A redox-mediated molecular brake: Dynamic NMR study of 2-[2-(methylthio)phenyl]isoindolin-1-one and S-oxidized counterparts

Article abstract of DOI:10.1021/jo034613g

A redox-mediated molecular brake based on the sulfide-sulfoxide redox cycle is illustrated by modulation of the rotation rate of an N-Ar "shaft" by varying the oxidation state of sulfur in 2-[2-(sulfur-substituted)phenyl]-isoindolin-1-ones. N-Ar rotationa

Full text of DOI:10.1021/jo034613g

rate of rotation of an N-Ar “shaft” by varying the
oxidation state of a proximate sulfur atom in 2-[2-(sulfur-
substituted)phenyl]isoindolin-1-ones 1-3. Oxidized sulfur
acts as the braking mode (rotation hindered) while the
reduced [S(II)] counterpart shows “free” rotation. This
approach is attractive because there are numerous high-
yield chemical and electrochemical processes for both
sulfur oxidation to sulfoxide7,8 and sulfoxide deoxygen-
ation to sulfide.9,10 Thus, the processes of applying and
removing the brake are readily reversible, easily control-
lable actions.
A Red ox-Med ia ted Molecu la r Br a k e:
Dyn a m ic NMR Stu d y of
2-[2-(Meth ylth io)p h en yl]isoin d olin -1-on e
a n d S-Oxid ized Cou n ter p a r ts
Parag V. J og, Richard E. Brown, and Dallas K. Bates*
Department of Chemistry, Michigan Technological
University, 1400 Townsend Drive,
Houghton, Michigan 49931
dbates@mtu.edu
Received May 9, 2003
Abstr a ct: A redox-mediated molecular brake based on the
sulfide-sulfoxide redox cycle is illustrated by modulation
of the rotation rate of an N-Ar “shaft” by varying the
oxidation state of sulfur in 2-[2-(sulfur-substituted)phenyl]-
isoindolin-1-ones. N-Ar rotational barriers in methylsulfinyl
(2) and methylsulfonyl (3) derivatives (13.6 kcal mol-1) are
∼5 kcal mol-1 higher than sulfide 1. Rate reduction for N-Ar
rotation is ∼104 s-1 (280 K) upon oxidation. Correlated
N-pyramidalization/N-Ar rotation reduces the effectiveness
of the brake by decreasing the energy barrier to N-Ar bond
rotation.
Simple isoindolin-1-ones exist as enantiomeric rota-
tional isomers with slow rotation about the aryl C-N
bond giving rise to diastereotopic methylene protons.11
Ortho-substitution of the aryl group of 2-phenylisoindo-
lin-1-one with sulfur-containing groups (compounds 1-3)
had a pronounced line broadening effect on methylene
Rotational motion is an integral behavior of molecules.
Controlling these motions in a reproducible fashion is a
key design element for molecular machines. For a mo-
lecular brake,1 an integral component of a molecular
machine, reversibility and hindrance to motion are the
two most important aspects. Recently, organic molecules
designed specifically to achieve certain desired motions
leading to a molecular motor have been reported.2 For
example, a ratcheted “drive shaft” containing intramo-
lecular features which allow rotation of the shaft in only
one direction has been reported,3 and approaches to
intramolecular brakes based upon changes of pH,4 metal
ion concentration,1,5 or coordination number (or oxidation
state of the metal)6 have been disclosed.
1
proton signals in the H NMR spectra (25 °C) (Figure 1)
indicating the sulfur oxidation level dramatically affects
the rate of rotation about the N-Ar bond in these
compounds.
On cooling below -20 °C, the methylene “bump” in
sulfone (3) splits into an AB quartet (∆ν )191.5 Hz and
J AB ) 16.8 Hz at 400 MHz in the absence of exchange)
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We now wish to introduce the concept of an organic-
based redox-mediated molecular brake. The system is
based on the sulfide-sulfoxide redox cycle and is il-
lustrated in a minimalist system by modulation of the
* To whom correspondence should be addressed. Fax: (906) 487
2061. Phone: (906) 487 2059.
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10.1021/jo034613g CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003
8240
J . Org. Chem. 2003, 68, 8240-8243

