Radial control of recognition and redox processes with multivalent nanoparticle hosts

Article abstract of DOI:10.1021/ja016894k

Mixed Monolayer Protected Gold Clusters (MMPCs) featuring both hydrogen bonding and aromatic stacking molecular recognition functionalities have been used to create multivalent hosts for flavins. Multitopic binding of these hosts to flavin was shown to have a strong radial dependence: when the recognition site was brought closer to the MMPC surface, recognition was enhanced ～3-fold due to increased preorganization. The effect of preorganization is reversed upon reduction of flavin, where the MMPC with longer side chains bind the flavin guest ～7-fold stronger than the short chain counterpart due to unfavorable dipolar interactions between the electron-rich aromatic stacking units of the host and the anionic flavin guest. This fine-tuning of recognition and redox processes provides both a model for enzymatic systems and a tool for the fabrication of devices.

Full text of DOI:10.1021/ja016894k

Published on Web 04/17/2002
Radial Control of Recognition and Redox Processes with
Multivalent Nanoparticle Hosts
Andrew K. Boal and Vincent M. Rotello*
Contribution from the Department of Chemistry, UniVersity of Massachusetts,
Amherst, Massachusetts 01003
Received August 20, 2001
Abstract: Mixed Monolayer Protected Gold Clusters (MMPCs) featuring both hydrogen bonding and
aromatic stacking molecular recognition functionalities have been used to create multivalent hosts for flavins.
Multitopic binding of these hosts to flavin was shown to have a strong radial dependence: when the
recognition site was brought closer to the MMPC surface, recognition was enhanced ∼3-fold due to increased
preorganization. The effect of preorganization is reversed upon reduction of flavin, where the MMPC with
longer side chains bind the flavin guest ∼7-fold stronger than the short chain counterpart due to unfavorable
dipolar interactions between the electron-rich aromatic stacking units of the host and the anionic flavin
guest. This fine-tuning of recognition and redox processes provides both a model for enzymatic systems
and a tool for the fabrication of devices.
Introduction.
Conversely, recognition-mediated control of redox processes
provides a tool for the creation of molecular scale electronic
devices.8,5c
Tuning of cofactor reduction potentials through redox-state
dependent interactions is central to the function of redox
enzymes. For example, flavoproteins use specific interactions
such as hydrogen bonding, aromatic stacking, and dipolar effects
to regulate the recognition, and hence redox potential of the
flavin cofactor in various oxidation states.1 Preorganization of
the flavin binding site in these enzymes is determined through
a complex pattern of intraprotein and protein-cofactor interac-
tions provided by the protein matrix. The degree of preorgani-
zation of the active site plays an important role in controlling
cofactor redox processes,2 variably enhancing favorable and
enforcing unfavorable protein-cofactor interactions in different
cofactor redox states.3
While there have been a number of systems made to explore
mono- and multivalent redox-dependent host-guest interac-
tions,9 the ability to tune recognition and redox properties
through control of preorganization remains an important chal-
lenge.10 Mixed Monolayer Protected Gold Clusters (MMPCs)11
bearing molecular recognition elements in the monolayer12,13
are a potential tool for creating tunable receptors for model
systems14 and device applications.15 The monolayer coatings
of MMPCs are radial in nature: order decreases with increasing
distance from the gold core.16 This effect has been probed earlier
(7) Otsuki, J.; Tsujino, M.; Iizaki, T.; Araki, K.; Seno, M.; Takatera, K.;
Watanabe, T. J. Am. Chem. Soc. 1997, 119, 7895-7896.
Effective models and mimics of enzymatic systems enhance
our understanding of these complex systems.4,5 Moreover, redox
enzymes provide prototypes for the creation of devices: bio-
mimetic redox modulation of recognition processes allows
access to molecular devices such as shuttles6 and switches.7
(8) Pease, A. R.; Jeppesen, J. O.; Stoddart, J. F.; Luo, Y.; Collier, C. P.; Heath,
J. R. Acc. Chem. Res. 2001, 43, 433-444.
(9) See, inter alia: (a) Kaifer, A. E. Acc. Chem. Res. 1999, 32, 62-71. (b)
Yano, Y. ReV. Heteroatom Chem. 2000, 22, 151-179.
(10) (a) Fernandez-Saiz, M.; Schneider, H.-J.; Sartorius, J.; Wilson, D. W. J.
Am. Chem. Soc. 1996, 118, 4739-4745. (b) Hettich, R.; Schneider, H.-J.
