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7 Conclusion: The Prospects for Harnessing Nature's Catalytic Principles

7 Conclusion: The Prospects for Harnessing Nature's Catalytic Principles

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observed for enzymes. For example, the machine-like catalyst 6 turns over 5 H2

s−1 for at least 5 days of continuous operation with no observable deactivation.31

It is just as active at the end of the 5 days as it was at the beginning. Its turnover

number during that time exceeds 1,000,000 per catalyst molecule.38 Hill’s Copolyoxotungstate water oxidation catalyst also achieves an enzyme-like turnover

frequency of >5 s−1 at pH 8.58

Several of the new catalysts, furthermore, open new vistas in fields that are critically important to humankind but extraordinarily challenging. For example, solar

water splitting is achieved without need of an external energy input by 14+ /Nafion

in a dye-sensitized solar cell.51 The ability of 14+ /Nafion to selectively split seawater without generating toxic Cl2 gas must also rank as an important advance.55

Industry standard water oxidation catalysts like Pt and commercial electrolyzers

cannot achieve this feat.

These developments are cumulatively extremely promising and bode well for

the future. While it is still an open question as to whether the current understanding

of enzymes is complete, we have, at the very least, discovered a range of new and

powerful catalysts. These catalysts are a significant advance on what was previously

possible; they set a new benchmark for synthetic catalysis in a variety of reactions.

This is precisely what would be expected if the current understanding of Nature’s

catalytic principles has at least some measure of validity and is trending toward a

fuller understanding.

The challenge now is to continue the quest and to harness the knowledge that we

have available in the development of still more powerful synthetic catalyst systems.

Whatever the pitfalls, bioinspired catalysis is clearly a field with enormous potential

that is eminently worth pursuing.


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Biomimetic Amphiphiles and Vesicles



Organic Chemistry Institute and Graduate School of Chemistry, Westfalische

ă Munster,


Corrensstrasse 40, 48149 Munster,






Without exaggeration, it could be stated that a bilayer of phospholipid molecules is

all that separates “internal” from “external” in living organisms. Biological membranes play a key role in the protection of the integrity, stability, and shape of a

cell as well as its interaction and communication with its environment. Moreover,

crucial processes such as recognition and adhesion of cells, membrane fusion, signal transduction, and enzyme catalysis occur at the membrane surface. In addition,

even the simplest of cells contain numerous subcompartments, each of which are

secluded by a separate bilayer membrane. Several key functions of cell membranes

are highlighted in Figure 8.1. It was shown by Bangham and Horne in 1964 that

phospholipid bilayer membranes can easily be formed in vitro1 and it was reported

by Kunitake and Okahata in 1977 that the formation of bilayers is not restricted

to biological phospholipids.2 Vesicles (Lat. vesicula = small bubble) have been an

important topic in both chemistry and the life sciences ever since. On the one hand,

vesicles are of interest as highly dynamic supramolecular structures that mimic the

remarkable properties of biological membranes. On the other hand, vesicles are of

interest as self-assembled responsive capsules that may be applied in drug delivery,

as nanoreactors and nanosensors, or in the design of soft materials.

This chapter focuses on the use of abiological amphiphiles to generate

biomimetic vesicles. The chapter opens with a general introduction to the use of

synthetic amphiphiles as building blocks for biomimetic vesicles. The major part

of the chapter is organized according to a number of sophisticated functions that

are typical of biological cell membranes. First, we discuss biomimetic vesicles

that display molecular-recognition-induced adhesion and fusion of membranes.

Second, we describe vesicles that are senstitive to stimuli-responsive shape

control. Third, we focus on vesicles that are capable of transmembrane signaling

Bioinspiration and Biomimicry in Chemistry: Reverse-Engineering Nature, First Edition.

Edited by Gerhard F. Swiegers.

© 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.




Figure 8.1 Schematic representation of key functions of a biological cell membrane.

and vesicles that can be used to compartmentalize chemical reactions. Finally, we

address the issue of formation of subcompartments within a vesicle. The chapter

closes with a brief outlook.

