4326
Copyright
Reprinted from the_Journal of the American Chemical Society, tgg4, 116.
O 1994 by the American Chemical Society and reprinted by pe"-issib"
of ihe copyright
owner.
Self-Assemblythrough Hydrogen Bonding: Peripheral
Crowding-A New Strategy for the Preparationof Stable
Supramolecular
Aggregates
Basedon Parallel,Connected
CAl.Ml Rosettes
JohnP. Mathias,Eric E. Simanek,and GeorgeM. Whitesides'
Contributionfrom the Department of Chemistry, Haruard (Jniuersity,
Cambridge, Massachusetts 02 I 38
ReceiuedSeptember 29, 1993. Reoised Manuscript ReceiuedFebruary 27, 19948
Abstract: The self-assemblyof two new typesof stable hydrogen-bondedsupramolecularaggregates-bisrosettes-that
are based on parallel, connected CA3.M3 rosettes is reported. The minimization of intermolecular steric
hindrance-peripheral crowding within the aggregate-is proposedas the structural feature responsiblefor selecting
the cyclic CA3'M3 rosetteover competing linear hydrogen-bondednetworksavailableto the precursors. One series
of aggregates-3bis(M)2:6(CA)-is composedof 3 equiv of a bulky bismelamine-bis(M)2-and 6 equiv of a bulky
isocyanurate(CA). Thesecondseriesofaggregates-3bis(CA)2:6(M)-iscomposedof3equivofabisisocyanurate-bis(CA)2-and 6 equiv of a melamine (M) bearing two bulky substituents. The nine particles in theseaggregatesare
stabilizedby 36 hydrogen bonds in two connectedCA3.M3 rosettes. Each aggregatehas been characterizedby rH
NMR spectroscopy,gel permeationchromatography,and vapor pressureosmometry. Correlationsbetweenthe size
of the substituentsand the preorganizationof the precursorsand the stability of the aggregatesderivedfrom them are
discussed.Observationsfrom tH NMR spectroscopyand gel permeationchromatographyindicate that aggregates
comprisingtwo connectedCA3'M3 rosettesare more stablethan thosestabilizedby a singleCA3.M3 rosette,for similar
extentsof peripheral crowding in the rosettes.
Introduction
phenyl)melamine(2) forcethesemoleculesto associateusingthe
hydrogen-bonded network that places these groups far apart.
This paper describesa strategy for the preparationof stable
This criterion is satisfied by the self-assemblyof the CAl.Mr
hydrogen-bonded self-assernblingaggregates in which steric
*rosette' (3) (Scheme
I ). The crystalstructureof the rosette(3)
hindrance is used to select for the formation of one particular
formed on crystallization from a solution of equimolar portions
network of hydrogenbondsover many alternatives. The motif
of I and 2 in toluene/isopropylalcohol (l:1, v/v) is shown in
we wish to favor is the cyclic CA3.M3 *rosette'comprisingthree
Figure 2.r0 Although this aggregatedisplays
a surprisinglyhigh
melamines(M) and three isocyanurates(CA) (Scheme l).ra
degreeof stability in solution (consideringthat six particles are
Two additional cyclic hydrogen-bondedmotifs haverecently been
stabilized in a single aggregateby only l8 hydrogen bonds), it
demonstratedas the basis for supramolecular aggregates.5,6
is the leaststablesupramolecularaggregate
comprisingmelamines
Peripheral crowding is the strategy we utilize here for assisting/
and isocyanuratesthat we have characterizedto date.ll
directing the assembly of supermolecular aggregatesbased on
Our objective in this study was to develop the principle of
the CA3:M3 roSette.T
peripheral crowding observedin the solid state into a general
In previouspublications,we havedescribedthe self-assembly
strategy for the self-assemblyof stable hydrogen-bonded agof hydrogen-bonded
supramolecularaggregatesin which a *hub
gregatesin solution. Our strategy was to assemblea new series
and spoke" architecturewas used to preorganizethe melamine
of aggregates-bisrosettes-based on two parallel, connected
and isocyanuratecomponentsfor the formation of stableCAl.Ml
CA3.M3 rosettes. The qualitative basisfor this approach was to
rosettes(Figure l; neohex(CA) = naohexylisocyanurate).2'8,e
increase the difference between the favorable enthalpy of
Intermolecular steric hindrance between substituents in the
association(a value correlatedwith the number of hydrogenbond
hydrogen-bondednetwork can also be used to select the cyclic
stabilizing the aggregate) and the unfavorable entropy of
*rosette'
CA3.M3
in preferenceto competing linear motifs, in
association(related to the number of particles associatedin the
both the solid and solutionstates(Scheme1).7 The presenceof
final aggregate).r2 The progression from supramolecular aglarge substituentson barbital (l) and {N,-bis( -tert-butylgregatesbasedon singleCA3.M3 rosettestoag$egatescomprising
two connectedCA3.M3 rosettesis illustrated in Scheme 2. The
e Abstracrpublishedin AduanceACS Absnacls,April l,1994.
*bisrosette'6
comprises3 equiv of the bismelamine4 and 6 equiv
( I ) Whitesides.
G. M.; Mathias,J. P; Seto,C.T. Science1991.254.t312r3 1 9 .
of the bulky isocyanurate5. The nine particlesin 6 are stabilized
(2) Seto,C. T.; Whitesides,
G. M. J. Am. Chem.Soc.1993.I I 5.905-916.
by 36 hydrogen bonds. By contrast, the six particles in 3 were
(3) Seto,C. T.; Mathias,J. P.;Whitesides,
G. M. "I.Am. Chem.Soc.1993.
stabilized by only l8 hydrogen bonds. We predicted, therefore,
I t 5, t32t-t329.
(4) Seto. C. T.; Whitesides,G. M. J. Am. Chem.Soc. 1993,tIS. t33C_
that 6 would be more stable than 3.
I 340.
(5) Zimmerman,S. C.; Duerr,B. F. Org. Chem.1992,57, ZZts-Z2tj .
"r.
(6) Geib, S. J.; Vicent,C.; Fan, E.; Hamilton, A. D. Angew.Chem.Int.
E d . E n g l . 1 9 9 3 ,3 2 , l l 9 - 1 2 1 .
(7) Mathias,J. P.:Simanek,E. E.; Zerkowski,J. A.; Seto,C. T.; Whitesides,
G. M. "I. Am. Chem.Soc. Submitted for publication.
(8) Mathias,J. P.;Seto.C. T.: Simanef,e. g.; Whitesidcs.G.M. J. Am.
Chem.Soc.1994.116. l'725-1736.
(9) Mathias,J. P.;Simanek,E. E.; Seto,C. T.;Whitesides,G. M. Angew.
Chem.Int. Ed. Engl. In press.
(10) Zerkowski,J. A.; Seto,C. T.; Whitesides,
G. M. J. Am. Chem. Soc.
1992.r r4. 5473-5475.
(l l) tH NMR exchangeexperimentsindicatethat the ground-statefree
energyfor the CA3.M3rosette3 is greater than 3 kcal/mol highcr (it is tess
stable) than that for the supramolecularaggregatehub(M)3:3barbital-an
(Figure l).
analogof hub(M)3:3neohex(CA)
( 12) The correlation of the stability of an aggregateto the number of
hydrogcnbondsstabilizingit and thc numberofparticlesassociated
hasbeen
presentedon a qualitative level in ref 8.
0002-786319411516-4326$04.50/0
0 1994American ChemicalSocietv
J. Am. Chem.Soc.,Vol. l16, No. 10, 1994 4327
Self- Assembly through Hydrogen Bonding
SchemeI
Linear Tape
CA 3.M3 Rosette
h h
I
- *-a-"-a
^ l l "l
.- -, ll: lA t -
Crinkled Tape
hub(MM)3z6neohex(CA)
of two typesof supramolecular
Figure l. Schematicrepresentations
for self-assembly
that preorganized
aggregates
basedonCA:-Ml rosettes
througha 'hub and spoke"architecture.