J. Am. Chem. Soc. 1997, 119, 5638-5647.
* Corresponding author. E-mail: rotello@chem.umass.edu.
(1) Fraaije, M. W.; Mattevi, A. Trends Biochem. Sci. 2000, 25, 126-132. For
an extensive discussion of flavoenzyme structure and function, see:
Chemistry and Biochemistry of FlaVoenzymes; Mu¨ller, F., Ed.; CRC: Boca
Raton, FL, 1991; Vols. 1-3.
(2) Kasim, M.; Swenson, R. P. Biochemistry 2000, 39, 15322-15332.
(3) (a) Anthony, C. Biochem. J. 1996, 320, 697-711. (b) Ghisla, S.; Massey,
V. Eur. J. Biochem. 1989, 181, 1-17. (c) Popov, V.; Lamzin, V. S.
Biochem. J. 1994, 301, 625-643. (d) Blakley, R. L.; Benkovic, S. J.
Chemistry and Biochemistry of Pterins; Wiley: New York, 1985.
(4) For a recent example of the synergy between biochemical studies and model
systems of flavoenzymes, see: Bradley, L. H.; Swenson, R. P. Biochemistry
2001, 40, 8686-8695. Cuello, A. O.; McIntosh, C. M.; Rotello, V. M. J.
Am. Chem. Soc. 2000, 122, 3517-3521
(5) (a) Kirby, A. J. Acc. Chem. Res. 1997, 30, 290-296. (b) Riley, D. P. Acc.
Chem. Res. 1999, 32, 2573-2588. (c) Niemz, A.; Rotello, V. M. Acc. Chem.
Res. 1999, 32, 44-52. (d) Gust, D.; Moore, T. A.; Moore, A. L. Acc. Chem.
Res. 2001, 34, 40-48. (e) Hasford, J.; Kemnitzer, W.; Rizzo, C. J. Org.
Chem. 1997, 62, 5244-5245.
(6) Anelli, P. L.; Spencer, N.; Stoddart, J. F. J. Am. Chem. Soc. 1991, 113,
5131-5132.
(11) (a) Brust, M.; Walker, M.; Bethell, D.; Schiffrin, D. J.; Whymann, R. J.
Chem. Soc., Chem. Commun. 1994, 801-802. (b) Hostetler, M. J.;
Templeton, A. C.; Murray, R. W. Langmuir 1999, 15, 3782-3789.
(12) For a recognition study in a planar SAM, see: Motesharei, K.; Myles, D.
C. J. Am. Chem. Soc. 1998, 120, 7328-7336.
(13) For a flavoenzyme model study using a planar SAM, see: Tam-Chang,
S.-W.; Mason, J.; Iverson, I.; Hwang, K.-O.; Leonard C. J. Chem. Soc.,
Chem. Commun. 1999, 65-66.
(14) (a) Boal, A. K.; Rotello, V. M. J. Am. Chem. Soc. 1999, 121, 4941-4942.
(b) Boal, A. K.; Rotello, V. M. J. Am. Chem. Soc. 2000, 122, 734-735.
(15) (a) Shipway, A. M.; Willner, I. Acc. Chem. Res. 2001, 34, 421-432. (b)
Liu, J.; Xu, R.; Kaifer, A. E. Langmuir 1998, 14, 7337-7339. (c) Aherne,
D.; Rao, S. N.; Fitzmaurice, D. J. Phys. Chem. B 1999, 103, 1821-1825.
(d) Fitzmaurice, D.; Rao, S. N.; Preece, J. A.; Stoddart, J. F.; Wenger, S.;
Zaccheroni, N. Angew. Chem., Int. Ed. Engl. 1999, 38, 1147-1150. (e)
Liu, J.; Alvarez, J.; Kaifer, A. E. AdV. Mater. 2000, 12, 1381-1383. (f)
Labande, A.; Astruc, D. Chem. Commun. 2000, 1007-1008. (g) Kim, Y.;
Johnson, R. C.; Hupp, J. T. Nano Lett. 2001, 1, 165-167.
(16) (a) Luedtke, W. D.; Landman, U. J. Phys. Chem. 1996, 100, 13323-13329.
(b) Hostetler, M. J.; Stokes, J. J.; Murray, R. W. Langmuir 1996, 12, 3604-
3612.
