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AP+ROACHESTO SYNTHESISBASEDON NON-COVALENTBONDS
GeorgeM. whitesides,Eric E. Simanek,andChristopherB. Gorman
Harvard University
Departmentof Chemistry,Cambridge,MA 02138
Two self-assembling systems
SAMs (self-assembledmonolayers) and
aggregatesbased on CA'M (cyanuric acid.melamine lattice) - iu'e not unique in noncovalent synthesis,but they illustrate many of the ideas of non-covalentsynthesis,and
suggestthe ways in which this areadiffers in its philosophy and objectivesfrom covalent
synthesis.
L. Targets for Synthesis
What are the current targets for organic synthesis? The traditional activity of
organic chemistry has been to synthesizemolecules. The history of organic synthesisis
reflected in its target molecules: dyes, polymers, specialty chemicals, natural products
and pharmaceuticalshave eachbeen a favored subject at some period in the development
of synthetic chemistry. A second function of organic synthesis has been to develop
technology - often using molecules isolated from nature as stimuli - that is generally
useful in synthesis.
The targets of synthetic activity - that is, the areasin which new methods and
new strategiesare most needed- are defined by the areasof scienceand technologythat
are themselvesespecially active and that rely heavily on molecules and materials. Four
areas(among others) seemespecially to define the fields that require new synthesesand
synthetic technology:
1.1. MEDICINE
The pharmaceuticalindustry continues to require a high level of expertise in
organic synthesis. While the specific classesof compoundstbat are required in medicinal
*t't"
chemistry change with time,
the strategies used to synthesize them represent an
extension of paradigms that are now familiar in organic synthesis.Increasing emphasis
and creativity is being placed on the developmentof low-cost processes,on processesthat
yield ehantiomerically pure compounds, and on environmentally friendly Processes.
These challenging problems make certain that chemistswill continue to be an important
part of medicinal chemistry for as long as new drugs are developed.
T.2. BIOLOGY
Biology is now posing a range of new types of challengesto synthesis. Current
efforts in the synthesis of molecules relevant to biology are concentratedon the major
classesof biomolecules: polypeptides,proteins,nucleic acids and oligosaccharides.The
need for efficient methods for the synthesisof biomoleculeshas been a valuable stimulus
to synthetic chemistry. This motivation has resulted in several new methodologies
including the incorporation of synthetic methods basedon enzymes and fermentation into
standard synthetic technology, and in the generationof new methodologiesapplicable to
water-soluble and charged species, and to linear macromoleculessuch as proteins and
'
polynucleotides. It seems probable that biological synthesis,in the future, will be a
hybrid of chemical and biochemical methods,with the particular set of methods chosen
depending on the efficiency and appropriatenessof each to the problem at hand.
Advanced targets for organic synthesisrelevant to biology - for example, the synthesis
of catalytically functional aggregates,of self-replicating structures,or of simple viruses
- are still too complex to attract the attention of other than the most adventurous.
1.3. MATERTALS SCIENCE
Participation in materials sciencerequires a more substantialchangein attitude for
organic synthesisthan does biology. In biology, the targetsare moleculeswith unfamiliar
properties (for chemists) in that they have high molecular weights, are water soluble and
are often highty charged. They are, nonetheless,stlll molecules. In materialsscience,the
targets of synthesis are often molecules that either form or perfonn as aSSregates. In
many materials systems,the properties of interest may dependabsolutely on aggregation
or collective behavior. For example, liquid crystals, organic conductors and polymer
matrices for high-performance composites all depend on the behavior of collections of
molecules: the characteristics of single molecules are important only to the extent that
they contribute to collective behavior. In synthesisdirectedtoward materials,the desired
physical propertiescannot be dissociatedfrom synthesis,and a more complete
understandingof the relationshipsbetweensynthesis,processingand propertiesare
required.
1.4. EN\{IRONMENTALLY FRIENDLY SYNTHESIS
Probablythe most seriousproblem now facing the chemicalindustry is to
developenvironmentallycompatibletechnologyfor synthesis(especiallylarge-scale
synthesis). The field of environmentallyfriendly synthesisis a peculiarone. It is
unarguablyimportant,and it presentsa rangeof interestingand engagingchallenges.