In additionto determiningwhetherthe progressionfrom single
rosettesto bisrosettesis accompaniedby an increasein stability,
we also hoped to (i) examine the effects of changesin the steric
bulk and preorganization of the componentson the formation
and stability of the supramolecularaggregatesand (ii) compare
and contrast the stability and structural integrity of aggregates
obtainedby peripheralcrowdingto thosewe haveobtainedusing
covalentpreorganizationto assistself-assembly.We expected
that the potential for intermolecular steric hindrance between
neighborswould increaseasthe sizeof the peripheral substituents
increased,and predictedthat the formation of the cyclic CA3.M3
rosettewould, therefore, becomeincreasingly favorable, relative
melamine(N{t
I
oA"A '-"-n
I
hub(M) 3z3neohex(CA)
i
"- "
cyanuric acid ( C A i
to the other linear hydrogen-bondedmotifs rSchenc . r j
*Preorganization"of the bismelamines(such as {. S;ne:re l
refers to the extent to which the relativegeometr\ oi lhe I'ro
matchtherrgeor:e:rr
melaminesin the uncomplexedcomponents
Asthe substituen:t s q . ;-P: r
inthefully-assembledaggregate.ta
on the m-xylyl linker in structuressuchas 4 increases:: s:ze.ti:e
melaminesshouldbe forcedto point away from the l:nke: rr tl"e
geometryrequiredby the CAl.Ms rosette:thel'should.:he:efore.
of tne agg:eg3tc
be increasinglybetterorganizedfor self-assemblv
This featureshouldpromoteformationof the rosettein nreference
to other hydrogen-bondednetworks.
In this paper, we report the synthesis of a series of
bismelamines-bis(M)z-G and 7-10) that bear substituents
with differentstericbuik on the melaminesand the nr-rr lr : linkers.
Three equivalentsof these bismelaminederivativesundergo
r,i'ithsix equivalentsof 3.3.3self-assemblv
hydrogen-bonded
(Ph3Pr(CA): 5) in chloroform to
triphenylpropylisocyanurate
afford five new supramolecularaggregatesof composition3bisare shown
(M)z:6Ph:Pr(CA) (6 and ll-14). Theseaggregates
in Scheme3. Likewise,3 equivof a bisisocyanurate-benz(CA)z
supramolecular aggregatesof
15 or furan(CA)2 l6-form
compositionbis(CA)z:6(l-BuPh)2M(17 and 18, respectively)on
mixing with 6 equivof N,N'-bis(4-lerr-butylphenyl)melamine(r-BuPh)zM-(2). These aggregatesare shown in Scheme4.
Results
Designand Synthesisof the Components. Two strategieshave
beenusedfor the synthesisof the bismelaminederivatives4 and
7-10. The stepwisesynthesisof the bismelamine4 is shown in
Scheme5. The other symmetricalbisrnelaminederivatives7-10
were synthesizedusing the more direct strategy shown for 7 in
Scheme6. The synthesesof 2,25,815,3and 163havebeenreported
previously.
The structures of the bismelamines are easily modified by
synthesis. The feature has allowed specific hypothesesrelating
(13) Zerkowski,J. A.; Seto,C. T.; Wierda,D. A.; Whitesides,G. M. J.
Am. Chem.^Soc.1993, In press.
(14) Cram, D. J. Angew.Chem.,Int. Ed. Engl. 1986,25, 1039-1057.
4328 J. Am. Chem.Soc.,Vol. I16, No. 10, 1994
o
Hydrogen
o
Carbon
o
e
Mathias et al.
Nitrogen
Oxygen
tigure 2. X-ray crystal struciure of thc CAr.Mr rooctteformcd on mixing .quimolar portions of barbital and ,VJv.bis(+ten-butylphcnyl)melaminc
in a solutionof toluenc/isopropyl
alc.hol (l:l v:v).
to the steric bulk of the substituentson the melamines and
preorganizationof the componentsto be tested. Linking two
melamines(as in 4 and 7-10) doesnot constrainthem to lie over
eachother (eclipsed)or away from each other (staggered);they
are free to rotate freely relativeto eachother. This featurecreates
the potentialfor conformationalisomerismin the self-assembled
aggregates.
The bisisocyanurates
15 and 16are more difficult to synthesize
in structurallymodified forms than are the bismelamines.These
compoundsalsoexhibit low solubilitiesin chloroform(<0.1 mM).
Using bisisocyanuratesas the basis of a strategy for the selfassembly of aggregatesis, therefore, less practical than using
bismelamines. Both 15 or 16 bear isopropyl groups that may
contribute to the self-assemblyof CA3.M3 rosettesby peripheral
crowding.
Design and Preparation of Supramolecular Aggregates. We
have developed two closely related strategies to prepare selfassembledaggregatesthat are basedon peripheral crowding and
are stabilizedby two parallel,connectedCA3.M3rosettes. In the
first approach, 3 equiv of the bismelamines 4 and 7-10 were
mixed with 6 equiv of the monomericisocyanurate5 in chloroform
to afford aggregates of composition 3bis(M)2:6Ph3Pr(CA)
(Scheme 3). Although the solubility of the uncomplexed
bismelamine and isocyanuratecomponentsin chloroform is low
(<2 mM in all cases),the supramolecularaggregates6 and lll4 were obtained as homogeneoussolutions after sonicating the
components(-15 s) and heatingto reflux (-20 s).15 In the
secondapproach, 3 equiv of the bisisocyanurates15 or 16 were
mixed with 6 equiv of the melamine 2 in MeOH/CHCI3 (l:9
v/v) to give aggregatesof composition3bis(CA)2:6(l-Buph)zM
(Scheme4). The suspensionwas heated to reflux (-15 s) to
afford a homogeneoussolution. Removal of the solventin vacuo
gave the aggregatesl7 and 18, respectively,as white solids that
were soluble in chloroform alone. Although the solubilities of
the aggregatesbasedon bisrnelamines6 and ll-14 in chloroform
were higher than thosebasedon the bisisocyanuratesl7 and lE,
both of these new types of aggregates exhibited the lowest
solubilitiesof any aggregatesthat we have studiedto date (< I 5
mM in chloroform in all cases). The solubility of the rosette3
(Scheme2) in chloroform was )80 mM.
Characterization of the Supramolecular Aggregates. We have
described previously the characterization of hydrogen-bonded
aggregatesusing rH/r3C NMR spectroscopy(local structure),
gel permeationchromatography(molecularsize,dispersity,and
relative stability), and vapor pressureosmometry (molecular
weight and concentration-dependent
behaviorin solution). Data
obtained from these three techniques are presented for the
aggregates6 (Scheme 3) and 18 (Scheme 4) to illustrate the
structural features, size, and stability of these aggregates. The
emphasisof this section,however,is to compare and contrast the
behavior/structure of these new *bisrosettes' aggregateswith
those of single rosettesTand aggregates based on connected
CA3.M3 rosettesobtainedusing covalentpreorganizationto direct
self-assemblY.z'l'a
(i) rH NMR Spectroscopy. Figure 3 shows the rH NMR
spectraof the aggregates6and 18. Thesespectracan be assigned
to the structures shown for 6 and IE using COSY, NOESY, and
l-D NOE measurements(Figure 4). Resonancesin the spectra
of the uncomplexedcomponents4 and 16 in CDCI3 and DMSOd6are significantly lesswell-definedthan thosefor the aggregates,
as a consequenceof self-associationand hindered rotation.
Both 6 and l8 exhibit two resonancesfor the isocyanurate
protons, 11t'z (see Figure 4 for labeling), with chemical shifts
between6 14 and 16 ppm in CDCIi (Figure 3). The low-field
chemicalshifts of thesesignalsareconsistentwith the involvement
of the isocyanurate protons in a strong hydrogen-bonded
network.16The observationof two resonanc€s
for the isocyanurate
protonsin 6 suggeststhat the two parallel CA3.M3 rosettesin this
aggregate are related by symmetry and that rotation of the
isocyanuratesaround their 2-fold axesis slow on the NMR time
scale. The unsymmetrical substitution of the melamines in 6
imparts two different environmentsto the isocyanurateprotons,
J. Am. Chem.Soc.,Yol. l16, No. i,0,1994 4329
Self- Assembly through Hydrogen Bonding
Scheme2. Strategy for Increasingthe Stability of AggregatesObtained by PeripheralCrowding Involvesthe Progressionfrom
SrructuresCompriiing a Single CAs.Ms Rosetti (f) toagisrosettes" Such As 6 in Which the Two RosettesAre Connected
through Covalent Linkers betweenMelamine or Isocyanurate(Not Shown) Derivatives
^
J
N^N
^/-.^^
"/\"
ts++
+ 6 l,-*x**t;-
-X
a
tl
? -\i;\H
ln
+3
Q.d
-r-r- ofF**"
u
o
*t*4
i;**il1e+
)
II
4
V
3
Scheme3.
