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Non-Ionic Thermoresponsive Polymers in Water

April 2010
Advances in Polymer Science 242(1):29-89

April 2010
242(1):29-89

DOI:10.1007/12_2010_57

In book: Advances in Polymer Science (pp.29-89)

Authors:

Vladimir Aseyev

University of Helsinki

Heikki Tenhu

University of Helsinki

Francoise Winnik

Université de Montréal

Numerous non-ionic thermally responsive homopolymers phase separate from their aqueous solutions upon heating. Far fewer neutral homopolymers are known to phase separate upon cooling. A systematic compilation of the polymers reported to exhibit thermoresponsive behaviour is presented in this review, including N-substituted poly[(meth)acrylamide]s, poly(N-vinylamide)s, poly(oxazoline)s, protein-related polymers, poly(ether)s, polymers based on amphiphilic balance, and elastin-like synthetic polymers. Basic properties of aqueous solutions of these polymers are briefly described. KeywordsAmphiphilic-LCST-Polymer-Solution-Thermoresponsive-Water

The most recent reviews devoted to the water-soluble thermoresponsive polymers

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continued)

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Typical microcalorimetric endotherm at a heating rate of 15 • C/h (solid line) and turbidity curve at a heating rate of 24 • C/h (circles) obtained on an aqueous poly(N-isopropylacrylamide) solution (M w = 414,000 g/mol, PDI = 2.8, c = 0.04 wt%). T max , temperature of the maximum heat capacity; ΔC p , difference in the heat capacity before and after the transition; T dem , demixing temperature; T cp. temperature of the first appearance of cloudness. Reprinted with permission from the American Chemical Society [105]

…

Neutral thermoresponsive homopolymers, for which the solubility in water decreases

…

continued) Structure Properties

…

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Adv Polym Sci (2011) 242: 29–89

DOI:10.1007/12_2010_57

Springer-Verlag Berlin Heidelberg 2010

Published online: 20 April 2010

Non-ionic Thermoresponsive Polymers in Water

Vladimir Aseyev, Heikki Tenhu, and Françoise M. Winnik

Abstract Numerous non-ionic thermally responsive homopolymers phase separate

from their aqueous solutions upon heating. Far fewer neutral homopolymers are

known to phase separate upon cooling. A systematic compilation of the polymers

reported to exhibit thermoresponsive behaviour is presented in this review, includ-

ing N-substituted poly[(meth)acrylamide]s, poly(N-vinylamide)s, poly(oxazoline)s,

protein-related polymers, poly(ether)s, polymers based on amphiphilic balance, and

elastin-like synthetic polymers. Basic properties of aqueous solutions of these poly-

mers are brieﬂy described.

Keywords Amphiphilic ·LCST ·Polymer ·Solution ·Thermoresponsive ·Wate r

Contents

1 Scope of the Review ........................................................................... 31

2 Synthesis ....................................................................................... 32

3 Polymers in Aqueous Media: Selected Reviews ............................................. 33

4 Thermal Responsiveness versus Hydrophobic Association ................................. 39

4.1 Sensitivity and Responsiveness........................................................ 39

4.2 The LCST-Type Transition ............................................................ 41

4.3 Phenomenological Classiﬁcation ...................................................... 43

4.4 The Hydrophobic Interaction .......................................................... 43

V. As e y ev ( ) and H. Tenhu

Laboratory of Polymer Chemistry, Department of Chemistry, University of Helsinki,

PB 55, FIN-00014 HY, Helsinki, Finland

e-mail: vladimir.aseyev@helsinki.ﬁ;heikki.tenhu@helsinki.ﬁ

F.M. Winnik

Department of Chemistry and Faculty of Pharmacy, University of Montreal, CP 6128 succursale

Centre-Ville, H3C 3J7, Montreal, QC, Canada

e-mail: francoise.winnik@umontreal.ca

30 V. Aseyev et al.

4.5 Cooperativity of the LCST Transition................................................. 44

4.6 Elastin-Like Polymers ................................................................. 46

5 Self-Organization versus Steric Stabilization ................................................ 47

5.1 Colloidal Stability ...................................................................... 47

5.2 Hydrophobic Self-Association......................................................... 48

5.3 Protein-Like Copolymers .............................................................. 50

5.4 Mesoglobules of Homopolymers ...................................................... 50

6 List of Thermoresponsive Homopolymers ................................................... 51

7 Some Generalizations ......................................................................... 69

7.1 Structural Effects ....................................................................... 69

7.2 Structural Isomers of PiPAAm ........................................................ 70

7.3 Hysteresis ............................................................................... 71

7.4 Effect of Macromolecular Architecture ............................................... 72

7.5 Cyclic Polymers ........................................................................ 73

7.6 Telechelic Amphiphilic Polymers ..................................................... 74

7.7 Cononsolvency ......................................................................... 75

8 Postscript....................................................................................... 76

References .......................................................................................... 76

