PF6 and 1d-
2PF6, X-ray diffraction analysis of the crystals thus obtained con-
firmed atomic connectivity and hexafluorophosphate ions. α,αЈ-m-
xylylene-N,NЈ-bis(2-phenylpyridinium) dihexafluorophosphate (1a-
2PF6): To a solution of α,αЈ-m-xylylene-N,NЈ-bis(2-phenylpyrid-
inium) dibromide,[13] 1a-2Br (66 mg, 0.115 mmol) in water (20 mL)
was added ammonium hexafluorophosphate (50 mg, 0.307 mmol).
A white precipitate formed immediately which dissolved upon heat-
ing under N2. Slow cooling of the solution to room temperature
gave white needle-like crystals of 1a-2PF6 (73.4 mg, 91% yield);
Acknowledgments
The authors thank the National Science Foundation USA (#
0111578) for funding this research; we are also grateful to the Uni-
versity of Kentucky’s Center for Computational Sciences.
[1] G. J. Karabatsos, D. J. Fenoglio in Rotational Isomerism about
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1,3-Bis[(biphenyl-2-yl)methyl]benzene (2a): Reactions were per-
formed under N2. An oven-dried, 50 mL flask, fitted with a con-
denser was charged with α,αЈ-dibromo-m-xylene (394.5 mg,
1.5 mmol), Pd(PPh3)4 (115.5 mg, 0.1 mmol), and 20 mL 1,2-dime-
thoxyethane (DME). The bright yellow solution was stirred at
room temperature for 20 min. Sequential addition of 2-biphenylbo-
ronic acid (682.4 mg, 3.45 mmol), tBuOK (672 mg, 6.0 mmol),
tBuOH (3.0 mL) and Ag2O[54] (1.4 g, 6.0 mmol) resulted in a dark
solution and the formation of a dark precipitate. The mixture was
refluxed under nitrogen at 85 °C for 17 h. The mixture was cooled,
concentrated in vacuo, and partitioned between EtOAc/H2O (1:1,
120 mL). The layers were separated and the aqueous layer was
washed with two additional 60 mL portions of EtOAc. The com-
bined organic layers were dried with MgSO4 and concentrated in
vacuo. Silica gel column chromatography (hexane/CHCl3, 4:1) gave
2a as a colorless solid that crystallized from 10:1 hexane/EtOAc
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Received: July 4, 2008
Published Online: August 28, 2008
Eur. J. Org. Chem. 2008, 5511–5517
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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