18 hydrogenbonds
36 hydrogenbonds
6 particles
9 particles
6 andll-14
3bis(M)z:6PhrPr(CA)
Self-Assemblyof SupramolecularAggregatesof Composition
6
Oc+e-O
ll
:>*:^
o;
H.^'
i;-*XI|'1{H-'ta,
;>n;"
R'
/
(}
,,
":*-/-\*
X;-*.{{:,>_
H'-
P h s P ( C A )5
R
\__l
R'
lso-Pr ted-Bu
H
iso-Pr
Me
ferf-Bu
H
tert-Bu
Me
such that Ht + H2 in each CA3'M3 rosette. One isocyanurate
proton (Ht) is adjacent to the z-xylyl group and the second
isocyanurateproton (H2) is adjacent to the p'tert-butylphenyl
substituent(Figure 4). Figure 5 showstwopossibleconformations
that would allow the adjacentrosettesto be related by at least
2-fold symmetry. These conformations are (i) an eclipsed
conformation,in which melaminesand isocyanuratesin adjacent
rosetteslie in registry with each other-the two rosetteswould
then be relatedby a mirror planeof symmetry;top = bottom-and
(ii) the staggeredconformation,in which the melaminesin one
rosette lie over isocyanuratesin the connected rosette and visa
versa-the two rosetteswould then be related by a rotation of the
rso-Pr terl-Bu
H
iso-Pr
terf-Bu
Me
tert-Bu
H
HMe14
6
11
12
13
4
7
I
I
10
aggregateby 180o about an axis running through the atoms k
and I in the linker (labels shown in Figure 4)' The staggered
conformationis obtainedfrom the eclipsedby a rotation of l80o
about one of the melamineNH-xylyl bonds.rT
The observationof two resonancesfor the isocyanurateprotons
for all other protonsin the CA3'M3 rosette
H1'2in l8 (resonances
are also doubled) suggeststhe two rosetteslie staggeredrelative
to each other, with the melaminesover the cyanurates,rather
(15) The formation of these aggregatesas homogeneoussolutions tn
chloroform from their insolubleprecursorsis a commonfeaturein thesesystems.
(16) Theseprotonsappearat 6 11.2in the free isocyanuratedissolvedin
DMSO-d6.
4330 J. Am. Chem.Soc.,Vol. I16, No. 10, 1994
Mathias et al.
Scheme
4. Self-Assembly
of Supramolecular
Aggregates
l7 and l8 of Composition
3bis(CA)z:6(t-BuPh)zM
!
".N
l:*-*l-<*
(ferf-BuPh)2M 2
?
3,-
+ 6aO-------+
_\rJ
L
I
I
I
t
I
JnF
F#"
lxF
17
3furan(CA)2:6(tert'BuPh)2M
18
:>'{-^
hq"
b e n z (C A )2
15
Scheme5.
3benz(CA)z :6(terf-BuPh)
2M
fu ra n ( C A )216
Synthesisof the BismelamineDerivative 4
a
cl
Tt'
-T-
+
*4,
ruAN
r-rr',Ar.rA
cl
->
,,A*A",
,\
Y
T 21
20
NHr
(c)
_--=_->
r'rAr.r
w
NHI
ill
19
cl
cl
(a)
-A;
,*A*A*,
(d)
#
"*,,tBoc
(e,f)
(g)
24
than directly in registry,with melaminesover each other and a
horizontalplaneof symmetry. The staggered/tiltedconformation
of the parallel CA3.M3rosettesin l8 suggeststhat there must be
a driving force for the rings not to lie eclipsed. We suggestthat
the origin of this effect is to avoid steric crowding between the
/erl-butylphenylgroupsin adjacentCA3.M3rosettes.The tilting
of the furanyl linker introducesan asymmetryto l8 that is similar
to that observedfor 6. One isocyanurateproton (Ht) lies away
from the directionin which the linker is "tilting" and the second
isocyanurateproton (H2) lies toward the direction in which the
linker is *tilting" (Figure 4). The upper and lower (CA).(M)
(f 7) We believethat the actual structure of 6 is, in fact, the staggered
conformationshownin Scheme2. This conformationreducesunfavorable
stericcrowdingbetweenthe threetriphenylpropyl and thre* p-tert-butylphenyl
groupson the periphcryof eachadjacentCA:.Mr rosetteby allowing them
to intcrdigitate more effectivelyaround the edge of the hydrogen-bonded
network. The staggeredconformationmay alsoallow matchingof the partial
chargesin the'stacked" hetrocyclicisocyanurateand melamines.
tBoc
HN/
22
ery
HruA*A**
Tt'
"*,,tBoc
T*'
ruAru
ruAr1
+w+
+rr+
HruAruAnrH
,*A*A*
4
units shown for 18 in Figure 4 are,therefore, related by a C2axis
of rotation. The observationof two distinct sets of resonances
for l8 suggeststhat interconversionbetweenthe two enantiomers
l8a and l8b (Figure 6) must be slow on the NMR time scale.
The appearanceof two resonancesfor the furanyl protons H5
and H5'of 18 is also compatible with a chiral aggregate. Two
setsof the resonances(H6"7')for the isopropyl methyl groupsare
hidden by a large signal for the p-tertbutylphenylgroupson the
melamines.
Strong NOE interactionsbetweenprotonsconfirm thegeometry
of the hydrogen-bondedCA3.M3 rosettesin 6 and 18. These
interactionsare tabulatedin Figure 4. There are no significant
changesin chemicalshift,line width/shape,relativeproportions
by integration, or number of resonancesfor either 6 or 18 as the
temperature is decreasedfrom 298 to 233 K.
tH NMR spectra from the titration of 2 equiv of the
isocyanurate5 into I equiv of the bismelamine4 in CDCI3 are
J. Am. Chem. Soc.,Vol.I16, No.10,/,9944331
Self- Assembly through Hydrogen Bonding
Scheme6.
o
Synthesis of the Bismelamine Derivative 7
cl
NHz
25
+
r.rAr.,r
crAruAcr
cl
cl
(a)
----+
ct
r.,Ar,r
ruAru
Hr.rAr.rAruH nr.rAlrAr.r*
NAr.r
nruA*Ac,
20
27
NHr
NHr
-A;
-A;
H*Ar.rAr.rH
HruAnrAr.rH
7
alsoshownin Figure 3. At a stoichiometryof I :2 for 4:5, asingle
is visiblethat can be assignedto the aggregate
set of resonances
6 (Figure 4). At stoichiometrieslessthan I '.2for 4;5, resonances
for the fully assembled aggregate 6 and the uncomplexed
bismelamine4 are visible. An additional set of resonances(.;
Figure3) can alsobe seenat this stoichiometry.The sharpnature
of the additional resonancesand the presenceof two resonances
around d 15 ppm leads us to suggestthat the origin of these
signalsmay be anaggre9atein which only a singleCA3.M3 rosette
hasassembled.r8This type of aggregatewould be a direct analog
of the rosettesformed between3 equiv of bulky melamines and
isocyanurateswe have reported previously.T
for the complexed
The observationof separatesetsof resonances
and uncomplexedstatesduring the titration of 5 into 4 indicates
that exchangebetween these states is slow on the time scale of
NMR spectroscopy. This stability toward exchangecontrasts
with the instability of rosettes formed between monomeric
melamines and barbiturates; in these cases,exchangebetween
the assembledand uncomplexed states was rapid on the NMR
time scale.T The progressionfrom aggregatesbasedon a single
CAl.Ml rosette to those comprising two parallel, connected
CAl.Ml rosettesis, therefore, accompaniedby a decreasedrate
of dynamic exchangeat 298 K.
Dilution of solutions of the aggregatesin chloroform from 3
to 0.05 mM did not result in any dissociationof the aggregates,
asjudged by tH NMR spectroscopy. We observedno changein
the chemical shifts of the hydrogen-bondedprotons on dilution.
This feature again contrasts to the behavior observed for
aggregatescomprising a single CA3.M3 rosette.T In thesecases,
dilution of the aggregatesin chloroform below 3.5 mM resulted
in large upfield shifts of the hydrogen-bonded protons and
suggesteda reduction in the degreeof hydrogen bonding as the
concentration was decreased.
(ii) Gel Permeation Chromatography. Figure 7 shows traces
for 6 and 18 from gel permeation chromatography (GPC) using
chloroform or rnethylenechloride as the eluent. In eachcase,the
aggregatesgive well-definedpeaksby GPC. The relatively sharp
leading edges (to shorter retention time) and moderate tailing
exhibited by 6 and 18 contrast to observationsmade by GPC for
aggregatessuch as 3 that are basedon a single CA3.M3 rosette.