process, the centerline of the absorptions migrated
linearly upfield, becoming constant in appearance and
chemical shift at about 120 °C (CDBr3). This behavior is
unique to the sulfoxide; both the sulfide and the sulfone
showed classical decoalescence upon warming from the
absence of exchange regime to give a singlet having a
chemical shift equal to the average values for Ha and Hb
in the low-temperature AB quartet. In analogy with
sulfide (1) and sulfone (3), coalescence of the low-
temperature AB quartet in sulfoxide (2) is a physical
manifestation of increased N-Ar rotation. However, in
2, even as Ha and Hb rapidly exchange, they are diaste-
reotopic due to the presence of the chiral sulfoxide moiety,
hence the reappearance of separate signals for Ha and
Hb at higher temperatures. In other words, as noted by
Lunazzi,12 sulfoxides which contain a chiral center and
also a stereogenic axis (in our case the N-Ar bond) will
display a set of conformational enantiomers (or atropi-
somers) at low temperature (under conditions of slow
exchange) and a pair of configurational enantiomers
when exchange is rapid.
F IGURE 1. 1H NMR spectra of isoindolin-1-one sulfide (1),
sulfoxide (2), and sulfone (3) (400 MHz, CDCl3, 25 °C).
For sulfoxide 2, ∆Gq and k were determined at the
coalescence temperature (280 K, 13.6 kcal mol-1 and 1.3
× 102 s-1, respectively). By comparison, k280 for 1 and 3
are 1.6 × 106 and 1.4 × 102 s-1, respectively. As expected
from the scant literature available,13 the sulfoxide and
sulfone barriers to rotation are very similar. Thus, at 280
K, oxidation of sulfide 1 to either the sulfoxide 2 or
sulfone 3 slows this rate of rotation by about 104 s-1 14
.
Based on a “rigid shaft” model, we had expected an
increase in rotational barrier of more than 5 kcal/mol
upon sulfur oxidation. Examination in models of the
N-Ar rotation reveals a severe steric interaction during
F IGURE 2. Line-shape analysis of 1.
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Parts a and b of ref 13 are more representative of the molecular motions
in 1-3.
TABLE 1. NMR P a r a m eter s a n d Th er m od yn a m ic Da ta
for Isoin d olin -1-on es (1-3)
∆G- d
TC
(K)
∆H-
∆S-
∆G- c
(kcal mol-1
)
compd
(kcal mol-1
)
(cal mol-l
)
(kcal mol-1
)
(computed)
1a
2b
3b
<188
280
295
8.10
-1.5
8.4 (8.6)
(13.6)
13.6 (13.7)
9.2, 9.0
10.4, 11.9
17.2, 13.5
12.2
4.9
a
b
NMR in toluene-d8. NMR in CDCl3. c Experimental value
d
from line-shape analysis or (coalescence measurement). Calcu-
lated from minima on either side of the transition state.
with a coalescence temperature (Tc) of 22 °C. These data
provide a value of 13.7 kcal/mol (57.2 kJ /mol) for the free
energy of activation (∆Gq) of 3. Line-shape analysis of
spectra obtained at various temperatures confirms this
value (∆Gq ) 13.6, 56.9 kJ /mol) and allows calculation
of ∆Hq and ∆Sq (Table 1). Similarly, sulfide (1) gives Tc
) -85 °C (188 K) and ∆Gq ) 8.56 kcal/mol (35.8 kJ /mol)
[∆Gq ) 8.40 kcal/mol (35.1 kJ /mol) by line-shape analy-
sis]. The rate data obtained from line-shape analysis of
1H NMR spectra of 1 are shown in Figure 2.
1
Analyses of the variable-temperature (VT) H NMR
spectra of sulfoxide 2 were problematic. The methylene
signals appeared as an AB quartet in the absence of
exchange (Ha ) 4.95, Hb ) 4.85, J ) 16.78 Hz, CDCl3,
-60 °C). As the sample was warmed these peaks gradu-
ally collapsed to a single broad peak and, upon further
heating, decoalesced into another AB quartet (Ha ) 4.86,
Hb ) 4.80, J ) 16.78 Hz, CDCl3, 50 °C). Throughout this
J . Org. Chem, Vol. 68, No. 21, 2003 8241