This chapter is intended to provide insights into the fascinating supramolecular

chemistry of biomimetic vesicles by highlighting a selected number of recent

publications. A comprehensive review of the literature is not provided. Langmuir–

Blodgett films and supported bilayers—which are also versatile biomimetic

membranes—are not covered in this chapter.



Vesicles are dynamic supramolecular structures that consist of a molecular layer

that encapsulates a small amount of solvent. Vesicles are predominantly formed in

aqueous solution. The term “liposome” is generally reserved for vesicles composed

of natural phospholipids, while the term “vesicle” includes vesicles composed of

synthetic amphiphiles, phospholipids, or any other components. “Polymersomes”

are vesicles composed of polymers.

Bilayer vesicles are closely related to liposomes and biological membranes.

Most molecules that form bilayer vesicles in water are amphiphilic: they have a

hydrophobic and a hydrophilic part. The hydrophilic part (“head group”) of the

molecule interacts favorably with the surrounding water, while the hydrophobic

part (“tail”) minimizes its exposure to water. Hence, the amphiphiles arrange in a



bilayer and the formation of vesicles is driven primarily by hydrophobic interaction.

Typically, the head group is polar and/or charged and contains phosphate, sulfate,

ammonium, amino acid, peptide, carbohydrate, or oligo(ethylene glycol) groups.

Typically, the “tail” is apolar and uncharged. The tail is usually composed of

long hydrocarbon chains, which may be saturated or unsaturated, linear, cyclic or

branched, aromatic or aliphatic, or fluorinated. In accordance with the concept of

the packing parameter,3 the amphiphile must have an approximately cylindrical

shape, so that the molecules arrange into a bilayer, which may be slightly curved

so that it can close into a spherical vesicle. It should be noted that the packing

parameter cannot be defined exclusively on geometric considerations: attractive and

repulsive interactions of head groups should also be taken into account.

With the advent of polymersomes and vesicles of other “nonconventional” (i.e.,

not phospholipid-like) amphiphiles, numerous examples of monolayer vesicles in

water have been reported. Typically, monolayer vesicles are prepared from small

molecules with a hydrophobic core and two hydrophilic head groups (bolaform

amphiphiles, see below) or from triblock copolymers with two hydrophilic terminal

blocks. The molecule must have a cylindrical or rectangular shape, so that it can

arrange into a monolayer.

Irrespective of their composition, it is useful to differentiate between small

unilamellar vesicles (SUVs, <100 nm), large unilamellar vesicles (LUVs,

100–1000 nm), giant unilamellar vesicles (GUVs, >1 μm), and multilamellar

vesicles (MLVs) (Figure 8.2). SUVs, LUVs, and GUVs have a unilamellar

membrane composed of a single molecular bilayer (or monolayer). SUVs and

LUVs are the most widely studied types of vesicles. GUVs are of particular

interest as biomimetic membranes since their size is comparable to living cells.4

MLVs have an onion-like structure and consist of many concentric bilayer (or

monolayer) membranes. It can easily be calculated that the smallest SUVs (ca.

50 nm) of small amphiphiles contain about ten thousand molecules, whereas

LUVs contain about a hundred thousand molecules, and GUVs and MLVs contain

many millions of molecules. The number of molecules in one vesicle can only be

Figure 8.2 Small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), giant

unilamellar vesicles (GUVs), and multilamellar vesicles (MLVs).



given as an approximate average, because it is difficult to prepare vesicles of an

exactly defined size (see Section 8.4).