The stability of 3 was too low for it to elute intact from the GPC
column; no peaks were observed. We infer that 3 dissociated
completelyduring the time required for analysis (7-9 min).re
in rH NMR spectros@py
(18) We do not usually seedefinedresonances
from "irregular" or more random H-bondedolio/polymers.
The observationof well-definedpeakswith retention times in the
range 8-9 min for 6 and 18 is consistentwith data obtainedfor
other stable hydrogen-bonded aggregates we have described
previously. These results for 6 and 18 are, therefore, another
indication that the progressionfrom aggregatesstabilizedby single
CAI.M: rosettesto aggregatesstabilizedby two connectedCA3'M3
rosettes-whether the constitutionis 3(CA)z:6(M) or 3(M)z:
6(CA)-is accompaniedby a substantialincreasein stability.
The peak shapesfor 6 and 18 suggestthat the stability'of these
aggregatesis comparableto hub(MM),:6neohex(CA)8and
greaterthan hub(M\:3neohex(Ce;2. Tracesfor theseaggregates
are also shown in Figure 7 for comparison.
(iii) Vapor PressureOsmometr-v.Molecular *'eightsfor 6 and
18 have been determined by vapor pressure osmometry in
chloroformsolution (Figure 8a). Plotsof AV/concn vs concn
from which the molecular weightswere obtainedare illustrated
in Figure 8b.20 The data for 6 (r. solid line) display a modest
positiveslope. Thosefor 18 (., dashedline), however,display a
negative slope.2l The latter observation is consistent with
associationof this aggregate.22Nonconcentration-dependent
specific associationof l8 would explain why the valuesobtained
for the molecular weight of this aggregate in solution are
consistentlyhigher than the expectedvalue.
Aggregate Formed betweenComplementaryBismelaminesand
Bisisocyanurates. Mixing equimoiar portions of the bisisocyanurate 15 with the bismelamine4 doesnot afford an aggregate
in which 3 equiv of each component combine in two parallel
CA3.M3 rosettes(Scheme7). Although the mixture affords a
homogeneoussolution in chloroform, lH NMR spectroscopydoes
not reveal the presenceof a well-defined aggregate,such as 29.
Instead, the resonancesare poorly defined, broad, and many.
This feature is illustrated clearly by the many separateresonances
observedfor the isocyanurateprotons shown in Figure 9a. The
structural complexity evident from this portion of the tH NMR
spectrum of the aggregate is also seenin the remainder of the
spectrum. The result of mixing 4 and 15 appears,therefore, to
be an extended hydrogen-bonded structure containing many
( I 9) A discussionof the correlationbetweenstability of an aggregateand
its peak shapein GPC is presentedin ref 8.
(ZO)VpO requirescalibrationagainsta standardof knownrnolecularweightThe standardand the new aggregateof unknownweight are then relatedby
= MWorgrr*,"limc--oIAVlc"ss.$"|.Theratio
MWr1",,6"r6limg-aflVfctwd^ro]
l,Vlc (in thc limit as c * 0) is determinedby VPO (c = concentration,A/
is proportionalto the changein vapor pressuremeasuredby VPO).
(21) An ideal solutewould give a straightline with zero slopein a plot of
AVlconcn vs concn.
(22)We have discussedthis feature in refs 2 and 4.
4332 J. Am. Chem. Soc., Vol. I16, No. 10, 1994
Mathias et al.
aggregare
l8
--L
a g g r e g a t6
e
,l'
(bismelanr
t\--h-iL
T2
lt ll
b i s m e i a m i n- el + i e c u i v5
b i s m e i a m i n4e
16
15
1.1
It
10
PPM
Figure 3. IH NMR spc.lm of thc supramolccnlaraggrcgatcs6 and l8 (CDClr 500 MHz). Annotationsrcfc! to Figurc 4. Th. r.sonanccsindicatcd
by . ara Fopos€d !o bclong to a partly formed atgregat. containirg onc rosettc; s€cthc tcrt for discussion.
different structural subelements. One possibility may be a range
'vernier-type" polymers,
of different
such as that representedby
30 (Scheme7). The multiplicity in this spectrumis not an artifact
of the kinetics of assembly: there is not change in the spectrum
of the mixture on heating the solutionat 45 oC for 7 days. We
note that benz(CA)z 15 doesform an aggregate(17; Scheme4)
of composition3benz(CA)z:6(t-BuPh)2Mwith the melamine2.
The steric requirementsfor assemblyof CA3.M3 rosetteswith 15
should, therefore, be satisfied by the bismelamine 4. One
explanationfor the failure of 4 and l5 to yield a discreteaggregate
may be the inability of the conformationally rigid bisisocyanurate
to satisfy the staggeredarrangementthat we believeto be favored
by the bismelamine4 in the aggregates6 and ll-14.
Aggregates Formed by Unsymmetrical Bismelamines. Mixing
3 equiv of the unsymmetrical bismelamine3l with 6 equiv of the
isocyanurate5 in chloroform does not afford a single aggregate
(for example, 32) in which the three melamines adopt the same
'orientation" (Scheme
8). Instead, in this instance tH NMR
spectroscopyreveals the presenceof multiple resonancesand
suggeststhe formation of severaldifferent hydrogen-bondedstates.
There doesnot appear to be any preferencefor the bismelamine
components to orient themselvesin a discrete a9gregate (32)
with thep-/erl-butylphenyl substituentin one CA3.M rosetteand
theneohexylsubstituentsin theother CA3-M3rosotte. A mixture
of the isomers32 and 33, however,could, in principle, generate
many local environmentsfor the isocyanurateprotons. No change
occurs in this spectrum on heating the solution at 50 oC for 5
days.
Discussion
Changing the steric bulk and preorganization of the components has a significant effect on the self-assembly of supramolecular aggregatesbasedon peripheral crowding. We have
examined the effectsof four different aspectsof the structure of
the uncomplexed components on the structural integrity and
stability of supramolecularaggregatesderived from them. They
J. Am. Chem.Soc.,Vol. 116, No. 10. 1994 4333
Self- Assembly through Hydrogen Bonding
(a)
Ph -5
'h^-en
3,3'
*5-*1
-'';kG
4'Ph
-F;7,n0
"6H:.,'\i-i:
";*-< ftf:a
ui
N
nl
6
nOe
Intensity
H1+Hg
H1+ H1
H1+H1
H 2-+ H 6
18o/"
H2+ Hs
H6+ H2
H6+ H6
Hg+ Hs
H n - +H g
11o/o
H.+ H2
Hr-+ Hr
1SYo
10%
7%
18%
18o/"
19%
16%
14%
19o/"
(b)
nOe
H1+ H6
H1+ Ha
H 2 - +H g
H 2-+ H 1
H 6-+ H 1
18
Hn+ H2
H 1-+ H 2
H3+H1
Intensity
15%
11o/o
21%
17%
16"/"
19%
15o/"
13%
Figure 4. Assignmentof resonancesand selc.lcd NOE interactionsin thc rH NMR sp€ctraof the aggr€gates6 (a) and lt (b). hbcls rcfcl to thc
peak shown in Figure 3. NOE interactionswith intensitiasbelow 5% are not includcd
-(a
--o
-
OE_
'Staggered'
---O
'Eclipsed'
Figure5. Schematicrepresentation
of two extremeconformations
that
are possiblefor aggregates
basedon bismelamine
derivatives.
are the role of (i) the steric bulk of the substituent(the group R'
in Table 1) on the melaminesin aggregatesbasedon bismelamines,
(ii) the steric bulk of the isocyanurateor barbiturate in aggregates
basedon bismelamines,(iii) the preorganizationof the melamines
in the bismelaminesfor assemblyof the CAI-M: rosette,i.e.,size
of the group R in Table 1,and (iv) the stericbulk of the melamines
in aggregatesbased on bisisocyanurates. These aspectswill be
discussedin turn.
The outcomeof mixing 3 equivof the bismelamines4 and 7-10
with 6 equiv of the isocyanurates5 or 34 or with the barbiturates
I or 35 is illustratedin Table l. Successfulformation of a stable
*bisrosette"
aggregate (as judged by tH NMR spectroscopy)is
indicated by ++. Failure of the 3 equiv of the bismelamineto
solubilize6 equiv of the isocyanurate/barbiturateis denotedby
The soluble portion obtained by filtering these suspensions
did not contain any well-defined aggregates. Instead, the
resonances
in the tH NMR spectrawere poorly definedand broad.
The marker * denotesthe formation of an ^ggregate from which
the original homogeneoussolution exhibits slow, but significant,
precipitation over tirne (>24 h).