Abbreviations

ρAverage density

ηViscosity

A2Second osmotic virial coefﬁcient

Ac Acetate

Ad Adenine

Al Alcohol

cPolymer concentration

CAC Critical aggregation concentration

CMC Critical micellization concentration

CMT Critical micellization temperature

CpPartial heat capacity

DLS Dynamic light scattering

DLVO Derjaguin–Landau–Verwey–Overbeek theory

DSC Differential scanning calorimetry

ELP Elastin-like polymer

Es Ester

Eth Ether

LCST Lower critical solution temperature

kBBoltzmann constant

MnNumber average molar mass

MwWeight average molar mass

Oz Oxazoline

PDI Polydispersity index

SANS Small angle neutron scattering

SLS Static light scattering

Non-ionic Thermoresponsive Polymers in Water 31

tTime

TΘTheta temperature

Tcp Cloud-point temperature

Tdem Demixing temperature

TgGlass transition temperature

Tmax Temperature of the maximum heat capacity

TM-DSC Temperature-modulated differential scanning calorimetry

UCST Upper critical solution temperature

Note that in order to keep style and consistency we abbreviate poly(N-

isopropylacrylamide) as PiPAAm, though other abbreviations are typically used

(PNIPAM, pNIPAAm, etc.). We also use such abbreviations as Ac for acetate, Ad

for adenine, Al for alcohol, Eth for ether, Es for ester, Oz for oxazoline.

1ScopeoftheReview

Numerous supramolecular structures of varying complexity are formed in nature

upon self-assembly of biomacromolecules via non-covalent interactions in aqueous

media. Many of such molecules are amphiphilic, i.e. they consist of hydrophilic

and hydrophobic moieties. Thus, ionic or highly polar groups provide the over-

all solubility of the molecules in water. Formation of hydrogen bonds between

the hydrophilic polar groups of a macromolecule and water molecules contributes

favourably to the free energy of mixing. Synthetic amphiphilic macromolecules also

form self-assembled structures in aqueous media. They are widely used in indus-

trial applications as emulsiﬁers and viscosity modiﬁers. Their newer applications

include various nanocontainers, nanoreactors, etc. Their ultimate self-organization

derives from the relative contribution of non-covalent interactions, such as hydrogen

bonding, van der Waals interactions, ionic interactions, metal–ligand interactions,

hydrophobic interactions, and the entropy contribution. One can also induce self-

assembly or trigger transitions between different geometries of the assemblies by

adjusting the solvent quality. Such polymeric systems serve as stimuli-responsive

materials, for which speciﬁc properties can be tuned by an appropriate stimulus.

Among the possible stimuli are temperature, pH, electric and magnetic ﬁelds, ions,

reactants, visible and UV radiation, and mechanical stress. These materials are also

known as smart, intelligent, or environmentally responsive materials.

The last few years have seen the development of new interdisciplinary branches

of science that have led to ordered supramolecular architectures based on well-

deﬁned polymers assembled via non-covalent interactions. Our analysis of the

literature (using SciFinder Scholar software [1]) reveals a faster-than-linear growth

of the number of publications on this topic during the last decade. Thus, the an-

nual number of publications (journals, patents and reviews) on “self-assembling

polymer” (as a keyword) increased ﬁvefold, reaching almost 1000 articles per year.

The number of publications on “stimuli-responsive polymers” or on “thermorespon-

sive polymers” in 2008 was about 100, which is six to seven times higher than the

32 V. Aseyev et al.

number published in 1998. The most widely studied water-soluble thermoresponsive

polymer, poly(N-isopropylacrylamide), PiPAAm, was the subject of about 700 pub-

lications in 2008 (word search), which is about four times higher than in 1998. The

number of reviews on “poly(N-isopropylacrylamide)”in highly ranked international

journals is ﬁve to ten per year, and we believe that this number is an underestimated

value. In contrast, there are only a few studies on other thermoresponsive polymers.

For example, about 17 and about 25 papers per year, respectively, have been pub-

lished on two of the structural isomers of PiPAAm: poly(2-isopropyl-2-oxazoline)

and polyleucine.