F IGURE 4. Surface plot of N-Ar angle and virtual dihedral
angle for 1.
F IGURE 3. Potential energy surface plot for 1 (Gaussian 98).
work (∼8.5 kcal mol-1). Similar calculations were per-
formed on 2 and 3 (Table 1). These values also agree quite
well with experimental results but are not as close as
for 1. Theoretical values may deviate slightly from the
experimental values due to chirality considerations or
parametrizations in the PM3 program. The barrier to
passage of o-SMeAr over the methylene portion of the
isoindolinone is calculated to be much lower than for
passage over the carbonyl (3.3 kcal mol-1).
A major finding of the calculations is that pyramidal-
ization of the amidic nitrogen is predicted in all three
2-(o-substituted phenyl)isoindolinone derivatives. This
process cannot be observed by NMR in our model
systems. Calculations show the degree of nitrogen pyra-
midalization18 in the highest energy conformations greatly
increases with the initial oxidation from -S- to SdO
(9.6° to 13.3°), but changes little upon further oxidation
(13.3° to 13.9° in the sulfone). One can visualize nitrogen
pyramidalization during N-Ar bond rotation in our
model system as a “wobbling” rotating shaft rather than
a rigid rotating shaft. At torsion angles where steric
repulsion of the indolinone ring and o-Ar substituent is
minimal, N-pyramidalization is also minimal. However
as the steric interaction increases so does N-pyramidal-
ization.
the passage of the ortho substituents over the carbonyl
group during rotational interconversion of enantiomers.
Transition-state nitrogen pyramidalization to avoid steric
interactions during rotational motion has been reported.15
To get a better picture of rotational processes and to
determine theoretical rotational barriers, semiempirical
molecular orbital calculations were performed on com-
pounds 1-3.16 Figure 3 shows the potential energy
surface diagram for sulfide 1 for concurrent N-Ar and
S-Ar rotations, with central maxima and minima on
either side indicating noncorrelated N-Ar and S-Ar
rotations.17 The calculated barrier is ∼9 kcal/mol for
passage of o-SMeAr over the carbonyl group, which
matches well with the values obtained from experimental
(14) As a practical matter, oxidation to the sulfone state offers little
or no increase in the barrier to rotation, while methods for converting
sulfones to sulfides are not nearly as diverse nor simply executed as
for sulfoxide deoxygenation. This is why our focus is on the S T SdO
redox cycle even though DNMR studies are, in general, easier to
conduct on sulfone derivatives.
(15) (a) Tsubrik, O.; Burk, P.; Pehk, T.; Maeorg, U. THEOCHEM
2001, 546, 119. (b) Yamamoto, G.; Nakajo, F.; Mazaki, Y. Bull. Chem.
Soc. J pn. 2001, 74, 1973. (c) Kiefl, C. Eur. J . Org. Chem. 2000, 3279.
(d) Glover, S. A.; Mo, G.; Tucker, D. J .; Turner, P. J . Chem. Soc., Perkin
Trans. 2 1999, 2053. (e) Ferretti, V.; Bertolasi, V.; Gilli, P.; Gilli, G. J .
Phys. Chem. 1993, 97, 13568. (f) Bennet, A. J .; Somayaji, V.; Brown,
R. S.; Santarsiero, B. D. J . Am. Chem. Soc. 1991, 113, 7563. (g) Gilli,
G.; Bertolasi, V.; Bellucci, F.; Ferretti, V. J . Am. Chem. Soc. 1986, 108,
2420.
(16) PM3 method as implemented in Gaussian 98: Frisch, M. J .;
Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman,
J . R.; Zakrzewski, V. G.; Montgomery, J . A., J r.; Stratmann, R. E.;
Burant, J . C.; Dapprich, S.; Millam, J . M.; Daniels, A. D.; Kudin, K.
N.; Strain, M. C.; Farkas, O.; Tomasi, J .; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J .;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski, J .; Ortiz,
J . V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.; Al-laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P.
M.; J ohnson, B. G.; Chen, W.; Wong, M. W.; Andres, J . L.; Head-
Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian 98, revision A.7;
Gaussian, Inc.: Pittsburgh, PA, 1998.
The calculations suggest (and it is reasonable to expect)
N-Ar rotation and N-pyramidalization to be coupled or
correlated motions. The coordinated movement of two
proximate groups in order to minimize steric interactions
during rotation of these groups is termed correlated or
cogwheel rotation and is a well-studied phenomenon.17,19-21
Motions in which rotation is coupled to nitrogen inversion
(18) Different measures have been used to describe nitrogen pyra-
midalization: (a) Degree of pyramidalization equals 360 - ∑ bond
angles to the nitrogen atom (Ganguly, B.; Freed, D. A.; Kozlowski, M.
C. J . Org. Chem. 2001, 66, 1103). (b) Measurement of a virtual dihedral
angle (Rankin, K. N.; Boyd, R. J . J . Phys. Chem. A 2002, 106, 11168)
and (c) measurement of the distance from the nitrogen atom to the
plane containing by the three atoms bonded to nitrogen (Schweizer,
W. B.; Procter, G.; Kaftory, M.; Dunitz, J . D. Helv. Chim. Acta 1978,
61, 2783).
(17) (a) Casarini, D.; Grilli, S.; Lunazzi, L.; Mazzanti, A. J . Org.
Chem. 2001, 66, 2757. (b) Grilli, S.; Lunazzi, L.; Mazzanti, A. J . Org.
Chem. 2001, 66, 4444. (c) Grilli, S.; Lunazzi, L.; Mazzanti, A. J . Org.
Chem. 2001, 66, 5853.
(19) Mislow, K. Acc. Chem. Res. 1976, 9, 26.
8242 J . Org. Chem., Vol. 68, No. 21, 2003