4334 J. Am. Chem.Soc.,Vol. II6. No. 10. 1994
Mathias et al.
slow
---+
18a
18b
Figure 6. Interconversionof the two enantiomersl8a and l8b is slow on the NMR time scale.
EIuent
18
CHtCI z
cHCt3
6
18
cHCl 3
c}Izct 2
hub(M) l3neohex(CA;
c}tzct2
hub(MM) s6neohex(CA)
6.0
8.0
10.0 12.0 14.0
Retention
time(min)
filrue 7. Tracesfrom Grc for thc aggrcSatcs6 and lE with chloroform and methylcncchlorideasthc clu€m. Traccsfor two sclf-assemblcdaggrcgates
basedon covalentprcorganizadon,bub(M)3:3teohex(CA) and hub(MM)3:6r"ohcr(CA), arc includcd for comparisonof thc pcak s[ap6 and rctcntion
timcs. Mcthylcne chloridc rvasthc clucnt in thcsccases,and p xylcnc (darkcncd) wasi;clud.d as an internal rcfcrcncc. (Th; diffcrcncc in rhc widths
oJ thc Pcakdu. to p'xylcnc is due to thc agin€ of thc cohrmn.) The lack of tailing for 6 and lt is not a rcflection on reiative stability but rathcr
on
thc insolubility of thcsc aSSregatcsupon thc lo6sof onc or morc componcnts, ThJ hub aggrcgatesarc significantly morc solubleupon lo6sof
onc or
more mokcul€s of CA.
The changefrom 4 (R'= tBu) to 7 (R, = H) reducesthe steric
bulk associated with the melamines. This feature should.
therefore, reduce the extent of peripheral crowding involved in
the association of these components with isocyanurates. We
J. Am. Chem. Soc.,Vol. ll6, No. 10, 1994 1335
Self-AssemblythroughHydrogen Bonding
(a)
a
substituentson the m-xylyl linker in the bismeiamine4 inhibi:
rotation about the bondslinking the melaminesto the linker and,
therefore, hold them preorganizedin the geometry required ior
formation of the bisrosette.We preparedthe threebismelamines
4, (R = ,Pr),8 (R = Me), and 9 (R = H), to examinethe effects
of altering the degreeof preorganizationon the self-assembly'oi
CA3.M rosettes(Table 1). We expectedthat reducingthe size
of thesubstituentR would reducethe degreeto which thegeometry
of the two melamines in the uncomplexedstate matchesthat in
the aggregateand, therefore,reducethe ability of the components
to assemblesuccessfullyinto bisrosettes.Again, mixing 3 equiv
of the bismelamines4, 8, and 9 with 6 equiv of the bulky
isocyanurate5 affords a self-assembledaggregateof composition
3bis(M)z:6Ph(CA)3(Table I ). Thestability of theseaggregates
as discretestructural entitiesover time (96 h), however,appears
to differ, as judged by their tendencyto precipitate.
s.o
o0
-
rr
4.0
qJ
q,
ll
z
3.0
Aggregate 18
Aggregate 6
(b)
'.\
b
Fl
)<
C)
I
q)
!)
2.0
1.5
l0
r5
20
25
30
conc(ilL)
Figure8. (a) Estimationof the molecularweightsin solutionby vapor
pressure
of the aggregates
6 and lE. Calculatedmolecular
osmometry
weightsfor eachaggregate
aregivenin eachcolumnby solidhorizontal
weremade
numbers.In eachcase.measurements
barsandtheassociated
againstfourdifferentstandards:
N,N.bis-'Boc-gramicidin
S (MW 1342)
(av MW 5050,
(.), sucrose
(MW 679) (O), polystyrene
octaacetate
(MW 3321)(tr).
polydispersity
1.05)(r), andperbenzoyl-B-cyclodextrin
of measurements
Error barsrepresent
standarddeviations
on aggregate
weremadein chloroformat 233 K with
andstandards.Measurements
concentrations
in the range0.5-6 mM. (b) Plot of LVf concnvs concn
showingthe differencein the concentration-dependence
of data from
VPOfor 6 and 18(AZis thechangein voltagerequiredto maintainthe
thermistorat constanttemperature). Lines representleast-squares
analysis
of thesedata.
expect,therefore,that the driving force selectingfor the formation
of the CA3.M3 rosetteover competing linear hydrogen-bonded
networkswould be lower in 7 than in 4. Both 4 and 7 form stable
aggregates
of composition3bis(M)2:6Ph3Pr(CA)on mixing with
5 (Table l). As the steric requirementof the isocyanuratewas
reduced (35 < 34 < I ( 5), however, the effects on the selfassemblyof CAI.M: rosettesbecomeapparent with 7 before 4.
For example, while 4 forms a stable aggregate on mixing with
neohexylisocyanurate
34,7 doesnot. Theseobseruatioruindicate
that reducingthestericbulk of the substituentsonthe melamines
and those on the isocyanuratesand barbiturates decreasesthe
stability of aggregatesbasedon CAE M s rosettes. The proclivity
ofthe bulky isocyanurate5 to form aggregatesbasedon connected
CAI.M: rosettes,even in the absenceof sterically demanding
substituentson the melamines,reinforcesthe suggestion-indicated
by studieson aggregatescomprisinga singleCA3.M3 rosetteT-that
this particular isocyanurate provides a strong driving force
selectingfor the self-assemblyof CA3.M3 rosettes. These data
demonstratethe importanceof the size of the substituentR on
the melamines in biasing self-assemblyin favor of aggregates
basedon CAI.M3 rosettes.
We have also useda secondlevel of steric hindrance to assist/
select for the self-assemblyof these aggregates. The isopropyl
Precipitationoccursfrom solutionsof the aggregatesformed
betweenPhrPr(CA) 5 and the bismelamines8 or 9 on standing.
The suspensionsformed over time in thesecasescan be solubilized
by adding methanoland additionalchloroform,concentratingin
vacuo, and redissolvingin chloroform alone. Spectra of these
solutions from lH NMR show that the aggregateshave reassembled,before precipitation occursonce again. Precipitation
(from the initially homogeneoussolution) occurs in the order 9
(much precipitation) > 8 (slight precipitation) > 4 (no precipitation). We note that precipitation (9 > 8 ) 4) from these
aggregatescorrelateswith the reductionin preorganization(4 )
8 > 9). The progressiue reduction in preorganization from 4
through 8 to 9 correlates with the failure of the componentsto
self- assemb I e and affor d t her mody namic a I Iy st abI e aggr egat es
basedonconnectedCAyM jrosettes. Threeplausibleexplanations
for this precipitationare (i) the aggregateis dissociatinginto its
constituentmolecules,which are then precipitatingfrom solution,
(ii) the aggregateis dissociatingslowly and the free components
oligo/polymer,or
reassociatinginto a random hydrogen-bonded
(iii) the aggregateis associatinginto larger assemblies. The
correlation betweenthe preorganization of the componentsand
the degreeof precipitationsuggeststhat either (i) or (ii) is the
most likely causeof precipitation. As preorganizationis related,
the discrete aggregateappearsto becomea metastablestate (the
rather than a thermodynamically
kinetic productof self-assembly),
stable hydrogen-bondedstate.
The bismelamine l0 (R' = M€, R = H) demonstratesthe
effect of reducing both the steric bulk of the substituentson the
melaminesand the preorganizationof the two melaminesfor
self-assembly.This componentis the leastsuccessfulat forming
of composition3bis(M)z:6(CA)on mixing with 6 equiv
aggregates
of isocyanuratesor barbiturates. This result supports the
conclusionsthat both stericbulk at the peripheryof the aggregate
and preorganization of the componentsplay a significant role in
selecting for/directing the self-assemblyof CA3.M3 rosettes.
Mixing 3 equiv of the bisisocyanurate,15 or 16, with 6 equiv
of the melamine derivatives36-38 that are substituted by groups
smaller than p-tert-butylphenyl (as in 2) does not affford welldefined bisrosettes(Table 2). Homogenous solutions of the
componentsin CHCI3 are not obtained on mixing the molecules
in chloroform, even after sonication and heating. tH NMR
spectroscopyon the soluble portions of these mixtures do not
reveal the presenceof any well-defined aggregates. The steric
bulk of the two p-tert-butylphenyl groups appears,therefore, to
be responsible for selecting for the formation of the CA3.M3
rosettesin thesecases. Reducing the steric bul k of t he substituent s
on the melamines decreasesthe stability of CAyMj rosettes.
This observationcorrelatesstrongly with thosernadeon aggregates
comprising a single CAr.Ml rosette in the previous paper. The
self-assemblyof CA3.M3 rosettesbetweenbarbital (l) and N,N'substituted phenylmelamineswas equally sensitiveto the steric
bulk of the substituent of the phenyl rings. Derivatives of
r994
Scheme7.