The apparent discrepancy between the numbers of publications also reﬂects dif-

ferences in the terminology used in various branches of science and in different

scientiﬁc schools, which may lead to miscommunication between scientists. Thus,

the terms “thermoresponsive” and “thermosensitive” or “lower critical solution tem-

perature” and “cloud point” are used interchangeably, although their meanings are

not necessarily identical. The latter case is particularly unfortunate because it pre-

vents quantitative comparison of the literature values. Another factor to consider

is that the number of publications on applications of PiPAAm is growing much

faster than the number of reports on its fundamentalproperties. The upcoming years

may witness the disappearance of the gap between synthetic and natural water-

soluble polymers, that is, between chemistry, biology, medicine and physics. The

design, synthesis, characterization and controlled self-organization of well-deﬁned

polymer-based nanomaterials will be key research areas in the next decades.

Due to the large number of existing reviews on stimuli-responsive materials, we

limit this publication to articles focussed on dilute aqueous solutions of neutral ther-

moresponsivelinear homopolymers and refer our readers to the most recent publica-

tions covering other related cases, e.g. copolymers, various gels, self-organization

of block and graft copolymers with highly hydrophobic blocks, applications, etc.

Unfortunately, the number of intelligent copolymers currently available is so vast,

that the self-organization in aqueous solutions of each one of them cannot be de-

duced de-novo on the basis of our current understanding of basic self-assembly

principles. We trust that the understanding of these principles for homopolymers is

the ﬁrst step to the further understanding of more complex systems. For this rea-

son, in this publication we review homopolymers that either exhibit a lower critical

solution temperature (LCST) or those few polymers for which solubility in water

decreases upon cooling.

2Synthesis

The synthesis of well-deﬁned polymers and of complex polymer architectures has

been greatly facilitated by recent developments in controlled radical polymeriza-

tion, which has opened up new possibilities in the design and also in the preparation

of functional nanostructures based on supramolecular assembly. Controlled radical

polymerization is an attractive alternative to anionic polymerization for preparing

polymeric building blocks of well-deﬁned size and a low polydispersity index

Non-ionic Thermoresponsive Polymers in Water 33

(PDI). It allows the precision synthesis of a variety of novel well-deﬁned polymer

architectures having exciting structure–property–function relationships (such as

block and graft copolymers, stars, brushes and bottle-brush structures) starting from

a vast array of commercial functional monomers. Thus, controlled radical poly-

merization has been investigated extensively for poly(N-alkyl)acrylamides by using

atom transfer radical polymerization (ATRP) [2–15], reversible addition fragmen-

tation chain transfer (RAFT) [16–22], nitroxide-mediated polymerization (NMP)

[23–26] and degenerative chain transfer polymerization (DTP) [19,27–29]. In this

review, discussion of polymer synthesis has been kept to a minimum. Interested

readers are referred to other reviews or books listed in Table 1. The syntheses of

various thermoresponsive homopolymers, block copolymers and end-functionalized

polymers have been reviewed recently by Aoshima and Kanaoka [30].

3 Polymers in Aqueous Media: Selected Reviews

The years 2006–2008 were the most productive in terms of the number of reviews on

amphiphilic polymers. Over ten detailed reviews on thermoresponsive water-soluble

polymers were published in English in 2006 [1]. In Table 1we list the reviews to

date that are the most related to the scope of the current review and, from our point

of view, those that fully cover all aspects of thermoresponsive polymers. The key

phrases in the table are not just the key words given by the authors, but rather the

highlights of the contents.

Tab l e 1 The most recent reviews devoted to the water-soluble thermoresponsive polymers

Title Authors Key phrases Year Ref.

Synthesis of water-soluble polymers

Synthesis of stimuli-

responsive polymers by

living polymerization:

poly(N-isopropylacrylamide)

and poly(vinyl ether)s

Aoshima S,

Kanaoka S

Synthesis of various functionalized

N-isopropylacrylamide- and

vinylether-based polymers;

grafting onto various substrates;

detailed review of

thermoresponsive polymers,

block and graft copolymers;

synthesis of PiPAAm of various

shapes; ionic and neutral block

copolymers; self-assembly;

stimuli-responsive polymers; new

initiating systems and synthetic

methodologies

2008 [30]

RAFT-synthesized diblock

and triblock copolymers:

thermally induced

supramolecular assembly

in aqueous media

McCormick CL,

Sumerlin BS,

Lokitza BS,

Stempka JE

Stimuli-responsive block copolymers

via RAFT; micelles and vesicles;

postpolymerization modiﬁcation

utilizing crosslinking and

copper-catalysed azide–alkyne

click chemistry

2008 [21]

(continued)

34 V. Aseyev et al.

Tab l e 1 (continued)

Title Authors Key phrases Year Ref.