The first report on bilayer vesicles formed from synthetic amphiphiles dates

from 1977, when Kunitake and Okahata described the formation of vesicles from

di-n-dodecyl dimethyl ammonium bromide in aqueous solution.2 In the 1980s, it

was shown by many groups that a wide range of amphiphilic molecules can form

vesicles in water. In a sense, these amphiphiles are all very similar to phospholipids:

they generally have two hydrophobic tails and a hydrophilic head group, so that

the molecule has a cylindrical shape and packs efficiently into a bilayer sheet,

which curves and closes into a vesicle. On the other hand, the structural variety

of synthetic amphiphiles provides vesicles with a range of functions that clearly

surpass the properties of liposomes. Among others, synthetic vesicles can be made

light sensitive, vesicles can be made pH sensitive, and vesicles can be polymerized.

The pioneering work on synthetic vesicles is summarized in reviews by Kunitake,5

Ringsdorf et al.,6 and Engberts et al.7

Small amphiphiles must not necessarily have a phospholipid-like structure with

two tails and one head group. For example, bolaform (or bipolar) amphiphiles

are amphiphilic molecules that contain two head groups separated by an extended

hydrophobic chain. Bolaform amphiphiles form monolayer vesicles, in which

each amphiphile extends across the monolayer membrane, exposing both head

groups to water and sheltering the hydrophobic chain from water.8 However, these

types of vesicle-forming amphiphiles are in fact also inspired from Nature: many

extremophilic bacteria have membranes that contain a high percentage of bolaform

amphiphiles.9 Monolayer membranes of bolaform amphiphiles are much more

robust than bilayer membranes and contribute to the stability of extremophiles in

acidic, alkaline, and hot environments.

The innovative design of small amphiphiles continues to give rise to unconventional vesicles. Recently, there has been increasing interest in synthetic amphiphiles

equipped with a recognition unit.10 In many cases, such amphiphiles can form vesicles by themselves. Alternatively, they can be mixed with conventional amphiphiles

or phospholipids. In this way, it is possible to functionalize vesicles with complementary recognition motifs that can guide the selective adhesion and even fusion

of bilayer vesicles (see Section 8.3). Amphiphilic macrocyclic host molecules

have been investigated for many years. Vesicles composed of or containing synthetic host molecules are versatile model systems for receptors in biological membranes. Among others, it is known that amphiphilic crown ethers,11 cryptands,12

calixarenes,13 cyclodextrins,14 and cucurbiturils15 can form bilayer vesicles in aqueous solution. However, the host–guest chemistry of such host vesicles remained

largely unexplored for many years.

Ravoo and Darcy prepared bilayer vesicles composed entirely of amphiphilic

cyclodextrin host molecules.14 Such vesicles have a membrane that displays a high

density of embedded host molecules that bind hydrophobic guest molecules. The

characteristic size-selective inclusion behavior of the cyclodextrins is maintained,

even when the host molecules are embedded in a hydrophobic membrane. For

example, adamantane carboxylate binds preferentially to β-cyclodextrin vesicles



(Ka = 7000 M−1 ), weaker to γ -cyclodextrin vesicles (Ka = 3000 M−1 ), and very

poorly to α-cyclodextrin vesicles (Ka < 100 M− 1).16

Cucurbiturils are another class of host molecules that have been assembled

into bilayer vesicles in water. Kim and co-workers synthesized an amphiphilic

cucurbit[6 ]uril that forms vesicles and forms host–guest complexes at the vesicle surface.15 It is possible to decorate the surface of the host vesicles with guest

molecules. Exposure of cucurbituril vesicles to a fluorescent spermidine derivative

leads to fluorescent vesicles. Exposure of the cucurbituril vesicles to α-mannose

substituted spermidine leads to vesicles coated with α-mannose, which bind specifically to the lectin concanavalin A (ConA). ConA does not bind when the vesicles

are coated with a galactose spermidine conjugate. These experiments demonstrate

how synthetic host membranes can interact with proteins via multivalent interactions mediated by carbohydrates.

