tremendous interest for nanotechnology."
The authors did a number of control experiments to exclude
several possible effects of the capsules other than geometrical
confinement. They excluded the possibility of direct hydrogen
bonding of one of the capsule molecule's hydroxyl groups to the
reactants by synthesizing a molecule similar to the capsule
molecule (with essentially the same functional groups) but with
different global stereochemistry (an "S" shape instead
of a "C" shape) that precluded formation of a capsule.
This variant did not accelerate the reaction. The authors also
methylated the hydroxyls of the capsule molecule, preventing the
formation of the hydrogen bonds that held the capsule together
and again suppressed the acceleration. A variant of the reactants
was also examined. Replacing the p-quinone with napthoquinone (a
larger molecule that does not fit in the capsule) eliminated the
This work is applicable to nanotechnology because it illustrates the control of a reaction forming covalent bonds via nonbonded geometrical constraints on the reactants without the use of enzymes or other biopolymers. The authors write that the "interior of cage-like molecules can be considered to provide a new phase of matter, in which it become possible to stabilize reactive intermediates and to observe new forms of stereoisomerism." This "new phase" has an absence of solvent molecules or other non-reactant species and the presence of a constraining network around the reaction site. Both of these features are analogous to conditions during machine phase chemistry in molecular manufacturing.
The third article on parallel techniques discusses beta peptides. Natural proteins are composed of alpha amino acids, compounds where the amino nitrogen and carboxylic acid group are bound to the same carbon atom. Writing in [Nature 385:113-114 9Jan97], B. L. Iverson describes work by the research groups of S. Gellman and D. Seebach on oligomers of beta amino acids, compounds where the amino and acid groups are attached to adjacent carbons. Gellman's group found that a hexamer forms "well-defined helices in methanol solution and in the solid state." Seebach's group also found evidence of a helix in solution. The helices formed are analogous to alpha helices in natural proteins. In these oligomers they are "stabilized by hydrogen bonds between every third unit. This folding pattern results in 14-atom 'rings' being formed by the hydrogen bonds, so Gellman has called the structure the 14-helix." From an engineering viewpoint, the attractive feature of these compounds is the stability of their secondary structure even in very short polymers. By comparison, the shortest alpha peptide that I am aware of that forms a well-defined helix is 23 residues long [Science 271: 342-345 19Jan96]. Perhaps the fold prediction and fold engineering problems will prove to be intrinsically easier with beta peptides than with alpha peptides. These experimental results are "extraordinary, especially when one considers that the extra -CH2- group of the beta-amino acids might be expected to make the resulting resulting beta-peptides more flexible than alpha-amino-acid peptides, not more structured." Each of the two non-carboxylic carbons in a beta peptide residue can carry a side chain, so the potential design freedom for these peptides is higher than for alpha peptides. Further work will tell how much of this design freedom can be exploited while retaining the stable 3D structures demonstrated by Gellman's and Seebach's groups.
In the fourth article on parallel methods, J. C. Hogan,
writing in [Nature (supp) 384:17-19 7Nov96]
describes trends in combinational chemistry for drug development.
He describes past attempts to generate drug leads from peptide
and oligonucleotide libraries, but describes them as having been
unproductive pharmocologically. He also mentions a wide variety
of other oligomer libraries which have been produced by solid
phase synthesis, writing: "the synthesis of oligomeric
N-alkyl glycines shown in Fig. 1 is an excellent non-peptidic
example. Using this [solid phase, with a single coupling
chemistry] approach, libraries of oligocarbamates, peptide
phosphonates, vinylogous polypeptides and other oligomeric
scaffolds have been produced." This spectrum of oligomers
would seem to provide a good selection of candidates for stably
folded strands with well defined 3D structures for both drug and
machine part applications, however Hogan goes on to write:
"These molecules generally possess flexible backbones, which
can weaken target binding and can also hinder the application of
Hogan goes on to describe new techniques where "multiple variable groups are arranged about a central scaffold or core." In the examples that he shows, the cores appear to be fairly rigid in two of the three cases, with aromatic rings present and only two or three torsional degrees of freedom in the core. Unfortunately, the variable substituents are joined to the core with single bonds in all of the cases that he cites, so the molecules as a whole have quite a bit of flexibility. From a machine perspective, the current trend in synthetic libraries would become much more helpful if cyclization reactions between the substituents were incorporated.
|Foresight Update 28 - Table of Contents|
Advances in Sequential Techniques
The other major strategy for building precise structures relies on sequential operations at some point in the techniques. This may include sequential scanning probe tip placements in a tunneling or force microscope or it may involve electron beam flashes in e-beam lithography. In general, these techniques allow more predictable geometrical control at the cost of slower fabrication than in the parallel methods. The three papers in this section describe advances in these sequential techniques.