RAFT radical

polymerization and

the synthesis of

water-soluble

(co)polymers under

homogeneous

conditions in

organic and aqueous

media

Lowea AB,

McCormick CL

Stimuli-responsive polymers;

controlled-structure (co)polymers;

detailed list of monomers and chain

transfer agents; RAFT mechanism;

limitations of homogeneous

aqueous RAFT; modiﬁcation of

gold surfaces; control over the

copolymer structure for subsequent

self-assembly in response to

changes in temperature

2007 [31]

Controlled/living

radical

polymerization:

features,

developments, and

perspectives

Braunecker WA,

Matyjaszewski K

Structure–reactivity correlations and

rules for catalyst selection in

ATRP; chain transfer agents in

RAFT; mediating agent in stable

free-radical polymerization;

nitroxide-mediated polymerization;

degenerative transfer

polymerization

2007 [3]

Carbocationic

polymerizations

Goethals EJ,

Du Prez F

Living/controlled polymerizations;

vinyl ethers; disubstituted oleﬁns

and styrenics; pseudo-cationic

polymerization; block copolymers;

telechelic polymers

2007 [32]

Supramolecular structures formed by amphiphilic polymers

Polymer-assisted

fabrication of

nanoparticles and

nanocomposites

Rozenberg BA,

Tenne R

Principles of nanoparticle stabilization

against aggregation; interaction

forces; polymeric surfactants;

polymer adsorption;

nanotechnology; properties of

nanoparticles and nanocomposites

2008 [33]

Supramolecular

assemblies of block

copolymers in

aqueous media as

nanocontainers

relevant to

biological

applications

Harada A,

Kataoka K

Physicochemical aspects of

self-assembly of

hydrophilic–hydrophobic block

copolymers; Pluronics; block

copolymers with a peptide or ionic

segment; micelles with cross-

linking in the core or in the corona;

drug delivery systems; capillary

electrophoresis; surface

modiﬁcation; non-viral gene

vectors

2006 [34]

Block copolymers

in nanoscience

Lazzari M, Lin G,

Lecommandoux S

A collection of reviews on block

copolymer self-assemblies, from

synthesis to applications; vesicles

and micelles; stimuli-responsive

assemblies; polypeptide-based

block copolymers; nanotubes and

nanoﬁbres; applications

2006 [35]

(continued)

Non-ionic Thermoresponsive Polymers in Water 35

Tab l e 1 (continued)

Title Authors Key phrases Year Ref.

Solution self-assembly

of tailor-made

macromolecular

building blocks

prepared by

controlled radical

polymerization

techniques

Lutz JF Synthesis; macrosurfactants,

polysoaps, polyelectrolytes as

building blocks; preparation of

spherical, cylindrical,

multicompartment, and

schizophrenic micelles, polymer

vesicles, polyion complexes;

bottom-up self-assembly;

stimuli-sensitive colloids

2006 [36]

Block copolymers in

solution:

fundamentals and

applications

Hamley IW Monograph; from basic physical

chemistry to applications; theory,

modelling and experiment; dilute

and concentrated solution; neutral

and polyelectrolyte block

copolymers; variety of phase

transitions; phase diagrams;

adsorption; applications

2005 [37]

Block copolymer

micelles

Gohy JF Micelles from AB and ABC block

copolymers in organic and aqueous

solvents; preparation, control of

micellar morphology; new trends in

the ﬁeld

2005 [38]

Linear and non-linear

triblock

terpolymers.

Synthesis and

self-assembly in

selective solvents

and in bulk

Hadjichristidis N,

Iatrou H,

Pitsikalis M,

Pispas S,

Avgeropoulos A

Linear, star-shaped miktoarm, and

cyclic ABC terpolymers;

self-organization in aqueous and

organic solvents; microphase

separation in the bulk: theory and

experiment

2005 [39]

Phase behaviour and

morphologies of

block copolymers

Abetz V,

Simon PFW

Linear, star, cyclic, and other

topologies of block copolymers;

phase diagrams: theory and

experiment; microphase separation;

crossing the boundaries between

different phases; blends;

superlattice

2005 [40]

Micellization of block

copolymers

Riess G Synthesis and self-assembly in solution

and on solid surfaces; theories and

computer simulations; AB and

ABA block copolymers; micellar

architectures; co-micellization;

colloidal nanostructures; controlled

drug delivery; polyion micellar

complexes; metal nanoparticles;

surface modiﬁcation

2003 [41]

(continued)

36 V. Aseyev et al.

Tab l e 1 (continued)

Title Authors Key phrases Year Ref.