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J. AM. CHEM. SOC. 2002, 124, 5019-5024
5019

A R T I C L E S
Boal and Rotello
Table 1. Binding Constants and Reduction Potentials for
MMPC-Fl Complexes
-
K (Flox
)
∆G
(kcal/mol)
∆E
K (Flrad
)
∆G
a
(kcal/mol)
a
a
1/2
(mV)a
a
MMPC
(M-1 a
)
(M-1 a
)
1
2
3
4
196 ( 8b
185 ( 11
320 ( 20c
930 ( 47
-3.09
-3.06
-3.38
-4.01
+86b
+75
+49
-26
6400 ( 1100
3900 ( 800
2300 ( 400
<320
-5.1
-4.8
-4.5
<-3.4
a At 296 K, all E1/2 values are (5 mV. Uncertainties for Ka(Flox) were
obtained from the standard error of the titration curve fit. Uncertainties for
-
Ka(Flrad ) were based upon the uncertainty of Ka(Flox) coupled with a (5
mV uncertainty in the E1/2.
b Values from ref 14a. c From ref 14b.
during sequential addition of each of the hosts were readily fitted
to a 1:1 binding isotherm.20 As expected, there was no difference
in the affinity of monotopic receptors 1 and 2 on the recognition
of Flox (Table 1). In contrast, there was a large radial effect
observed for ditopic MMPC receptors 3 and 4. With the longer
chain length system, ditopic receptor 3 binds Flox ∼2-fold more
strongly than the corresponding monotopic receptor 1. A much
stronger enhancement in recognition is observed with shorter
chain length, with ditopic receptor 4 binding Flox ∼5-fold more
strongly than monotopic receptor 2. The greater contribution
of aromatic stacking to binding in the shorter chain length
MMPC 4 is a direct outcome of the increased preorganization
of this system.21
To further quantify radial control over multivalent binding
of MMPC hosts 1-4 on Fl, the reduction potential of Fl in the
presence of these hosts was measured using Square Wave
Voltammetry (SWV) (Figure 2). Addition of MMPCs 1 and 2
made the potential of the Flox-Flrad- reduction substantially less
negative due to the hydrogen bond-mediated stabilization of
Flrad- (Table 1).5c As was observed for binding of Flox by
monotopic receptors 1 and 2, there was no appreciable effect
of chain length on the observed reduction potential of Fl. Ditopic
receptors 3 and 4, however, had strikingly different effects on
the reduction potential of Fl, with the longer chain length
MMPC 3 making the reduction potential less negative and the
shorter chain length MMPC 4 making this potential more
negative.
Figure 1. MMPCs 1-4 and flavin Fl.
by us in a study of intramonolayer hydrogen bonding in
MMPCs, where a steady decrease in hydrogen bonding ef-
ficiency was observed.17 We report here the extension of this
radial control to the redox-specific multivalent recognition of a
flavin guest.
The differing effects of MMPCs 1-4 on the reduction
potential of Fl can be understood by comparing the binding of
these receptors to Flox and Flrad-. The binding constants of
MMPCs 1-4 with Flrad- provided in Table 1 were obtained
through the relation:
Results and Discussion
To provide a series of MMPCs for quantifying the effect of
chain length on mono- and ditopic recognition of flavin Fl,
MMPCs 1-4 were prepared (Figure 1). In this family, MMPCs
1 and 2 are functionalized with only hydrogen-bonding elements
(diaminopyridine) while MMPCs 3 and 4 contain both hydrogen-
bonding and aromatic stacking (pyrene) elements. Comparison
of MMPCs 1 and 2 featuring monotopic recognition sites with
ditopic MMPC receptors 3 and 4 respectively then allows direct
quantification of the effects of multitopic interaction. For all
MMPCs, the core size was ∼1.5 nm in diameter.18 Monolayer
composition was determined using NMR endgroup analysis. The
monolayers for MMPCs 1-4 contained approximately 12, 8,
12, and 11 diaminopyridine recognition sites (of a total of ∼90
total ligands), respectively.19
Ka(red)
1/2(bound)-E1/2(unbound))
) e(nF/RT)(E
(1)
Ka(ox)
A summary of association constants of both Flox and Flrad- to
MMPC hosts 1-4 is given in Figure 3.22 As expected from the
increase in electron density at the imide carbonyls that occurs
(20) See Supporting Information for titration plots.
(21) The increase in recognition observed for the diaminopyridine-pyrene
systems arising from multivalent recognition indicates the absence of
extensive phase segregation in these systems.