Mathias et al.
Atternpted Self-Assembly of an AggregatebetweenComplementaryBismelamineand BisisocyanurateDerivatives
3
3
+
X
\:
ilt
29
\
bF"
.((-,
'a
H
Fx'f"
15
Scheme8.
Attempted Self-Assemblyof an Aggregatefrom an Unsymmetrical BismelamineDerivative
+
6:
Il
3
ill
32
\nrt
hq"
31
33
melamine bearing two phenyl, adamantyl (37), or p-tolyl (38)
substituentsdid not form CA3.M3 rosetteswith barbital.
Isocyanurate protons are useful structural markers in the
characterization of self-assembled aggregates based on CATM j
rosettes. The full characterization of these self-assembled
aggregatesby tH NMR spectroscopyis important. We have
found the region between 6 13 and 17 ppm in the tH NMR
spectrum particularly useful in assessingthe fundamental
structural features of new supramolecular aggregatesbasedon
CA3.M3 rosettes;other regions of the NMR spectrum can be
SeU-Assemblythrough Hybogen Bonding
J. Am. Chem. Soc., Vol. 116, No. 10, 1994 4337
Trble l. Outcamcof Self-Asscmbly
of VariousBismclaminc
4 and7-10, with Diffdcnt Isocyanurates
andBarbituratesc
Derivativcs,
T",
NHr
-A;
,*A*A
A
\?
lR
R'
increasing
stericbulk of R'
o
Hr., A*.t H
ruAru
A#*,
)^a A
\?
ll
.-\r'<,
Rl
R'
increasingpreorganization
(sizeof R)
7
R'=H
R=iPr
4
R'=tBu
R=iPr
R'= tBu
R- Me
++
++
++
++
++
E
9
R ' = tBu
R- H
Me
H
ra
o\Ao
I
\
Ph--Ph
Ph
34
o
,-*An,
o{)<fo
++
H- -
rJ
' ++ lndicatcs succcssfulformation of a stable aggrcgatc. + Indicatasformation of the aggregatcas a homogcncoussolutionin chloroforrn fiom
which prccipitation occursover 2,1-96 b. - Indicatcs tbar a wcll-defined aggregatcis no1formcd on mixing thc componcnts.
complicated by overlap of different resonances. This low-field
region of the spectrum contains only the resonancesof the
hydrogen-bonded protons on the isocyanurates (Figure 9).
Overlap between different types of protons is, therefore, not a
problem. Furthermore, the isocyanurate protons are involved
directly in the hydrogen-bondedCA3.M3 rosette;their resonances
are, therefore, sensitive to the degree of hydrogen bonding,
concentration, temperature, environment, syrnmetry of the
hydrogen-bondednetwork, and exchangebetweenassociatedand
dissociatedstates. In summary,the resonancesfrom theseprotons
providea wealthof information about the global and local structure
of new self-assembledaggregates.
The utility of these resonancesin the characterizationof
aggregateshas been demonstrated by the assignmentof the
relationshipsbetweenadjacentCA3.M3 rosettesin 6 and 18. The
resonancesofthe isocyanurateprotons from theseaggregatesare
shown in Figure 9b,c, respectively. Once the symmetry of the
hydrogen-bondednetwork has been ascertained,the complete
assignmentof the resonancesto the aggregatescan be relatively
straightforward.
The cornplexityof the region in the rH NMR spectrumbetween
d 13 and 17 ppm in Figure 9a mirrors the irregularity of the
aggregates formed on mixing 4 and 15 (Scheme 7). This
complexity is not consistent with the formation of the desired
4338 J. Am. Chem.Soc.,Vol. 116, No. 10. 1994
Table 2.
Mathias et al.
Outcome of Self-Assembly of Two BisisocyanurateDerivatives, l5 and 16. with Different Melamine Derivativeso
.ao ----,>
3-
€
NH^
t\;
,A*A*,
hh
YV
++
)
z
liF
FF
1dF#"
<\b#"
L-ro ^
15
++
16
++
T*,
rvAru
,A*A**
n'f".
N'A'N
,A*A*"
0o
hs
AA
NH^
t\;
,A* *
aa
36
a ** Indicates successfulformation
of a stable aggregate. - Indicates that a well-defined ag1regateis not formed on mixing the components. The
relative size of the substituents on 37 (compared with others in the series) is unclear. The adamantyl groups may
be too large.
single aggregates29 and 32. The aggregate formed on mixing
3 equivof the bismelamine4 with 6 equivof niohexylisocyanurate
34 in chloroform provides another example of the information
provided by the resonancesof the isocyanurate protons. This
aggregatedisplays four resonances(the middle resonanceis the
superpositionof two singlets)for the isocyanurateprotons(Figure
9d). It hasa structure,therefore,in which both CA3.M3 rosettes
display two resonancesfor the isocyanurateprotons, and the two
rosettes,themselves,are not relatedby a mirror planeof symmetry
or by rotation through l80o about an axis parallel to that of the
isocyanurates. This feature contrasts to the aggregate6 formed
between4 and 5 in which the two adjacent rosettesare related
by suchsymmetry. Variable-temperaturelH NMR spectroscopy
is consistentwith the hypothesisthat all four resonancesin the
aggregatebetween4and 34arederived from as ingleconformation
of a single aggregate (Figure 9d,e). No changes in relative
proportion (by integration),chemicalshift, peakshape,or number
of peaks occur on cooling the sample from 298 to 233 K that
would indicate any exchangebetween conformations or associated/dissociatedstatesis occurring. Although the grossstructures
(i.e., composition) of the aggregateformed between 4 and 5 or
34 are the same-3bis(M)2:6R(CA)-the reduction in steric
demand on the change from 5 to 34 is accompaniedby changes
in the local structure of the aggregate. This feature indicates,
once again, that steric interactions ot the periphery of the
aggregatesdo play a significant role in determining the outcome
of the association betweenthese components.
Aggregates based on trto connectedCA1M j rosettes are more
stable than those based on a single CAyMj rosette. Both lH
NMR spectroscopyand gel permeationchromatographyindicate
that aggregatescomprising two connectedCA3.M3 rosettesand
showing peripheralcrowding are more stable than those based
on a single CA3.M3 rosette. The presenceof resonancesfor the
fully assembledaggregateof composition3bis(M)2:6ph:pr(CA)
in the tH NMR spectrum before addition of a full 2 equiv of
PhrPr(CA) to bis(M)2 (Scheme3) alongsiderhoseof uncomplexed
componentsand intermediatesalong the assemblypathway (see
Figure 3) indicates that the rates of interchangeof bisrosettesis
slower than those for aggregate comprising a single CA3.M3
rosette. The absenceof concentration-dependentdissociationof
6 and l8 on dilution of their solutionsreinforcesthis conclusion.
The observationof peaksfor the aggregates6 and 18 in GpC that
are relatively sharp also suggests that the stability of these
bisrosettesis greater than that of aggregatesbasedon a single
CA3.M3 rosette.
These observationscorrelate with those made on aggregates
that compriseincreasingnumbersof parallel, connectedCA3.M3
rosettesin the seriesbasedon covalent preorganization,such as
Self-AssemblythroughHydrogen Bonding
(a)aggregare
29R0
tu
J. Am. Chem. Soc.. Yol. l16, No. 10, 1994
4339
preorganization for the formation of supramolecular aggregates
stabilized by CA3.M3 rosettes.
The "rules/observations"
that were inferred to govern the
a s s e m b l y o f a g g r e g a t e s c o m p r i s i n g a s i n g l e C A r . M 3 r o s e t t e Tb y
peripheral crowding are paralleled by those for the aggregates
based on connected CA3.M3 rosett€S. Most importantl)', the
stability of CA3.M3 rosettes does decrease as the size of the
substituents on the melamines and isocvanurates is reduced.
(b) aggregate
6
18
(c) aggregate
Experimental
Section
General Methods. NMR experimentswere performed with a Bruker
AM 500 or 400 instrument. THF wasdistilledfrom sodium bcnzophenone
ketyl. Methylene chloride and triethylamine were distilled from calcium
hydride. Dimethylformamidewas dried and storedover 4 A molecular
sieves. The compounds that have a triazine unit in their chemical
in their lH and l3C NMR
structuresshow doublingof severalresonances
spectra due to slow exchangeof conformers around the NHR-triazine
bonds" Reagents were purchasedfrom Aldrich-Sigma and were used
without further purification. Abbreviations are used as follows: tri(DIPEA). Ammonium
fluoroaceticacid (TFA). diisopropylethylamine
hydroxide (NHTOH) was used as a 30Voaqueoussolution.