Stimuli-responsive polymers and self-assembly

Complex coacervate

core micelles

Voe t s IK ,

de Keizer A,

Cohen Stuart MA

Co-assembly of neutral-ionic blocks,

graft, random copolymers with

oppositely charged species in

aqueous solution; synthetic

(co)polymers of various

architectures; biopolymers;

multivalent ions; metallic

nanoparticles; surfactants;

polyelectrolyte block copolymer

micelles; metallo-supramolecular

polymers

2009 [42]

Smart polymers:

applications in

biotechnology and

biomedicine

Galaev I,

Mattiasson B

(eds)

A collection of reviews on

stimuli-responsive polymeric

materials and their application

2008 [43]

Protein-based smart

polymers

Rodríguez-

Cabello JC,

Reguera J,

Prieto S,

Alonso M

ELPs and block copolymers, adjustable

demixing temperature, TM-DSC

splits the dehydration of the

polymer and simultaneous β-spiral

formation, self- assembling,

ﬁlaments and ﬁbrils, pH- and

photoresponse, applications

2008 [44]

Smart polymers and

their applications as

biomaterials

Aguilar MR,

Elvira C,

Gallardo A,

Vázquez B,

Román JS

pH- and thermally responsive

polymers; PiPAAm neutral and

charged copolymers; hydrogels;

polymers with amphiphilic balance:

Pluronics or Poloxamer, Tetronics;

thermoresponsive biopolymers;

dual stimuli-responsiveness

2007 [45]

Thermosensitive

water-soluble

copolymers with

doubly responsive

reversibly

interacting entities

Dimitrov I,

Trzebicka B,

Müller AHE,

Dworak A,

Tsvetanov CB

Large collection of water-soluble

copolymers; controlled synthesis;

self-assembly; hydrogels; doubly

thermoresponsive polymers;

combinations of stimuli:

thermoresponsive and zwitterionic

properties, LCST and UCST

properties, thermo- and

pH-responsive properties, magnetic

ﬁeld and thermoresponsive

properties, thermo- and

light-sensitive polymers;

solvent-sensitive PEO conjugates

2007 [46]

Design of rapidly

assembling

supramolecular

systems responsive

to synchronized

stimuli

Choi HS, Yui N Thermoreversible supramolecular

assembly; fast gelation and slow

dissociation; intermolecular ionic

interactions; stimuli-sensitive

hydrogels

2006 [47]

(continued)

Non-ionic Thermoresponsive Polymers in Water 37

Tab l e 1 (continued)

Title Authors Key phrases Year Ref.

Towards smart

nano-objects by

self-assembly of

block copolymers in

solution

Rodríguez-

Hernández J,

Chécot F,

Gnanou Y,

Lecommandoux S

Nanoparticles, their preparation and

morphologies; responses to changes

in pH, temperature, ionic strength,

etc.; stabilization of self-assembled

morphologies in dilute solution via

various mechanisms; applications

in the biomedical ﬁeld

2005 [48]

Stimuli-reponsive

polymers and their

bioconjugates

Gil ES,

Hudson SM

One of the most cited reviews;

classiﬁcation of stimuli-responsive

polymers; temperature-responsive;

pH-responsive; smart polymers;

homo and block copolymers;

intelligent polymers; hydrogels;

micelles; bioconjugates; drug

delivery

2004 [49]

Self-assembly of block

copolymers derived

from

elastin-mimetic

polypeptide

sequences

Wright ER,

Conticello VP

Phase behaviour in aqueous solution;

thermo-reversible self-assembly of

elastin-mimetic diblock and

triblock copolymers into

protein-based nanoparticles and

nanotextured hydrogels

2002 [50]

Structural properties of

self-assembled

polymeric

aggregates in

aqueous solutions

Mortensen K SANS; block copolymer micelles;

polymeric surfactants;

PEO/PPO-based Pluronics or

Poloxamers

2001 [51]

Water soluble poly-

N-vinylamides:

synthesis and

physicochemical

properties

Kirsh YE N-Vinylamides, N-vinylpyrrolidone,

N-vinyllactams, monomers and

polymers, synthesis and properties

in aqueous solutions, hydration

phenomena

1998 [52]

Colloidal stability of thermoresponsive polymers above LCST

Conformation-

dependent design of

sequences in

copolymers

Khokhlov AR (ed) A collection of reviews on

temperature-responsive polymers;

polymer and biopolymer physics

and chemistry; colloidal stability;

protein-like copolymers

2006 [53]

Folding and formation

of mesoglobules in

dilute copolymer

solutions

Zhang G, Wu C PiPAAm; amphiphilic linear, grafted,

and segmented copolymers;

ionomers; hydrophilically and

hydrophobically modiﬁed PiPAAm;

viscoelastic effect

2006 [54]

Temperature

dependence of the

colloidal stability of

neutral amphiphilic

polymers in water

Aseyev V,

Tenhu H,

Winnik FM

PiPAAm; PVLC; PMVEth; microgels;

graft and block copolymers;

colloidal stability of homopolymers

beyond the phase separation

boundary; mesoglobules

2006 [55]

(continued)

38 V. Aseyev et al.

Tab l e 1 (continued)

Title Authors Key phrases Year Ref.