(22) Application of Formula (1) requires an accurate measurement of E1/2
(bound). With the slow scan rates used in this experiment, the degree of
binding observed during the reduction process is determined by the higher
Recognition of Flox by MMPCs 1-4 was quantified through
NMR titration in CDCl3. The shifts of the N(3) proton of Flox
-
affinity process (i.e. Flrad binding by MMPCs 1-3, and Flox by MMPC
4). By this measure, >90% complexation is predicted for each of the host-
guest dyads except MMPC 4 (where we can only obtain an upper limit for
the calculated affinity). For further examples of complexation at relatively
low host concentrations, see: Rotello, V. M. In Molecular Recognition
and Inclusion; Coleman, A., Ed.; Kluwer: Amsterdam, The Netherlands,
1998; pp 479-482.
(17) Boal, A. K.; Rotello, V. M. Langmuir 2000, 16, 9527-9532.
(18) Determined from UV-vis spectra, see: Duff, D. G.; Baiker, A.; Edwards,
P. P. J. Chem. Soc., Chem. Commun. 1993, 96-97.
(19) See: Ingram, R. S.; Hostetler, M. J.; Murray, R. W. J. Am. Chem. Soc.
1997, 119, 9175-9178.
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5020 J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002

Radial Control of Recognition and Redox Processes
A R T I C L E S
Figure 2. Square wave voltammograms of Fl (a) alone and with (b) MMPC
1, (c) MMPC 2, (d) MMPC 3, and (e) MMPC 4. Voltammograms were
recorded under the following conditions: [Fl] ) 0.05 mM (0.025 mM for
d); 100 equiv of MMPC-attached diaminopyridine units; solvent, CH2Cl2;
supporting electrolyte, 0.1 M Bu4NClO4; internal ferrocene reference set
to 0 mV potential; scan period, 400 ms; step height, 2 mV; T ) 23 °C.
Figure 4. Representation of the expected effects on chain length in redox-
-
modulated binding of Flox/Flrad to MMPCs with multivalent binding sites
(a) far from and (b) close to the nanoparticle surface as well as (c) a small
molecular multivalent receptor, 9.
corresponding mono- and multitopic MMPC receptors. For long
side chain MMPC 3, aromatic stacking increases the affinity
-
Figure 3. Association constants of Flox and Flrad to MMPCs 1-4.
upon reduction of the flavin moiety, monotopic MMPCs 1 and
2 show strongly enhanced binding of Flrad- relative to Flox. The
affinities of these two systems for Flrad- are similar, with the
longer chain system binding slightly more strongly, most likely
due to a slightly greater degree of congestion at the surface of
the shorter monolayer.
for Flox by 0.3 kcal/mol, and decreases the affinity for Flrad-
by 0.6 kcal/mol relative to the corresponding MMPC 1. For
the shorter side chain receptors 2 and 4 this effect is magnified,
with the aromatic stacking of 4 enhancing binding of Flox by
0.95 kcal/mol, and decreasing the binding affinity for Flrad- by
1.7 kcal/mol. The enhancement in binding of Flox by receptors
3 and 4 as compared to hosts 1 and 2 arises from the favorable
stacking interaction of the electron-deficient Flox with the
electron-rich pyrene side chains. Similarly, the decrease in
affinity of 3 and 4 with Flrad- arises from unfavorable interac-
The ditopic MMPCs 3 and 4 possess opposite selectivities
for Flox relative to Flrad-: MMPC 3 preferentially binds Flrad
-
while MMPC 4 preferentially binds Flox. This inversion in redox
state preference can be rationalized by comparison of the
9
J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002 5021

A R T I C L E S
Boal and Rotello
Scheme 1. Synthesis of MMPC 2
tions between the now electron-rich Flrad- and the electron-
rich pyrene (Figure 4a,b). The differences in these systems are
a direct consequence of the alkane chain length used to attach
the recognition elements to the nanoparticle surface. For MMPC
3, which is made with 11 carbon chains, the elements are not
tightly packed (Figure 4a). When Fl undergoes reduction, the
pyrene components can move away from the anion and thus
minimize repulsive interactions. This is not possible for MMPC
4, where the 6 carbon alkane chains translate into a denser
monolayer, providing a system that is unable to relieve repulsive
stacking interactions (Figure 4b). This enforcement of unfavor-
able interactions mimics that observed in a number of flavo-
enzymes,23 with the preorganization provided by the monolayer
serving the same role as that provided by the active site. It should
be noted that this behavior was not observed in our previous
small molecule multitopic enzyme models, e.g. 9 (Figure 4c).5c
In these systems, the mobility of the anthracene ring allows it
to move away from Flrad-, thus precluding the ability of the
system to enforce repulsive interactions.24
Conclusions
In summary, we have demonstrated that the radial structure
of MMPC monolayers can be used to tune multivalent recogni-
tion of guest molecules. This modulation of recognition arises
from the decrease in preorganization that occurs as the attached
recognition elements are moved further away from the nano-
particle surface. Extension of this process to redox-active guests
provides a biomimetic means of controlling guest redox
potential, and concomitantly a tool for regulating redox-state-
specific binding of guest systems. The ability to control
multivalent molecular recognition processes using monolayer
packing to enforce both attractive and repulsive interactions is
a unique aspect of functionalized MMPCs, and provides a new
tool for the creation of both enzyme models and functional
molecule-based materials.