In the first paper M. T. Cuberes, R. Schlittler, and J. K. Gimzewski, writing in [Appl. Phys. Lett. 69:3016-3018 11Nov96], describe the reversible positioning of individual C60 molecules adsorbed on to a step on a Cu(111) surface at room temperature. In a sense, this work is complementary to this group's earlier work on porphyrin manipulation. In that work the structure and flexibility of the mobile molecule, the porphyrin, helped control the binding to the surface, permitting controlled motion while avoiding thermal diffusion. In this case, the C60 molecules are rather rigid, but the Cu(111) surface contains a step edge that confines them to motion in one dimension. In addition "small kinks [in the step edge] are noticeable from the misalignment of the C60 molecules with respect to their neighbors ... The formation of kinks at the Cu steps around the C60 molecules increases the coordination of the molecule with Cu and hinders its diffusion along [emphasis added] the step edge." The authors demonstrated that an "STM tip can separate a C60 molecule from a molecular chain adsorbed at a monatomic Cu(111) [step] and shift it controllably and reversibly back and forth without significantly altering the position of the other atoms in the chain." This implies that STM tips can be remarkably clean, with sufficiently sharp surfaces on both sides that "pushing" molecules from either side can be done with little disturbance to adjacent molecules. This is not what one would expect, for instance, if STM tips always depended on a single critical atom on what otherwise was approximately a 100 nm sphere. This is a hopeful sign for many types of attempts to use scanning tips to build precise structures.
|"...our results show
promise for further advances in
bottom-up fabrication and operation of devices..."
There are limitations to the positioning in this system. The authors found that "only single molecules can be controllably repositioned in the current system. Attempts to move more than one molecule at a time distort the molecular rows." This, however, sounds like it is only a mechanical instability in a compressed row of spheres rather than a limitation on the precision with which the tip can apply forces. The description of the applicability to nanotechnology is best left in the original authors' words. They conclude: "Therefore, STM-aided manipulation can be used to fabricate a functional counting device based on the abacus mechanism at the molecular scale. Although the use of nanomechanics at the molecular level is still at an early stage of development, our results show promise for further advances in bottom-up fabrication and operation of devices with dimensions on the level of several nanometers."
In the second paper, A. van Blaaderen, R. Ruel, and P.
Wiltzius, writing in [Nature 385:321-323 23Jan97],
describe a technique for controlling the 3D assembly of colloidal
particles by initiating the assembly on a 2D patterned template.
Their template was "a 500-nm-thick fluorescent polymer, with
holes made with electron beam lithography." They deposited
fluorescent silica spheres with a radius of 525 nm by gravity on
their polymer template. In the absence of a template,
"hard-sphere-like colloidal dispersions are known to
crystallize with a random stacking of close packed planes."
In this experiment, a (100) pattern of holes in the polymer
caused the formation of a pure face centered cubic (FCC) crystal.
The 2D template controlled the long range order of the 3D
crystal. The (100) slice through the crystal was chosen rather
than a denser (111) slice because close packed (111) layers can
stack on top of each other in either of two possible positions,
creating the possibility of twinning at each layer. In contrast,
a (100) layer of hard spheres only permits one possible position
for the next (100) layer. "In other words, there is no
twinning possibility along this growth direction."
The authors also experimented with mismatched lattices, showing that templates with mismatched spacings generated defects which gradually converted the lattice to a random close packed one. Another experimental variation was to leave a gap between two patterned regions. When the gap was 11 diameters wide, a hexagonal region appeared between the two FCC regions. Manipulations like this might inject a considerable amount of information into the crystal. For example they might introduce twinning boundaries (at an angle to the template) at selected locations in the crystal. The authors suggest that their technique could be extended to charged spheres as well, using a charged template rather than purely hard-sphere-like repulsion.
While the present work does not create an atomically perfect structure, the substitution of virus particles, with well defined structures (and presumably with well defined interparticle contacts in a crystal) would permit lithographic control of a long range atomically perfect structure. This might permit molecular manufacturing to take advantage of the large investment that has been made in fine-line lithography.
The third paper is not directly about an advance in a
sequential technique, but rather describes an amplification
technique which might improve our ability to exploit sequential
techniques. Writing in [Nature 384:150-153
14Nov96], R. Maoz et. al. describe exponential replication of a
stack of partially condensed alkyl siloxanol layers. At each step
they have bilayers of n-octadecylsiloxanol (formally CH3-(CH2)17-Si(OH)3,
but with partial dehydration of the -Si(OH)3 groups, forming
lateral covalent Si-O-Si bridges within the layers). Alternate
layers have their hydrophilic -Si(OH)3 groups pointing
up and pointing down. Each replication is done in two steps.
First the stack is treated with wet acetone. This places water
molecules between the hydrophilic siloxanol groups. Next, the
stack is treated with n-octadecyltrichlorosilane, CH3-(CH2)17-SiCl3.
This enters the stack and reacts with the water to form
additional n-octadecylsiloxanol, which inserts a new bilayer in
between each existing pair of bilayers. The authors write that
"A stack of preformed bilayers thus functions as a set of
independent template units which define the discrete spatial
distribution of the water incorporated into the film, while
providing a succession of distinct polar interfaces, each of
which is capable of sustaining the spontaneous self-assembly of a
similarly structured bilayer." The authors also found that
these layers were mechanically robust, with AFM examination
showing "no defects, such as holes or steps", and
finding that "no surface defects could be induced by the
Ideally, it would be helpful if this work could be extended to allow the accurate complementary replication of layers containing mixed siloxanols. This would essentially yield a 2D analog to PCR. For example, if several different kinds of hydrophilic groups could bind selectively at the polar/polar interface of a bilayer, then an initial lateral pattern could be exponentially amplified to macroscopic quantities. This would greatly enhance the usefulness of the atomically precise patterns that can be produced sequentially with STMs today. One could program them and amplify them much as nucleic acids are handled today, but one would not be faced with predicting the folding of a 1D amino acid sequence into a 3D protein in order to produce a useful structure.
Foresight Update 28 was originally published 30 March 1997.
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