NOE Specna. The NOE spectraof thesesupramolecularaggregates
were recordedat 2 5 oC. u ith an evolutionperiodof 3.0 s and a relaxation
d e l a . 'o" f 6 . 0 s . T h e c o m p i e rt 5 . 0p m o l ) w a s d i s s o l v eidn 0 . 7 m L o f C D C I 3 ,
wrth five freeze-pump-thaw cycles.
and the sampleswas ciegassed
(d) bismelamine
4 + neohex(CA)273K
(e) bismelamine
4 + rreohex(CA)233K
16
15
14
1.3
t
Figure9. Portionsof the H N MR spectraof theself-assembled
aggregates
showing
with thehydrogen-bonded
theresonances
associated
isocyanurate
protons(CDCI3,500MHz).
hub(M)3:3zeohex(CA)and hub(MM)3:6neohex(CA)shownin
Figure l. In this case,the latter is more stablethan the former.s
In both of the series-one basedon peripheralcrowdingand the
other basedon covalentpreorganizationof melamines-we believe
that the increasein stability of the aggregatesbasedon parallel
CA3.M3rosettesrelativeto thosebasedon singleCAI.Ml rosette
is a consequenceof the extra preorganization imparted to each
CA3.M3 rosetteby the neighboringCA3.M3 rosette. It is also
reflectedin the ratio of hydrogen bondsstabilizing the aggregate
(enthalpy) to the number of particles involved in the ^ggregate
(entropy).
Conclusions
Supramolecular aggregatesbasedon two connectedCA3.M3
rosettes-bisrosettes 6 and l8-are more stablethan aggregates
basedon single CA3-M3 rosette 3. Indeed, bisrosettesbasedon
connectedCA3.M3units obtainedby peripheralcrowdingdisplay
a surprisinglyhigh degreeof stability. The structuresdescribed
in this paper illustrate that 36 hydrogen bonds can stabilize
supramolecularaggregatescomposedof nineparticles. The ability
to preparestableself-assembled
aggregatesby peripheralcrowding
rendersthis strategy a useful addition to that basedon covalent
Gel Permeation Chromatography. Gel permeation chromatography
was performedusinga Waters 600E HPLC with a Waters 484 UV detector
and Waters analytical gel permeationcolumn (Ultrastyragel, 1000 A
pore size). Elutions were performed at room temperature using HPLC
grade CH2Clz or CHCII (containing 3.0 mM p-xylene as an internal
reference)as the eluentat a flow rate of 1.0mL/min. The sampleswere
prepared at concentrations of the complexesof I mM. The injection
volume was 20 pL.
Molecular Weight Determinations by Vapor Pressure Osmometry.
Molecular weight determinationswere made with a Wescan Model 233
vapor pressureosmomet€roperated at 35 oc. The molecular weight of
the complexeswere measuredin HPLC grade, glass-distilledchloroform
at concentrationsof approxirnately0.5, l,2,4, and 6 mM. At each
concentration, 3-5 measurementswere taken. Calibration curves wer€
generated using four molecular weight standards: sucroseoctaacetate
(MW 679), perbenzoyl p-cyclodextrin (MW 3321), polystyrene (MW
5050, polydispersity= 1.05),and a derivativeof gramacidinS in which
the two ornithine amino groups had been converted to their rertbutylcarbamates (MW 1342).2
( l, ldimethylethyl)phenylpmino]
Carbamic Aci4 [[S[[[+AminoG[[4
l,3,9triazin-2-yllanrinolnethyl||4bis(l-methylethyl)phylJnethylll,ldimethylethylEster (241. A 100-mL, three-necked,round-bottomedflask
was chargedwith cyanuricchloride(362 mg,l.96 mmol), THF (30 mL),
and DIPEA (l mL), and the solution was cooled to 0 oC under an
atmosphere of nitrogen. To the solution was added p-tert-butylaniline
(0.31 mL,0.29 mg,l.96 mmol) in three portionsover l0 rnin. After I
h, the reaction mixture was warmed to room temperature, and the amine
22 (629 mg, 1.96 mmol)2 was added. This mixture was stirred at 30 oC
for 2 h. The reaction mixture was cooled to room temperature and
concentratedin vacuo. The residuewas partitioned betweenEtOAc ( I 25
mL) and brine (75 mL). The organic extract was washed with further
brine (75 mL), dried over MgSOr, filtered, and concentrated in vacuo
to afford the monochloro triazine 23. This material was dissolved in
1,4-dioxane( I I mL) and 30VoaqueousNH4OH (7 mL). The solution
was sealed in a Parr vesseland heated at 95 oC for 8 h. The mixture
was cooled to room temperature, depressurized,and concentrated in vacuo.
The residuewas partitioned betweenEtOAc (175 mL) and brine (125
mL). The organic extract was washedwith further brine (100 mL),
dried over MgSOa, filtered, and concentratedin vacuo. The residuewas
purified by column chromatographyon silica gel using a solution of NHrOH/McOH (l 119:vlv) in CHzClz Q ll9:v lv) to afford the product as
a white crystallinematerial (868 mg, 1.54mmol, 86Vo): tH NMR (500
MHz, DMSO-d6) 6 8.68 (br app d, I H), 7.61 (br s, I H), 7.54 (br s,
I H), 7.3O-7.10(br m, 6 H), 6.30-6.10 (br app d, 2 H), 4.5G-4.40(br
a p p d , 2 H ) , 4 . 0 9 ( b r s , 2 H ) , 3 . 2 0 - 3 . 1 0( 2 x m , 2 X I H ) , 1 . 3 5( s , 9 H ) ,
1 . 2 2( s , 9 H ) , a n d l . l 5 ( m , 1 2 H ) ; r 3 C N M R ( 1 2 5 M H z , D M S O - d 6 ) 6
1 6 4 . 3 9 ,t 4 4 . 5 5 , t 3 3 . 3 2 , t 2 4 . 6 5 . t 2 t . 2 9 , 1 1 9 . 4 0 ,7 7 . 5 5 , 4 0 . 9 1 . 3 3 . ' 1 5 ,
4340
J. Am. Chem. Soc., Vol. I16, No. 10, 1994
3 1 . 2 2 , 2 8 . 2 1 , 2 7 . 7 4 , 3 7 . 6 7 , a n d , 2 3 .H7R
4 :M S - F A B ( M + H ) + c a l c df o r
CrzH*NzOz 562.3869,found 562.3868.
N,N"'-lI4,GBis( l -methylethyl)- 1,3-phenylenepis(methylene)lbis[N'[4-( I, I -dimethylethyl) phenyl]f l,3,ltriazine.2,4,Gtriamine (4). A solution of 9 (800 mg, 1.43 mmol) in CH:Clz (50 mL) was cooled to 0 "C.
TFA (4 mL) was added dropwise over 10 min, and the mixture was
stirred for 2 h, under an atmosphereof nitrogen. The reaction mixture
wasdiluted with toluene( 50 mL ) and concentratedin vacuo. The residue
waspartitionedbetneenEtOAc (100 mL) and I N NaOH (75 mL). The
organicextract was washedwith brine (2 x 50 mL), dried over MgSOa,
filtered, and concentratedin vacuo to unprotectedamine. This material
was added to a solutionof 2l (424 mg, 1.43 mmol) (preparedin situ)
in THF (100 mL) and DIPEA (10 mL), and the solutionwas stirred at
30 oC for 5 h. The reaction mixture was cooled to room temperature
and concentratedin vacuo. The residuewas dissolvedin 1,4-dioxane( 15
mL) and 307oaQueousNHrOH (10 mL). The solutionwas sealedin a
Parr vesseland heatedat 105 oC for l2 h. The mixture was cooled to
room temperature,depresurized, and concentratedin vacuo. The residue
was partitioned between EtOAc (300 mL) and brine (200 mL). The
organic extract was washed with further brine (200 mL), dried over
MgSOa, filtered, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel using a solution of NHaOH/
MeOH ( I /9:v/v) in CHzClz ( I / 19:v/v) to afford the product as a white
c r y s t a l l i n em a t e r i a l( 6 1 2 m g , 0 . 8 7 m m o l , 6 I V o ) : t H N M R ( 5 0 0 M H z ,
D M S O - d e ) 6 8 . 7 5 - 8 . 6 2( b r m , 2 H ) , ' 7 . 6 1 - 7 . 5 2( b r m , 2 H ) , 7 . 2 5 - 7 . 0 5
(br m, l0 H), 6.3H.13 (br m, 4 H),4.494.40 (br m, 4 H), 3.22-3.15
( b r m , 2 H ) , a n d 1 . 2 8 - 1 . 1 0( b r m , 3 0 H ) ; r 3 CN M R ( 1 2 5 M H z , D M S O , 4 3 . 5 1 ,1 3 7 . 8 6 . t 2 5 . 4 4 , 1 2 4 . 8 3 , 1 2 1 . 4 9 , 1 1 9 . 5 0 ,
d 6 ) 6 1 6 6 . 6 5 ,1 6 5 . 8 3 1
1 1 3 . 8 43, 3 . 9 1 ,3 3 , 8 9 ,3 1 . 5 7 ,3 1 . 3 3 ,2 7 . 9 4 ,a n d 2 3 . 8 4 ;H R M S - F A B ( M
+ H)+ calcd for CmHssNrz703.4672,found 703.4689.