12.6 mmol, 1.4 mL) was then added dropwise. The reaction was
subsequently stirred overnight at room temperature, during which time
it became turbid. The reaction was quenched by the addition of H2O,
washed once with a saturated aqueous NaCl solution, and dried over
MgSO4. Solvent removal yielded an orange/brown oily solid, which
was purified by column chromatography (SiO2; EtOAc) to yield the
1
product as a white solid (2.7 g, 92% yield). H NMR (CDCl3, 200
MHz) δ (ppm) 7.90, 7.77, 7.69 (d, J ) 7.9 Hz; bs; t, J ) 7.9 Hz total
5H), 5.58 (m, 1H), 5.07 (m, 2H), 2.48 (m, 4H), 2.18 (s, 3H). IR (thin
film from CH2Cl2 on NaCl plate) νmax 3280, 3078, 2992, 2935, 1670,
1586, 1510, 1450, 1296, 1232, 1160, 995, 920, 810 cm-1. Anal. Calcd
for C12H15N3O2: C, 61.79; H, 6.48; N, 18.00. Found: C, 61.59; H,
6.48; N, 17.86.
2-N-Acetyl-6-N-(5-S-acetylmercaptopentanoyl)diaminopyridine
(11). 10 (2.5 g, 10.7 mmol) was dissolved in 40 mL of toluene in a
100 mL round-bottom flask. Thiolacetic acid (1.67 g, 22 mmol, 1.6
mL) and AIBN (∼100 mg) were then added and Ar was bubbled
through the solution for 30 min. The solution was then stirred at reflux
for 3 h and cooled to room temperature. The reaction was washed once
each with saturated aqueous NaHCO3 and NaCl solutions, then dried
over MgSO4. Solvent removal yielded a yellow/orange solid, which
was purified by column chromatography (SiO2; EtOAc) to yield the
Experimental Section.
General. 2-amino-6-acetylamidopyridine,25 flavin Flox,26 and MMPCs
1 and 314 were prepared according to literature methods. Toluene and
CH2Cl2 were distilled over CaH2 under argon. All reactions were carried
1
out in oven-dried glassware under an atmosphere of argon. H NMR
spectra were recorded in CDCl3 (purchased from Cambridge Isotope
Labs, Inc.) at 200 MHz and referenced internally to TMS at 0.0 ppm.
NMR spectra involving colloids were taken in CDCl3 that had been
stirred over K2CO3 for at least 24 h prior to use since it was found that
residual acid sometimes caused rapid decomposition of colloids. All
reagents and other solvents were used as received from commercial
sources. NMR titrations and electrochemical experiments were run as
previously described.14
2-N-Acetyl-6-N-(4-pentenoyl)diaminopyridine (10). 2-Amino-6-
acetylamidopyridine (1.9 g, 12.6 mmol) and triethylamine (3.1 g, 25.2
mmol, 4.2 mL) were dissolved in 100 mL of CH2Cl2 and cooled to
-78 °C in a 250 mL round-bottom flask. 4-Pentenoyl chloride (1.5 g,
1
product as a pale yellow solid (2.5 g, 76% yield). H NMR (CDCl3,
200 MHz) δ (ppm) 7.88 (d, 2H, J ) 8.3 Hz); 7.69 (t, 1H, J ) 7.9 Hz),
7.57 (bs, 2H), 2.91 (t, 2H, J ) 6.9 Hz), 2.41, 2.34 (m, s, 5H), 2.20 (s,
3H), 1.70 (m, 4H). IR (thin film from CH2Cl2 on NaCl plate) νmax 3270,
3080, 2490, 1673, 1589, 1511, 1462, 1303 cm-1. Anal. Calcd for
C14H19N3O3S: C, 54.36; H, 6.19; N, 13.58. Found: C, 54.50; H, 6.15;
N, 13.54.