Despitethesecharacteristics,
very few academicsyntheticchemistsare working in it.
Why? Onereasonis thatthe attentionof the communityof syntheticchemistshasnot yet
beencaught; a secondis that therearesurprisinglyfew leadsto appropriateprocesses,
and surprisingly few really good new ideas; a third is that economicand regulatory
considerations
arean integralpart of all environmental
synthesis,andacademicchemists
have traditionally been uncomfortablein problemsrequiring an understandingof
'economics.
Whetherthe field of environmentalsynthesisis ultimatelyattackedby
'chemistry by chemical
or
engineering
remainsto be seen.
2. Covalent and Non-covalent Synthesis
Organic synthesishas been dominatedby a single intellectual paradigm- that of
"covalent synthesis." In this paradigm, molecules - that is, collections of atoms
connected by strong, kinetically stable covalent bonds - are constructedin a series of
stepsfocused on stepwise,efficient formation of covalent bonds. Are there alternatives
to this paradigm? Both biology and materials scienceare replete with instancesin which
the crucial structural elements involve non-covalent bonding: examples include
interactions between proteins in aggregates,the interactions that give molecular and
liquid crystals their structuresand properties, and the interactions that hold together the
two strandsof DNA itself. In each of thesetypes of strucfures,covalent interactions are
important, but they are not sufficient: it is often possible to modify or even cleave the
amino acids in a protein and retain function, but the samepolypeptide sequencein native
and denatured stateshave very different function. In short, both covalent and noncovalent interactionsare important.
One alternative to covalent synthesis as a paradigm in organic synthesis is its
semanticconverse- non-covalentsynthesis. This paradigm is as important in complex
systems as covalent synthesis. Instead of energetically strong interactions dictated by
bond enthalpies, non-covalent synthesisutilizes weaker, non-covalent interactions that
are governed by equilibrium thermodyamics: entropic considerations become as
important as enthalpic ones. Non-covalent synthesis will never replace covalent
synthesis: the componentsof a complex structure will undoubtedly always be based on
covalent bonds. The assembly of these components into a functional aggre9atecan,
however, be accomplishedby either covalent or non-covalentmethods.
What are the advantagesof non-covalent synthesis? One way of addressingthe
question is to ask where non-covalent processesare already establishedto be important.
One answer -
and not necessarilythe only answer-
is when very large structuresare
required, and when the function of these structures must be controlled at room
temperature. There is no practical method of making a molecule of the three-dimensional
complexity of a protein by covalent synthesis: two-dimensionalsynthesisbased on a
reactions with very high yields, followed by non-covalentassembly (folding) is a more
practical procedure. The resulting structuresare, of course,unstable at even moderately
elevatedtemperatures(one wonders what strategieslife might have evolved if it had been
necessaryto survive environmentsof 500 C!). Similarly, the synthesisof a macroscopic
crystal, one bond at a time, is entirely out of the question. Non-covalent synthesis is a
strategy that is suited for preparation of these ensembles,where the yield losses that
inevitably accompany covalent synthesis are unacceptable. Non-covalent bonding aggregation,association,folding, annealing-
is an efficient strategy,ild one that can,
in principle, proceedin l00%oyield!
The issue of control is a more complex subject, and often has (at least in
biological contexts) to do with transitions between different but well-defined
conformational states. Although there are strong argumentsfor non-covalent structures
(and non-covalent synthesis) in systems subject to modulation and control at room
temperature,we will not addressthis subject here other than to note the obvious: only
non-covalent structures based on bonds of strengths comParable to kT can be
interconvertedby thermal processes.
2.1. PRECENDENTS FOR NON-COVALENT SYNTHESIS
There are a wide range of precendentsfor non-covalentsynthesis. Biological
stnrctures present a number of strategiesbased on structuresin which hydrogen bonds
and hydrophobic interactions are crucial []. Molecular crystals provide another very
important set (and one in which the basic rules are srill not defined!) 12-51. Liquid
crystals [6], black lipid films [7], micelles and liposomes[8], clathratesand co-crystals
[9], bubble rafts [l0], and phase-separatedpolymers [11], provide others. Nor
surprisingly, non-covalent interactions between covalently structured molecules are
important and common throughout complex systems; what is missing is a rational
processfor using theseinteractionsin synthesis.