Applications

The development of

microgels and nanogels

for drug delivery

applications

Oh JK,

Drumright R,

Siegwart DJ,

Matyjaszewski K

Heterogeneous polymerization; pre-

paration of hydrogels by means of

photolithographic and micro-

molding methods, continuous

microﬂuidics, modiﬁcation of bio-

polymers, and heterogeneous free

radical and controlled/living radical

polymerizations; reverse micelles

2008 [56]

Responsive polymers in

controlled drug

delivery

Bajpai AK,

Shukla SK,

Bhanu S,

Kankane S

Responsive stimuli-sensitive materials;

polymer blends; interpolymer

complexes; classiﬁcations of

interpenetrating networks; block

copolymers; drug delivery proﬁles

and systems

2008 [57]

Polymeric nanocarriers:

new endeavours for the

optimization of the

technological aspects

of drugs

Sosnik A,

Carcaboso ÁM,

Chiappetta DA

A comprehensive and updated patent

compilation of the most recent

inventions relying on polymer-based

nanoparticulated carriers; polymeric

nanoparticles, dendrimers,

polymeric micelles, and

polymersomes

2008 [58]

Smart polymers: physical

forms and

bioengineering

applications

Kumar A,

Srivastava A,

Galaev IY,

Mattiasson B

A reversible collapse of linear, free

chains in solution; bioseparation;

protein folding; covalently

crosslinked reversible gels;

chain-adsorbed or surface-grafted

forms; smart surfaces and

membranes; microﬂuidics and

actuators

2007 [59]

Functional copolymers of

N-isopropylacrylamide

for bioengineering

applications

Rzaev ZMO,

Dinçer S,

Pi¸skin E

N-Isopropylacrylamide-based random,

block and graft copolymers; ionic

and neutral blocks; bioconjugates

2007 [60]

Physical stimuli-

responsive polymeric

micelles for anti-cancer

drug delivery

Rapoport N Core–shell micelles; drug loading;

internal and external stimuli; pH,

temperature, ultrasound,

light-responsive polymeric micelles

2007 [61]

Functionalized micellar

systems for

cancer-targeted drug

delivery

Sutton D,

Nasongkla N,

Blanco E, Gao J

Nanomedicine; micelle

pharmacokinetics; multifunctional

polymeric micelles; responsive drug

release; N-isopropylacrylamide-

based core–shell micelles; Pluronics

2007 [62]

Molecular design of

functional polymers for

gene therapy

Jeong JH, Kim SW,

Park TG

Cationic polymers;

poly[2-(dimethylamino)ethyl

methacrylate]; nonviral carriers;

polylexes

2007 [63]

(continued)

Non-ionic Thermoresponsive Polymers in Water 39

Tab l e 1 (continued)

Title Authors Key phrases Year Ref.

Poly(2-oxazolines) in

biological and

biomedical application

contexts

Adams N,

Schubert US

Various architectures and chemical

functionalities prepared by living,

cationic ring-opening

polymerization; amphiphilic

polyoxazolines; block copolymers;

poly(2-oxazoline)-based

lipopolymers; poly(oxazoline)-based

vectors; stimuli-responsive systems

2007 [64]

Polymeric micelles to

deliver photosensitizers

for photodynamic

therapy

van Nostrum CF Pluronics; poly(ethylene glycol)–lipid

conjugates; pH-sensitive

PiPAAm-based micelles; polyion

complex micelles; drug loading;

biodistribution studies; therapeutic

efﬁciency

2004 [65]

4 Thermal Responsiveness versus Hydrophobic Association

4.1 Sensitivity and Responsiveness

Any ﬂexible macromolecule in solution is sensitive to temperature changes, which

typically result in a variation of the coil size. In a given solvent, excluded volume

interactions and elastic forces determine the swelling of a neutral linear macro-

molecule [66,67]. If the thermal energy kBTof the repeating units is high, excluded

volume interactions prevail over the attraction between the repeating units and, con-

sequently, the macromolecule swells. This is the case for a thermodynamically good

solvent, in which a linear homopolymer adopts the conformation of a very loose ex-

tended coil. The constraints limiting chain expansion are the C–C covalent bonds

and the entropy of the coil. The latter decreases with the coil swelling, due to the

lesser number of possible conformations.