2-N-Acetyl-6-N-(5-mercaptopentanoyl)diaminopyridine (5). 11
(1.0 g, 3.23 mmol) was dissolved in 20 mL of MeOH in a 50 mL
round-bottom flask. The clear solution was next purged for 20 min
with Ar, followed by the addition of NaOMe (0.6 g, 7.0 mmol, 1.5
mL of a 30 wt % solution in MeOH) followed with an additional 10
min of Ar purge. The reaction was then allowed to stir overnight, and
was quenched by the addition of excess saturated aqueous NH4Cl and
removal of the methanol. The resulting slurry was then dissolved in
EtOAc and washed twice with H2O and once with saturated aqueous
NaCl and dried over MgSO4. Solvent removal yielded a light yellow
solid, which was purified by column chromatography (SiO2; 1:1 EtOAc:
hexanes) to yield the product as a white solid (800 mg, 92% yield). 1H
(23) (a) Ludwig, M. L.; Luschinsky, C. L. In Chemistry and Biochemistry of
FlaVoenzymes; Mueller, F., Ed.; CRC Press: Boca Raton, FL, 1990; Vol.
3, pp 427-466. (b) Swenson, R.; Krey, G.; Eren, M. In FlaVins and
FlaVoproteins; Edmondson, D., McKormick, D., Eds.; de Gruyter: Berlin,
Germany, 1987; pp 98-107.
(24) For a system where aromatic stacking was enforced through covalent and
hydrophobic forces, see: Seward E. M.; Hopkins R. B.; Sauerer W.; Tam
S. W.; Diederich F. J. Am. Chem. Soc. 1990, 112, 1783-1790
(25) Bernstein, J.; Stearns, B.; Shaw, E.; Lott, W, A. J. Am. Chem. Soc. 1947,
69, 1151-1154.
(26) Breinlinger, E.; Niemz, A.; Rotello, V. M. J. Am. Chem. Soc. 1995, 117,
5379-5380.
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5022 J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002

Radial Control of Recognition and Redox Processes
A R T I C L E S
Scheme 2. Synthesis of MMPC 4
NMR (CDCl3, 200 MHz) δ (ppm) 7.89 (d, 2H, J ) 8.4 Hz), 7.70 (t,
1H, J ) 7.8 Hz), 2.57 (q, 2H, J ) 6.9 Hz), 2.40 (t, 2H, J ) 7.4 Hz),
2.20 (s, 3H), 1.56 (m, 4H), 1.38 (t, 1H, J ) 7.9 Hz). IR (thin film
from CH2Cl2 on NaCl plate) νmax 3275, 3081, 2928, 2875, 1675, 1591,
1511, 1423, 1305 cm-1. Anal. Calcd for C12H18N3O2S: C, 53.72; H,
6.76; N, 15.66. Found: C, 53.90; H, 6.65; N, 15.55.
MMPC 7. HAuCl4‚3H2O (250 mg, 0.64 mmol) was dissolved in
150 mL of deionized H2O in a 500 mL round-bottom flask to give a
golden yellow solution. Tetra-n-octylammonium bromide (700 mg, 1.3
mmol) and 150 mL of toluene were then added and the mixture was
stirred. After 15 min, the organic layer had become dark red and the
aqueous phase colorless. Pentanethiol (80 mg, 0.77 mmol, 0.1 mL)
was then added, causing the organic phase to become turbid orange.
NaBH4 (260 mg, 5 mmol) was then added dropwise as a solution in 5
mL of H2O, causing an immediate color change to dark brown and the
evolution of gas. After 3 h, the organic phase was collected and the
solvent removed. The resulting residue was dissolved in ca. 20 mL of
toluene and 200 mL of EtOH was added to precipitate the colloid. When
precipitation was complete, the product was collected by filtration and
washed multiple times with EtOH to fully remove unreacted thiol. 1H
NMR (CDCl3, 200 MHz) δ (ppm) 1.55 (bs), 1.25 (bs), 0.88 (bs). IR
(thin film from CH2Cl2 on NaCl plate) νmax 2915, 2890, 1485, 1320
cm-1. UV-vis (CH2Cl2 solution) λmax 230, 290, 495 (shoulder) nm.