2.2. TI{ERMODYNAIvIIC A}.ID KINETIC CONSIDERATIONS IN NON-COVALENT
SYNTIIESIS
A key idea in non-covalent synthesisis the importation of new ideas of bonding
into synthesis. Covalent synthesis is based on the use of strong, kinetically stable
networks of bonds to assemblekinetically metastablestructures. A wide range of bondtypes - coordination bonds, hydrogen bonds, charge transfer interactions,hydrophobic
interactions, charge-chargeinteractions -
are available for the construction of new
strucfures,but have been largely ignored as explicit components of,synthetic strategies
(although they have, of course, been the object of extensive interest in physical organic
chemistry, molecular recognition, biochemistry, solid-statechemistry and other areas).
Other types of considerationsa.realso important: for example,considerationsof enthalpy
dominate considerationsof the energeticsof covalent synthesis; in non-covalent
synthesis,enthalpy and entropy are both important. When entropy entersconsiderations
of synthetic strategy,ideas such as preorganizationbecomeimportant tlzl .
3. Systems
We have focused our work in non-covalentsynthesison two systems: selfassembled,two-dimensionalmonolayersbasedon orderedstructuresof alkanethiolates
chemisorbed on gold, and soluble three-dimensionalaggregatesheld together by
hydrogen bonds, and basedon the lattice formed by the 1:l aggregateof cyanuric acid
and melamine(CA.M).
,',','z',1,:,i:.f,j,',t,1,',',lrl,l,
Figure 1. Representationsof the CA.M lanice (left) and a
SAN{ (right, X = CH3, OH, COOH, C}1, etc.)
3.1. SELF-ASSEMBLED MONOLA\'ERS
Self-assembledmonolayers(SAlvIs) of long chain organic compoundson surfaces
of metals and metal oxides are increasingly useful in applications which require
structurally well-defined substrates. They are easily prepared in a wide variety of
structures(thicknesses,degreeof order, chain orientationwith respectto the surface)and
a range of functional groups can be incorporated into them. Several systemsof SAMs
have been investigated extensively,including those formed from alkanethiolateson gold,
silver 113, 141and copper [13, 15], atkanecarboxylicacids on alumina [6-18], alkanehydroxamic acids on metal oxides F9l, alkanephosphonates
[20-24] on zirconium and
aluminum oxides, alkyltrichlorosilanesor alkoxysilaneson silica 125-28Jand LangmuirBlodgett films on a range of supports[29, 30]. Of these,SAJvIsof alkanethiolateson
gold - a system first used for rational organic surfacechemistry by Nuzzo, Allara and
coworkers [3]-33] - has attractedthe most attention. This system is exceptionally easy
to work with, and is relatively stable. More importantly, it is very easy to introduce
complex functionality onto a surface using it, and it thus offers a high potential for
complex synthesis. SAMs are already significantly advancedas systemsin materials
science,and applications for them are appearingrapidly.
3.2. CYANURIC ACID.MELAIvIINE LATTICE
A second type of problem that we have examined is the design and synthesisof
complex, high-molecular weight ag$egated of molecules held together by networks of
hydrogen bond. We have chosen to work with ag$egates derived from the lattice of
hydrogen bonds formed from the I : 1 aggregateof cyanuric acid and melamine (CA.M)
I34l . This system has the advantagethat synthesisof the moleculesrequired is relatively
straightforward, and that the components have high symmetry. A range of structures
based on this system have been prepared. Simply mixing arbitrary derivatives of
cyanuric acid and melamine together usually does not generatethe desired species
containing the cyclic CA3M3 "rosette": either the componentsdissociatein solution, or
they precipitate as insoluble disorderedaggregatesor as linear or crinkled tapes.