have been studied extensively by both experimental and
computational methods22 and correlated rotation-nitro-
gen pyramidalization has been studied computationally.23
Lunazzi17 has developed a graphical method to demon-
strate correlated bond rotations by generating a contour
map of the potential energy surface described by incre-
mental rotations of the dihedral angles about the bonds
suspected of correlated rotation. Correlated rotation is
present when the rotation pathways (indicated by lines
joining energy minima) run diagonal to the x-y axes and
parallel to each other. To demonstrate computationally
the correlated nature of N-Ar rotation and N-pyrami-
dalization in 1-3, we have developed a variant of the
Lunazzi graphical approach: a “virtual dihedral angle”
is plotted against the N-Ar torsion angle. Rankin and
Boyd18b introduced the virtual dihedral angle as a means
of quantitating nitrogen pyramidalization. The virtual
dihedral angle given by C1-N2-C3-C4 (see structure
1) in compounds 1-3 having a value of 180° corresponds
to planar nitrogen (flat, sp2, degree of pyramidalization18a
) 0°) and a value of 120° corresponds to tetrahedral
nitrogen (sp3, degree of pyramidalization ) 31.5°). In the
calculations (PM3), the virtual dihedral angle and the
N-Ar torsion angle were locked, and then the other
angles and bond distances were allowed to relax to their
minima for each of the locked values. The N-Ar torsion
angle values were fixed in 20° increments from 0 to 360°
and virtual dihedral angle values were fixed in 10°
increments from -90° to +90°. The resulting plot (Figure
4) has the appearance of a Lunazzi diagram, but relates
N-Ar rotation to N-pyramidalization. Thus, diagonal
lines joining the energy minima in Figure 4 are indicative
of correlated motions.
Conversely engagement of the brake may be observed by
addition of a solution of m-CPBA (in CDCl3) to an NMR
sample of compound 1 equilibrated to -40 °C in the NMR
probe. This leads to a rapid replacement of the broad
singlet (δ 4.78) corresponding to the methylene hydrogen
atoms in the slowly rotating sulfide with an AB quartet
(δ 4.95) corresponding to the methylene hydrogen atoms
in the absence of N-Ar rotation in sulfoxide 2. These
reagents are nearly ideal for these experiments because
the reactions are rapid (even at -40 °C), quantitative,
and exhibit no interfering peaks in the region δ 4-5. A
sample spectrum from titration of 1 with m-CPBA to
approximately 80% conversion at -40 °C in an NMR tube
is shown in Figure 5 (Supporting Information). The redox
conversions may also be monitored by changes in inten-
sity of the methyl signals in 1 (δ 2.41) and 2 (δ 3.05).
In conclusion, we have shown that the rate of N-Ar
rotation in isoindolin-1-ones 1-3 is controlled by the
oxidation state of sulfur in a proximate ortho substituent.
The rate difference between sulfane and the sulfinyl/
sulfonyl forms is ∼104 s-1. The model compounds are
shown computationally to undergo correlated N-pyrami-
dalization and C-N bond rotation. As the o-Ar substitu-
ent passes the plane of the isoindolinone, N-pyramidal-
ization reaches maximum, but the nitrogen becomes
planar when the isoindolinone and Ar groups are nearly
orthogonal. Pyramidalization of nitrogen causes the redox
brake to be less effective than expected. Design of a
system in which shaft element flexing (in the form of
atom pyramidalization) is avoided should provide more
dramatic rate reductions using this molecular brake
concept.
Ack n ow led gm en t. We thank the NSF for an equip-
ment grant (CHE-9512445). P.V.J . thanks the Chem-
istry Department of Michigan Technological University
for financial support. The assistance of Mr. J erry L. Lutz
(NMR instrumental assistance) and Mr. Shane Crist
(computer system administration) is gratefully acknowl-
edged.
Redox disengagement/engagement of the molecular
brake can be observed in situ in an NMR tube. Addition
of a solution of Lawesson’s reagent9k (in CDCl3) to an
NMR sample of compound 2 equilibrated to -40 °C in
the NMR probe leads to a rapid replacement of the AB
quartet (δ 4.95) observed for the methylene hydrogen
atoms in the “stopped” sulfoxide with a broad singlet (δ
4.78) corresponding to the methylene hydrogen atoms in
sulfide 1 as rotation about the N-Ar bond takes place.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for preparation and characterization of compounds 1-3,
1H and 13C NMR spectra for compounds 1-3, 3D potential
energy surface plots for 2 and 3, PM3-computed Z-matrices
for the lowest energy conformation of compounds 1-3 (when
N-Ar and S-Ar torsion angles are locked and incremented),
2D surface plots of N-Ar torsion angle vs virtual dihedral
angle for 2 and 3, rate data for 3 from line-shape analysis,
and PM3-computed Z-matrices for the lowest energy confor-
mation of compounds 1-3 (when N-Ar and the virtual
dihedral angle torsion angle are locked and incremented). This
material is available free of charge via the Internet at
http://pubs.acs.org.
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