MMPC 2. MMPC 7 (500 mg) and 5 (90 mg, 0.34 mmol) were
dissolved in 40 mL of CH2Cl2 in a 100 mL round-bottom flask. The
resulting dark brown solution was purged with Ar for 30 min., then
allowed to stir for 2 days under Ar. The CH2Cl2 was removed, and the
resulting brown solid was stirred for several hours as a suspension in
CH3CN and filtered. This process was repeated as necessary, typically
twice, to completely remove unbound thiols as detected by either TLC
or NMR. 1H NMR (CDCl3, 200 MHz) δ (ppm) 7.89 (bs, 1H), 0.5-2.5
(mbs, 29H). IR (thin film from CH2Cl2 on NaCl plate) νmax 3320, 2995,
2910, 2885, 1630, 1520, 1485, 1310 cm-1. UV-vis (CH2Cl2 solution)
λmax 234, 292, 500 (shoulder) nm.
5-Bromopentane-1-pyrene ketone (12). 6-Bromohexanoic acid (5.3
g, 27 mmol) was dissolved in 40 mL of CH2Cl2 in a 100 mL round-
bottom flask. Oxalyl chloride (3.4 g, 27 mmol, 2.4 mL) was added,
followed by a drop of DMF, and an immediate evolution of gas was
observed. This reaction was allowed to stir until gas evolution stopped,
approximately 1 h. The solution of the acid chloride was then transferred
to a second, 250 mL round-bottom flask containing pyrene (5.0 g, 24.7
mmol) and AlCl3 (4.0 g, 30 mmol) in 40 mL of CH2Cl2 that had been
cooled to -78 °C. Upon addition of the acid chloride, the originally
deep red solution became dark green. The reaction was allowed to stir
for 3 h at -78 °C, and then quenched by the careful addition of 1 M
aqueous HCl. The deep yellow reaction mixture was then washed once
with aqueous NaCl and dried over MgSO4. Solvent removal gave the
crude product as a yellow-orange paste that was purified by column
chromatography (SiO2; 1:9 CH2Cl2:hexanes) to yield the product as an
off-white solid (4.2 g, 47% yield). 1H NMR (CDCl3, 200 MHz) δ (ppm)
8.88 (d, 1H, J ) 9.38 Hz), 8.03-8.36 (m, 8H), 3.46 (t, 2H, J ) 6.9
Hz), 3.26 (t, 2H, J ) 7.6 Hz), 1.97 (m, 4H), 1.66 9m, 2H). IR (thin
film from CH2Cl2 on NaCl plate) νmax 3042, 2950, 1692, 1248, 875
cm-1. Anal. Calcd for C22H19BrO: C, 69.66; H, 5.05. Found: C, 69.64;
H, 5.10.
(SiO2; 1:19 CH2Cl2:hexanes) to yield the product as a white solid (2.1
g, 95% yield). H NMR (CDCl3, 200 MHz) δ (ppm) 7.78-8.18 (m,
9H), 3.38 (superimposed triplets, 4H), 1.90 (m, 4H), 1.50 (m, 4H). IR
(thin film from CH2Cl2 on NaCl plate) νmax 3040, 2922, 2890, 1478,
840 cm-1. Anal. Calcd for C22H21Br: C, 72.33; H, 5.74. Found: C,
72.56; H, 5.56.
1
6-(1-Pyrene)hexanethiol Disulfide (6).27 13 (250 mg, 0.68 mmol)
was dissolved in 20 mL of nondistilled THF in a 50 mL round-bottom
flask. Bis-trimethylsilyl sulfide (150 mg, 0.85 mmol, 0.2 mL) was added
followed by tetra-n-butylammonium fluoride (0.75 mL of a 1.0 M
solution in THF, 0.75 mmol). The reaction rapidly changed color to
dark green, then slowly to yellow. After the solution was stirred
overnight, water was added, and the reaction was stirred an additional
2 h. The light yellow solution was then washed once with aqueous
NaCl, and the organic phase was collected and dried over MgSO4.