Two types of designshave been successfulin generating stable aggregatesbased
on the CA'M lattice (Figure 2, left). In one, one set of components (typically the
melamines,since they are easier to manipulate synthetically than are the cyanuric acids)
is "preorganized"by attachmentto a common "hub". This strategyencouragesformation
of the desired aggregates by reducing the change in translational (and perhaps
conformational) entropy required to form the aggregate(relative to the corresponding
change for the components independently free in solution). The second strategy
introduces large substituentsinto the componentsto discourage formation of tapes and
other, non-rosette structuresby introducing large unfavorable steric interactions into these
structures (Figure 2, right). There is, of course, an rich literature in the subject of
molecular recognition, with extensive work in systemsthat exhibit of the phenomenaof
molecularrecognition by Hamilton [34], Rebek [35], Stoddard[36], Irhn
[37J, Sauvage
[38J,Zimmerman [39], Breslow [40], Still t41l , Kunitake [a2], and Cram lLZ,43l,
among others.
PREORGANIZATION
PERIPTIERAL CROWDING
-4
.
-:
-\.
-€rosette
tape
Figure-2. Schematicrepresentationsgf
.preorganizationof three melamine by covalent
attachmentot a center hub (left) and the formation of a rosettestructuredueio large
groups (depicted here as spheres).qyperipheral crowdinS (righ|. Melamines an-d
cyanunc acld are representedas disks.
4. SELF.ASSEMBLED MONOLAYERS
SAMs illustrate a strategyfor synthesisbasedon the idea of reductionin
dimensionality. The genericidea underlyingSAMs is to use a surface,or someother
two-dimensionalor pseudotwo-dimensionalsystems,as a templateand to assemble
moleculeson it in reasonablypredictablegeometryusing appropriatecoordination
chemistryto connectthe surfacewith the adsorbedmolecules.For this strategyto work,
oneneeds:
o { suitable coupling reaction to connectthe adsorbateto the surface.
. Sufficient in-plane mobility for the adsorbate(at some stage in the Processes
that form the SAM) to allow it to order and to form a highly structured
crystalline or quasicrystalline surfacephase.
. A geometry for the adsorbatethat is compatible with an ordered surface phase.
. The capability to pattern the system in the plane of the surface.
The flrst of these requirementsis obvious: without coupling to the surface, the
SAI4 cannot exist. The secondis required to achievehigh order. If the moleculescannot
move on the surface, they cannot order. Bonding to the surfacethat is too tight interferes
with the development of the ordered, crystalline, thermodynamic minimum state- The
third requiremsnf - an appropriate geometry - is currently not well understood. Most
work with SAMs has been carried out with derivatives of fatty acids. These structures
crystalli ze Ln the solid state in layers, with the long axes of the chains approximately
parallel. Placing the same molecule in a SAM effectively freezesone plane from the
crystal on an appropriate surface. How many other structures that forrr layers in the
crystal can be transferred to a SAIvI remains to be established; there is virtually nothing
known about the SAIvIs that might be drawn from most classesof organic molecules.
for techniques to form patterns in the plane of the
SAM - is important for the development of molecule-like structures on surfaces.
Consider a circular patch of SAM of a C16 hydrocarbonon a surfacehaving a radius of
The fourth requirement -
50 nm (this radius is now achievable using relatively straightfonvard techniqueswhich
we describebelow). This patch will contain approximately4x104 molecules,and have a
"molecular weight" of approximately 107 D. This size is in the samerange as very large
polymers, and thus is approachingdimensions familiar to organic synthetic chemists
(albeit from the upper range, rather than from the more familiar smaller sizes).
Patterning will, we believe, be an essentialpart of connectingself-assemblingand noncovalent synthesis with more conventional methods of synthesis, and also will be
essentialfor many applicationsrequiring structuresin the mesorangeof sizes.
The chemistry and structures of SAMs of alkanethiolates on gold have been
extensively studied, and need not be reviewed here t44). In brief, when fully equilibrated
and in their most stable form, these SAMs seem to be two-dimensional quasicrystals,
with the sulfur headgroupsepita,''dalon the gold surface. A 30o tilt of the trans-extended
alkane chains brings these chains into van der Waals contact. Functional groups present
on the termini of the chains are exposedto the solution. Conformational disorder in the
systemis concentratedin the terrninalregionsof the chains.