It is worth stressing here that thermal sensitivity is a general phenomenon for

polymers in solution: the solubility of all polymers in any solvent depends on

temperature. For that reason, Allan Hoffman deﬁned intelligent stimuli-responsive

polymers as polymers that respond to a small physical or chemical stimulus with

large property changes [68–70]. The coil–globule transition is a typical polymer

response to a change in its solution temperature.

The internal energy of the segmental interactions, which represents the excluded

volume effect, can be expanded as a power series of the segment density ρ:

U=VkT ρ2A2+ρ3A3+....

The second osmotic virial coefﬁcient of the expansion, A2, is a measure of the

thermodynamic quality of the solvent for the polymer and accounts for binary

40 V. Aseyev et al.

interactions between the repeating units of the chain and depends on the temper-

ature and the form of the interaction potential between the segments. Under theta

conditions, i.e. when T=TΘ, the polymer adopts an ideal Gaussian coil conforma-

tion and its repeating units can be described simply as non-interacting molecules of

an ideal gas connected in a chain. Consequently, a polymer solution is in a Θ-state

when A2=0 and the molar mass of the polymer is inﬁnitely high [71].

The mean-ﬁeld theory adequately predicts the coil-to-globule transition of a sin-

gle polymer chain in organic solvents upon cooling below TΘ[72]: the thermal

energy of the repeating units becomes lower than the minimum of the potential

corresponding to the van der Waals interactions, the solvent turns into a thermody-

namically poor one (i.e. A2<0) and condensation of the repeating units takes place.

A single macromolecule of inﬁnite molecular weight undergoes the transition at TΘ.

However, for real polymers of ﬁnite molecular weight, e.g. polystyrenedissolved in

cyclohexane, the transition of the chain occurs at T<TΘ[73–75]. Light scattering

and osmotic pressure are typical experimentalmethods used to determine A2.These

methods require dilute solutions and extrapolation to zero polymer concentration.

If there are many chains in the solution, the attraction between the repeating units

causes intermolecular aggregation. Hence, TΘis experimentally deﬁned for a given

polymer/organic solvent system when M→∞and c→0.

This type of transition is conveniently represented as a phase diagram in which

the phase separation boundary, or binodal, indicates the temperature for which a

given polymer–solvent mixture passes from a one-phase system to a two-phase sys-

tem that consists of a polymer-rich phase and a polymer-poor phase. In other words,

the binodal corresponds to the temperature at which the coil–globuletransition takes

place followed by polymer precipitation (see Fig. 1a). The shared maximum of the

Two liquid phases

Temperature, T

Liquid and

solid (precipitate) phases

LCST

08C

dem

Two liquid phases

Glass

Temperature, T

Polymer concentration, c Polymer concentration, c

UCST T

dem

Liquid and

solid (precipitate)

phases

Tdem,M

∞

Tdem,M

∞

One phase (solution )

Solid water Glass

One phase (solution)

Fig. 1 Possible phase diagrams for polymers showing either (a) UCST (e.g. PS in cyclohexane)

or (b) LCST type II (e.g. PiPAAm in aqueous medium) phase separation behaviour. Tdem is the

demixing temperature, TΘis the theta temperature, and TBP is the temperature corresponding to the

Berghmans point [76]. For both polymers, Tgin their solid state is well above Tdem . For this UCST-

type polymer, Tgcannot be lower than TBP. At temperatures below TBP, the polymer is frozen in,

and phase morphology is preserved [77]. For the LCST-type polymer shown, partial vitriﬁcation

takes place at TBP <T<Tg[78]

Non-ionic Thermoresponsive Polymers in Water 41

spinodal and binodal is the upper critical solution temperature (UCST). Polystyrene

(PS) in cyclohexane is a classic polymer/organic solvent system known to show a

UCST behaviour [79–81]. In accordance with the Flory theory, the solubility of PS

in cyclohexane decreases and its UCST shifts towards lower polymer concentrations

on increasing the polymer molar mass.

Non-ionic polymers can also undergo a coil–globule transition in aqueous solu-

tions [82–99]. However, their transition signiﬁcantly differs from the transition of

polymers in organic media. Hydrogen bonds and hydrophobic and hydrophilic in-

teractions contribute much more to the solubility of a polymer in water than do short

range van der Waals interactions, which prevail in solutions of polymers in organic

solvents. For water-soluble polymers, the experimental value of A2reﬂects the bal-

ance of these interactions. In analogy with polymers in organic media, for a single

thermoresponsivemacromolecule of inﬁnite molar mass, the Θ-condition is realized

in water at T=TΘwhen A2=0, M=∞and c=0. Consequently, the col-

lapse of an amphiphilic homopolymer can be classiﬁed as a coil–globule transition

if A2<0 in the globular state.