N,N''-[[4,GBis( I -methylethyl) - 1,3-phenylene]bis(methylene)lbis[N'pheny[- I J,$triszine'2,4,6triamine ( 7). A I @-mL, three-necked,roundbottomedflask was chargedwith cyanuric chloride (303 mg, I .65 mmol),
THF (20 mL), and DIPEA (1.5 mL), and the solutionwas cooledto 0
oCunderanatmosphereofnitrogen. Aniline (25) (0.15mL, L65 mmol)
was added to the solution in two portions over 5 min. After 45 min the
reaction mixture was warmed to room temperature,and the bisamine 27
(182 mg, 0.825 mmol)3 was added. This mixture was stirred at25 "C
for 6 h. The reaction mixture was cooled to room temperature and
concentrated in vacuo. This material was dissolvedin 1,4-dioxane (13
mL) and 307oaqueousNHrOH (9 mL). The solution was sealed in a
Parr vesseland heated at I 15 oC for 28 h. The mixture was cooled to
room temperature, depressurized,and concentrated in vacuo. The residue
was washed with cold water and filtered, and the solid residue was
recrystallized from MeOH to afford the product as a cream solid (311
mg,0.528 mmol, 64Vo): tH NMR (500 MHz, DMSO-d6) , 8.98-8.74
( b r m , 2 H \ , - 1 . 7 8 - 7 . 6 4( b r m , 2 H ) , ' 1 . 2 1 - 4 . 8 1 ( b rm , 1 2 H ) , 6 . 3 7 ( b r
s , 4 H ) , 4 . 5 0 * 4 . 3 8( b r m , 4 H ) , 3 . 2 4 - 3 . 1 5( b r s , 2 H ) , a n d l . l 6 ( b r s , l 2
H ) ; t : 6 N M R ( 1 2 5 M H z , D M S O - d 6 )6 1 6 5 . 8 0 ,1 6 4 . 1 2 , 1 4 5 . 1 2 , 1 3 3 . 0 8 .
1 2 8 . 1 4 ,1 2 1 . 4 4 ,I 1 9 . 4 3 ,I 1 6 . 0 8 ,4 1 . 0 3 ,2 7 . 8 6 ,a n d 2 6 . 7 3 :H R M S - F A B
(M + H)+ calcd for C32H3eN12
591.3420,found 591.3426.
Mathias et al.
.rv,N"'-[(4,GDimethyl1,3-phenylene)bis(methylene)
lbis[N'-[4-(I, l dimethylethyl)phenyll|1,3,$triazine'2,4,6triamine(t). t H NMR (500
MHz, DMSO-d6)6 8.72-8.60(br m, 2H),7.6U7.50(br m, 3 H), 7.23(br m, 4 H), 4.36(br
7.15(br m, 4 H), 7.054.92(br s, 3 H), 6.28-6.15
s , 4 H ) , 2 . 2 1( s , 6H ) , a n d1 . 2 0( s ,l 8 H ) ; 1 3 CN M R ( 1 2 5M H z ,D M S O 135.02,
143.28,137.84,
164.37,
145.41,
d6) d 167.10, 166.79,165.9'1,
I I 9.4l, 43.26,33.66,3l .l'7,and I 8.I 4;
131.42,124.61,
I 24.58,119.52,
HRMS-FAB (M + H)+ calcdfor CreHczNn647.4046,found647.4040.
( I' I -dimethylethyl)
pheNJy''-[ l,]Phenyhnebb(methylene)JbislN'-l4(9). 'H NMR (500MHz, DMSO-d6)
nyll-1,3,5-trinine-?n4,Gtriamine
(br m, 8 H),
(br m,4 H), 7.30-7.11
(br m, 2H),'7.65-7.52
d 8.77-8.65
(br m, 4 H), 4.47(br s, 4 H), and 1.22(s, l8 H); r3CNMR
6.36-6.15
140.40,
l3-1.82,
(125MHz, DMSO-d6)
164.43,143.36.
d 166.83,
166.16,
1 2 1. 8 4 . 1 2 5 . 5152, 5 . 1 4 , 1 2 4 . 6119, 1. 5 5I ,1 9 . 4 34, 3 . 2 0 , 3 3 . 6a7n,d3 1 . 1 7 ;
found619.3748.
HRMS-FAB (M + H)+ calcdfor CrH+:N n619.3733,
1,3,5.^Y,N''-[1,]Phenylenebis(methylene)
lbis[Nr (4-methylphenyl)](10). tH NMR (500MHz, DMSO-d6)6 8.7'7triazine'2,4,Gtriamine
8 . 6 7( b r m , 2 H ) , 7 . 6 5 - 7 . 5(4b r m , 4 H ) , 7 . 2 7 - 7 . 1(8b r m , 4 H ) , 7 . 1 2
(br s, 2 H), 6.96(br s, 2 H), 6.46-6.17(br m, 4H),4.43 (b, "/"u= 6.8
6 166.81,
Ha4H),and2.l9 (s,6 H); r3CNMR (125MHz, DMSO-d6)
I ,1I 1 9 . 5 2 ,
1 6 6t.5 , 1 6 4 . 4 2 , 1 4 0 .15318, . 2 31,2 9 . 7, 7
1 2 8 . 5 61,2 7. 9 1 , 1 2 5 . 5
43.i l, and20.3l; HRMS-FAB (M + H)+ calcdforCzaHlN n535.2794,
found535.2789.
fY-[5-[[4-Amino-G[( 3,3dimethylbutyl)amino]I 3,$triazin- 2-yllaminolnethyll-2,4bis(l-methylethyl)pharyllnethyll-N'-[#(l,ldinethyl)pbe(31). 'H NMR (500 MHz, DMSOnyfl-1,3,$trisnne-2,4,,Gtriamine
(br m, 2 H), 7.64-'1.53
(br m, 2H),7.21-7.17(br m,
dr) 6 8.75-8.60
(br m, 4 H), 4.404.32(br m,
(br m, 2 H), 6.60-5.58
4 H), 7.01-6.80
4 H ) , 3 . 2 0 - 3 . 1(0b r r n ,2 H ) , 2 . 1 9( s ,6 H ) , l . 4 l - 1 . 3 2( b r m , 2 H ) , 1 . 2 2
(s,9 H), and0.95-O.78
(br s, 9 H); r3CNMR (125MHz, DMSO-d6)
133.42,
I 3I .40,124.59,
7
I 64.35.I 45.I 6, 135.24,
I
I
65.64,
6 I 66.7 . 65.95,
l l 9 . 4 l , 4 2 . 8 63, 6 . 3 3 3, 3 . 6 73, 1 . 1 82, 9 . 4 12, 9 . 2 4a, n d 1 8 . 1 4H; R M S found 599.4036.
FAB (M + H)* calcdfor CrzFLrNrz599.4046,
Acknowledgment. This work was supportedby The National
Science Foundation (Grants CHE-91-22331 to G.M.W. and
DMR-89-20490 to the Harvard University Materials Research
Laboratory). NMR instrumentation was supported by the
National Science Foundation Grant CHE-88-14019 and the
National Institutes of Health Grant I Sl0 RR4870. Mass
spectrometry was performed by Dr. A. Tyler. The Harvard
University Mass Spectrometry Facility was supported by The
National Science Foundation Grant CHE-90-20043 and The
National Institutesof Health Grant I Sl0 RR06716-01. We
thank Professor Robert Cohen (MIT, Chemical Engineering)
for the loan of his vapor pressureosmometer. J.P.M. was an
SERC/NATO PostdoctoralFellow. l99l-1993.