4.1. CHARACTERZATION
Characterization of these structurescan be accomplishedusing a number of
techniques,with the most useful being XPS [45], polarized infrared external reflectance
spectroscopy(PIERS) [46-48], measurement
of contactangles,ellipsometry[49,50] and,
increasingly, STM/AFM t5l-541. Computation has also been very useful in
'understanding
the order in thesestructures[55, 56]
4.2. MESO-SCALE STRUCTURES: MCRO-CONTACT PRINTING (pCP)
We have developed a number of techniquesfor patterning SAI\{s in the plane of
the monolayer t57-el. The objective of these methodsis to provide proceduresfor
achieving tme meso-scale fabrication -
that is, fabrication leading to stmctures with
dimensions in the range of l0 nm to 10 U.m- using techniquesavailable in synthetic
chemical laboratories. The most versatile of thesetechniquesis one basedon contact
printing (which we call microconractprinting, pcp) [60, &).
In microcontact printing, a pattern of a SAIvI (typically that from hexadecanethiol,
since it performs well in pCP) is formed by a techniquein which an elastomericstamp is
"inked" with the thiol, and then brought into contact with the surface of the gold.
Features present on the stamp are transferred to patterns of SAM on the surface with
remarkable fidelity: in favorable circumstances,it is possible to produce patterns with
feature sizes of 200 nm, and with edge resolution for thesefeaturesof approximately 50
nm. Once the initial pattern has been produced,the unpatternedareascan be filled in by
exposure to a solution of another alkanethiol, an additional pattern can be generatedby
stamping,or the initial patterncan be usedas a mask to protectthe gold film from
etchants.This techniquecan,therefore,be usedeitherto generatepatternsof SAMs on a
patternsof gold.
continuousgold film, or to generate
discontinuous
-rf>
Figure 3. SEM micrographsof a pattern formed by pCP followed
by chemical etching to remove gold not protectedby the SAM.
The stamp used in pCP is most commonly fabricated by photolithographic
procedures. An image is transferredinto a film of photoresist,the exposed resist is
developedto produce a three-dimensionalstructure,and this structure is then covered
with
the prepolymer from which the stamp is to be formed (typically
poly(dimethylsiloxane),PDMS). The PDMS is allowed to cure, and then peeledfrom the
master.
+
si
Photoresist
Use photolithography to
create a master
si
+
PDMS
Photoresistpattera
(1-2trm thiclness)
ExposePDI|{Sto
a_SolutiOn s6ar^ining
HS(CH2)rs
Crt
PDMS
PDMS
si
<--
+
alkrnethiol
Transf,er thiol and
form SAM by
stamping onto gol4
Photoresist patter:o
si
:f
_+-\
sAlt{s(r - 2 nm)
Au (5 - 2fiX) nm)
:-
1i ( 5- l0 nm)
Figure 4. Schematicof the processusedfor pCp.
BecausePDMS is an elastomer,it can generateconfonnal contact with a surface that is
rough. We have not defined its ability to conform to steps,irregular surface topologies
and imperfections on the surface of a gold film, but the fidelity of the contact printing
doesnot seemto be limited by this capabiliry. The abiliry of pCP to generatesharp edges
dependson the production of autophobic SAlvIs: in thesesystems,the extent of reactive
spreadingof the alkanethiol is limiled by the fact that the SAI4 that it forms is not wer by
it, and definition of the edge of the SAM is determinedby some combination of the rate
of reactive spreadingand the rate of formation of an organized,autophobicSAIyI.
4..3. EXTENSIONS TO QUASI THREE-DIMENSIONAL STRUCTURES.
Patternedgold structureson the surface of silicon/silicon dioxide can be used, in
combination with anisotropic etches for silicon, to form three-dimensionalstructures
of
the surfaceof the silicon (Figure 5). Although there are seriouslimits to the types
of
structuresthat can be formed using theseprocedures,they are unquestionablyuseful
in
generatingsimple surfacetopologies(grooves,plateaus,ridges,etc.).
Figure 5. SEM micrographs of a three-dimensionalstructure
fabricated by forming patternedSAlvIs and then using
appropriateselectiveetchesfor gold and silicon [64].
5. ITYDROGEN BONDED AGGREGATES BASED ON TTTFCA.M LATTICE
Thesestructuresare,in principle,moreeasilyenvisionedthanSAIvIs:theydo not
involve reduceddimensionalityor cooperativeeffectssuchas crystallization.They are
bffectively the applicationof the principlesof molecularrecognitionto the assemblyof
large,three-dimensional
structures.In practice,theyareremarkablydiffrcult to design,in
in organicof
thedepthof understanding
part becausecontrollingtheir entropychallenges
the secondlaw of thermodynamics.