A major innovation in the area of vesicles was triggered by Eisenberg and

co-workers, who demonstrated in 1995 that very large amphiphilic molecules can

form vesicles.17 In a pioneering Science report, it was shown that poly(styrene)block -poly(acrylic acid) can form bilayer vesicles in water. These polymersomes

were prepared by slow addition of water to a DMF solution of the block copolymer,

followed by dialysis to remove the remaining DMF. The hydrophobic poly(styrene)

forms the interior of the bilayer membrane, while the hydrophilic poly(acrylic acid)

is exposed to water. It has been shown since that many block copolymers can form

vesicles. Important advantages of polymersomes include their high kinetic stability

and their very low membrane permeability (which increases with the length of the

hydrophobic block).

Although block copolymers that merely contain a hydrophobic block connected

to a hydrophilic block can still be considered rather straightforward high molecular weight analogs of conventional small amphiphiles, the field of polymersomes

has benefited tremendously from the design of more complex block copolymer

architectures using new polymerization methods (such as atom transfer radical

polymerization, ATRP) and highly efficient conjugation protocols (such as click

chemistry). For example, ABA block copolymers can form monolayer vesicles.

In fact, ABA block copolymers are the macromolecular equivalent of bolaform

amphiphiles. ABC block copolymers can form bilayer vesicles if A and B (but not

C), or B and C (but not A), are of similar polarity, but they can also form monolayer

vesicles if A and C (but not B) are of similar polarity. Figure 8.3 outlines the most

important block copolymer architectures for polymersomes. Block copolymers can

also contain biopolymer segments, such as polypeptides or polysaccharides conjugated to synthetic segments (“biohybrid copolymers”).18, 19 Biohybrid copolymers

are important biomimetic amphiphiles, since they combine the biological activity of

membrane-embedded biomacromolecules with the ability to self-organize in kinetically stable vesicles and microcapsules. The blossoming field of polymersomes

has been the subject of several reviews.20, 21

The versatility of polymersomes was significantly advanced by Nolte and

co-workers, who expanded the scope of block copolymers from large to giant

biohybrid amphiphiles.22 The key innovation in their work is the conjugation



AB copolymers

ABA copolymers

BAB copolymers

ABABA copolymers

ABC copolymers

ABCA copolymers

Figure 8.3 Block copolymers for polymersomes. (Reproduced with permission. Copyright Royal Society of Chemistry: Ref. 21.)

of very large hydrophilic proteins to hydrophobic synthetic polymers. These

biohybrid block copolymers differ from other protein–polymer conjugates in

the sense that the protein to polymer ratio is predefined and the position of the

conjugation site is precisely known. In a particularly elegant experiment, giant

biohybrid amphiphiles self-assembled by cofactor reconstitution of poly(styrene)

modified heme and apo-horseradish peroxidase (HRP) as well as apomyoglobin.

The biohybrid amphiphiles were obtained by adding a THF solution of the heme

cofactor-appended poly(styrene) to an aqueous solution of the apoenzyme. TEM

revealed the formation of LUVs with diameters of 80–400 nm. The activity of

the HRP and myoglobin enzymes is retained in the polymersomes.

Vesicle-forming amphiphiles must not be held together by covalent interactions

exclusively: it is easily conceivable that an amphiphile is formed by noncovalent

interaction of two (or more) components. Hence, although the individual components cannot form vesicles, vesicles self-assemble upon mixing of the components

in the appropriate molar ratio. A remarkable example of a ternary complex that

self-assembles into vesicles was reported by Kim and co-workers.23 It was shown

that vesicles are formed spontaneously in a mixture of cucurbit[6 ]uril, n-alkyl viologen, and dihydroxynaphthalene (Figure 8.4). Viologen and dihydroxynaphthalene

form a stable charge transfer complex in the cavity of the cucurbituril host. The

ternary complex is amphiphilic due to the presence of the long alkyl chain on the

viologen. If the alkyl substituent is n-dodecyl, SUVs are formed; if the alkyl substituent is n-hexadecyl, LUVs are formed. The vesicles can be imaged by scanning

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7 Conclusion: The Prospects for Harnessing Nature's Catalytic Principles

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