Solvent removal gave the crude product as a yellow solid that was
purified by column chromatography (SiO2; 1:9 CH2Cl2:hexanes) to yield
1
the product as a white solid (190 mg, 86% yield). H NMR (CDCl3,
6-(1-Pyrene)bromohexane (13). AlCl3 (2.1 g, 15.2 mmol) was
dissolved in 20 mL of Et2O in a three-neck round-bottom flask fitted
with a reflux condenser. LiAlH4 (15.2 mL of a 1.0 M solution in Et2O,
15.2 mmol) was then added dropwise, producing a white solid. 12 (2.3
g, 6.1 mmol) was then added dropwise as a solution in CH2Cl2, giving
an immediate reaction, which caused the solution to boil. After the
mixture was stirred for 1 h, the reaction was quenched first by the
careful addition of water, followed by 1 M aqueous HCl. The reaction
was then washed with aqueous NaCl, and the organic phase was
collected and dried over MgSO4. Solvent removal gave the crude
product as a yellow solid that was purified by column chromatography
200 MHz) δ (ppm) 7.82-8.27 (m, 9H), 3.31 (t, 2H, J ) 7.94 Hz),
2.65 (t, 2H, J ) 7.22 Hz), 1.75 (m, 4H), 1.47 (m, 4H). IR (thin film
from CH2Cl2 on NaCl plate) νmax 2995, 2835, 1090, 835 cm-1. EI-
HRMS: (m/z) 634 (parent ion), 317, 215, 202.
MMPC 8. HAuCl4‚3H2O (470 mg, 1.2 mmol) was dissolved in 150
mL of deionized H2O in a 500 mL round-bottom flask, giving a golden
yellow solution. Tetra-n-octylammonium bromide (1.3 g, 2.4 mmol)
and 150 mL of toluene were then added and the mixture stirred. After
(27) Hu, J.; Fox, M. A. J. Org. Chem. 1999, 64, 4959-4961.
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J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002 5023

A R T I C L E S
Boal and Rotello
15 min, the organic layer had become dark red and the aqueous phase
colorless. Disulfide 6 (460 mg, 0.72 mmol) was then added, and the
reaction stirred for 30 min to ensure complete dissolution of the
disulfide. NaBH4 (500 mg, 10 mmol) was next added dropwise as a
solution in 5 mL of H2O, causing an immediate color change to dark
brown and the evolution of gas. After 3 h, the organic phase was
collected and the solvent removed. The resulting residue was dissolved
in ca. 20 mL of toluene and 200 mL of acetonitrile was then added to
precipitate the colloid. When precipitation was complete, the product
was collected by filtration, but repeated precipitation was unable to
fully remove unused disulfide. Further purification was possible by
stirring the colloid for several nights as a suspension in acetonitrile. A
final toluene/acetonitrile precipitation step was used to collect the
purified colloid. 1H NMR (CDCl3, 200 MHz) δ (ppm) 7.37 (vbs), 2.57
(bs), 1.55 (bs). IR (thin film from CH2Cl2 on NaCl plate) νmax 3080,
2920, 2850, 1525, 1395, 1275, 850, 720 cm-1. UV-vis (CH2Cl2
solution) λmax 248, 255, 272, 285, 323, 337, 350, 520 (shoulder) nm.
MMPC 4. MMPC 8 (400 mg) and 5 (40 mg, 0.15 mmol) were
dissolved in 30 mL of CH2Cl2 in a 50 mL round-bottom flask. The
resulting dark brown solution was purged with Ar for 30 min, then
allowed to stir for 2 days under Ar. The CH2Cl2 was removed, and the
resulting brown solid was stirred overnight as a suspension in CH3CN
and filtered. This process was repeated as necessary, typically four or
five nights, to completely remove unbound thiols as detected by either
TLC or NMR. H NMR (CDCl3, 200 MHz) δ (ppm) 7.45 (vbs), 5.15
(bs), 2.04 (s), 1.67 (s), 1.24 (s), 0.85 (bm). IR (thin film from CH2Cl2
on NaCl plate) νmax 3350, 3290, 3080, 2920, 2850, 1650, 1580, 1450,
1275, 820, 722 cm-1. UV-vis (CH2Cl2 solution) λmax 246, 268, 280,
332, 348, 520 (shoulder) nm.
1
Acknowledgment. This research was supported by the
National Science Foundation (CHE-9905492 and MRSEC
instrumentation) and the National Institutes of Health (GM
59249). V.M.R. acknowledges support from the Alfred P. Sloan
Foundation, Research Corporation, and the Camille and Henry
Dreyfus Foundation. A.K.B. would like to thank the American
Chemical Society, Division of Organic Chemistry and Boeh-
ringer Ingelheim Pharmaceuticals, Inc. for receipt of a 2000-
2001 Graduate Fellowship.
Supporting Information Available: Characterization data for
all intermediates and MMPCs (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA016894K
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5024 J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002