To achievethree-dimensional,non-covalentaggregatesone needs:
Bonding processesthat occur at equilibrium, to permit the structure to reach a
thermodynamic minimum
o
Interactions that are directional, to simplify the task of design
o
Practical synthesisof the components
a
Applicable strategiessuch as "preorganization"to reduce the entropic cost of
aggregation.
We have selectedsystemsbasedon the CA.M lattice as being the simplest that we
could identify that seemedto fit these criteria. The system is a very successfulone,
although it has so far generatedaggregatesof only intermediatesizes (Figure 6). These
systemsare easy to synthesize(althoughnot necessarilyeasy to design!). They provide
wide latitude in three-dimensionalstructure,but stability, characterizationand
application
are at a much earlier stage.
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Hydrogen
Bonds (tB)
Figure j
$.gg'egatesbasedon the CA.M lattice arrangedin approximare
order of stabiliry anAthe number of rosettes(mono-, bisl, or trisl) that they
incorporate [65-73]
"Particles" refers to the number of separate
molecules comprising the aggregate. 3(M\ ir" is molecular weight in liDa.
5.1. CHARACTERZATION
Characterization of these hydrogen-bondedaggregatesposes some interesting
challenges. It has not been possible to use mass spectroscopywith them: under
all
conditions that we have tried (including electrospray),they dissociateon introduction
into
the spectrometer. Single-crystal x-ray diffraction has also not been generally useful
becauseit has not been possible to grow crystals (although one relevant crystal stmcture
of an aggregatecontaining a rosettehas been obtained)t741. A range of techniqueshave,
howevei, provided information that has conributed to characterizationof the complexes.
Vapor pressureosmometry gives a approximate measureof average molecular weight.
(A major uncertainty with VPO is compensatingsimultaneouslyfor the non-idealities in
the solution behavior of the aggregateand the internal standard. If this problem could be
solved, VPO would be a very valuable quantitative technique.) Proton NMR
spectroscopy, especially of the N-H region characteristicof the cyanuric acid moieties, is
exceptionally useful in showing the symmetry of the aggregates,and in revealing the
presenceof isomers [75]. Gel permeation chromatographyhas been astonishingly useful
in providing qualitative indications of stabiliry. The peak shape of an aggregateas it
emergesfrom the gel permeation column immediately gives an indication of the rate at
which the aggregatedissociateson the column: if the peak is sharp, dissociation is slow
relative to the time of passagethrough the column, and the complex is relatively stable;
if the peak is broad and tails, dissociationis probably occurring on the colurnn. Although
qualitative, GPC provides a highly useful method of screening aggeg^tes for relative
stability.
The set of methods currently used for charactenzationprovides a set of strong
inferencesthat can help to prove or disprove a hypothesizedstructure for an aggregate.
They do not provide the type of unambiguous proof of structure on which much of
organic chemistry is built, and the development of new techniques for the
characterizationof non-covalentaggegates would be a welcome and useful addition to
the field.
5.2. LARGE STRUCTURES
The current techniques for the design and preparation of hydrogen-bonded
aggregatesoffer relatively straightforward approachesto structures with molecular
weights in the range of 5 - 8 kD; extensionsof thesetechniquesshould make it possible
to prepareaggregateswith molecular weights of approximately 10 kD. (The range we
have set as a target is substantially larger. Proteins of averagesize are typically 30 kD;
tRNAs are closer to 100 kD.)
6. PROGNOSIS: WHAT CAN NON-COVALENT SYNTIIESIS OFFER?
Non-covdent synthesis offers one approach to large, structured collections of
molecules (and hence of atoms and functional groups). Covalent synthesisprovides the
most flexible methodology now available for preparingstablemoleculeswith sizes up to
a few hundred atoms and a few thousandmolecular weight. Beyond this range,either the
flexibility of the synthetic method is compromised in order to achieve the required overall
yield (as in polymerization), or yields become very (often impractically) small. Noncovalent structures may provide a compromise between the structural precision of
covalent synthesis but unattractive yields characteristicof covalent synthesis,and the
high molecular weights but weak structural specificationprovided by polymerization.
Non-covalent aggregatesare, however, generally less stablethan covalent molecules. (It
is, however, worth noting the obvious: not all covalentmoleculesare stable; some noncovalent systemsare very stable- CA.M, which survivesfor substantialperiods of time
at 300 "C is an example; high stabiliry is not requiredin all applications.)
6.I. STRUCTURE
The development of methods for generatinglarge structuresby non-covalent
synthesis will certainly occur. Aggregates based on the CA.M structure are moving
rapidly toward the sizescharacteristicof small biopolymers; it should be equally possible
to extend aggregatesof the types exarrrinedby I€hn and coworkers - basedon transition
metal coordination compounds-
into this rangeof sizest371. Whether patternedSAMs
should be considered"aggregates"or even the productsof non-covalentsynthesisis an
issue partially of semantics, but these structures are now made in very large sizes
routinely, and methodology is moving from these macroscopicaggregates( I c^2 of a
SAM of hexadecanethiolateon gold contains approximately5x1014 molecules of the
thiolate, or 3x1016 atoms, excluding the gold atoms in the system) to sizes more
recognizableas quasimolecularentities (a 100 nm x 100nm squareof SAM - a size that
can now be approachedexperimentally - contains 5x104 molecules of alkanethiolate,
and has a molecular weight of approximately107).
Non-covalent synthesisis thus approachingmolecular aggregatesin the range
considered "big" from both below and above, and with development will provide a
number of new methods of synthesizing(or "fabricating") thesetypes of structures.
6.2. FUNCTION
SAMs are already establishedas providing a range of functions. They control
surface'properties such as interfacial free energy 1761,wettability 158, 77, 781 and
adhesionstrengh [79-81]; they influencecorrosion[82Jand adhesion[83-85]; they can
act as resists [59, 60, 86, 87]; they serve as electroactivelayers on electrodest88-941.
Many more functions will undoubtedbe developedfor this classof materials. Hydrogenbonded aggregateshave, asyet, no functions.
7. WIIAT LIMITS NON.COVALENT
SYNTHESIS?
In the short term, the most seriouslimitation to the construction of large, soluble
aggregatesby non-covalentsynthesisis probably the absenceof systemsthat can be used
to build stable aggregatesin water. Most work in non-covalent synthesisis presently
carried out in the traditional, non-aqueoussolvents of organic chemistry. Hydrogen
bonding is the bond type most used in assembly (metal-ligand coordination is probably
'second)
of the aggregates. Going to water-soluble systems, and incorporating
'hydrophobic interactions into the design of the aggregates,would not only make the
systems more relevant to biochemistry, but, perhapsmore importantly, provide reliable
strategiesbased on incorporationof chargedgroups to keep the relatively structuredand
conformationally limited speciesthat are the targetsof this kind of work in solution. It is
not an accident that the backboneof DNA has a chargedphosphatebetweenevery base,
or that proteins are at their lowest solubility when at their isoelectric point (where they
are overall electrically neutral).
In the long term, the most pressing need for non-covalent synthesisand selfassembly of macromolecular assembliesis to find applications for them. The state of
these activities dependsupon the area. SAMs and some other systemsdirected toward
rnaterials science are finding a number of applications in areasranging from protective
coatings to sensors. Applications for the hydrogen-bondedaggregatesare substantially
less obvious. Catalysis by design is still unattainablein any field, and it is not likely that
enzyme-like activity will emerge soon from these aggregates; applications in materials
sciencearejust beginningto be explored.
Acknowledgments.We wish to acknowledge
the indispensable
contributionsto
this work of a numberof individualsnot listed as authorsof the paper. In the areaof
SAMs, Colin Bain, Paul Laibinis,HansBiebuyck,Nick Abbott and Amit Kumar all
contributedvitally importantconceptsand results. Ralph Nuzzo and Mark Wrighton
have been essentialcollaboratorsat many stagesof the work. In hydrogen-bonded
aggregates,
Chris Seto and John Mathias laid the foundations,and Jon Zerkowski
contributedto understanding
them. Financialsupportcamefrom the Office of Naval
Researchand ARPA (N00014-93-l-0498),
and from the NationalScienceFoundation
(crm-gF2233r).
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