The majority of non-ionic water-soluble polymers undergo phase separation

upon heating. The phase separation of these polymers can be described by a phase

diagram with an LCST, which reﬂects a local structural transition involving wa-

ter molecules surrounding speciﬁc segments of the polymer in solution. There are

only a few reports on neutral water-soluble polymers, whose properties drastically

change upon cooling their aqueous solutions. To the best of our knowledge, the

UCST-type separation originating from the coil–globule transition has not been re-

ported, though a decrease of the A2value has been observed.

For further reading, readers are encouraged to consult the book by Koningsveld,

Stockmayer and Nies, which containsan extensive list of phase diagramsfor various

binary polymer–solvent mixtures [100]. The book also contains a detailed review of

the general thermodynamic principles of the phase equilibrium.

4.2 The LCST-Type Transition

The LCST was ﬁrst described by Heskins and Guillet for an aqueous solution of

PiPAAm [101]. When the temperature of a solution is raised above the phase sep-

aration temperature (a point on the binodal, also known as the demixing, Tdem,or

the cloud-point temperature, Tcp, depending on the experimental technique used),

the hydrophobic backbone and other nonpolar groups of the polymer tend to as-

sociate. This causes intra- and intermolecular aggregation leading to collapse of

the individual polymer chains (microphase separation) and precipitation of the

polymer (macrophase separation). The LCST depends upon pressure [97,98]and

the polydispersity of the polymer. The solution demixing is reversible when the

temperature drops below Tdem; however, the rate of polymer redissolution is often

slower and the chain expansion takes place at a lower T, which results in a so-called

42 V. Aseyev et al.

thermal hysteresis [95]. Studies on kinetics of the demixing and remixing processes

of PiPAAm/water solutions show that all molecular changes are reversible if the

temperature remains less than ca. 6–8 K above the LCST for less than a few min-

utes, and that the PiPAAm chains reswell into coils in less than a few seconds [102].

If a PiPAAm/water solution is annealed at higher temperatures, the time of remixing

mayincreaseupto1dayorevenmore[78].

The most common experimental techniques for constructing a phase diagram are

turbidity detection (Tcp)or microcalorimetry (Tdem). Change in turbidity of solutions

can be slow or abrupt, depending on the polymer, its concentration in solution, and

the heating/cooling rate. The temperature at which the transition is detected can vary

by as much as 30◦C for a given polymer, depending on these parameters. For the

same experimental settings, the temperature of the endotherm onset, Tdem,usually

coincides with Tcp, whereas the endotherm maximum, Tmax, is slightly higher than

Tcp (see Fig. 2)[103]. Unfortunately, different experimentalists deﬁne the position

of Tcp on the transmittance versus temperature curve in different ways, even for the

equilibrium heating/cooling (i.e. for the zero rates). Chytrý and Ulbrich have listed

existing deﬁnitions of Tcp obtained using a UV–Vis spectrometer [104]:

1. The temperature of the ﬁrst appearance of cloudiness (shown in Fig. 2)

2. The temperature of the intersection of the baseline (reading of absorbance of

unheated solution) with the tangent to the cloud curve drawn in the inﬂection

3. The temperature at the inﬂection point

4. The temperature of different stages (expressed in percentages) of absorbance in-

crease or transmittance decrease, e.g. 10% drop in transmittance

Tdem

Tcp

Tmax

Temperature (°C)

Optical Density

1.80

1.50

1.20

0.90

0.60

0.30

0.00

28 29 30 31 32 33 34 35 36

Fig. 2 Typical microcalorimetric endotherm at a heating rate of 15◦C/h (solid line) and turbidity

curve at a heating rate of 24◦C/h (circles) obtained on an aqueous poly(N-isopropylacrylamide)

solution (Mw=414,000 g/mol, PDI =2.8, c=0.04 wt%). Tmax, temperature of the maximum

heat capacity; ΔCp, difference in the heat capacity before and after the transition; Tdem, demixing

temperature; Tcp. temperature of the ﬁrst appearance of cloudness. Reprinted with permission from

the American Chemical Society [105]

Non-ionic Thermoresponsive Polymers in Water 43

For solutions of most polymers in organic and aqueous media, the phase separa-

tion temperature depends on the polymer mass fraction and, in some cases, on the

polymer molar mass. Taking into account differences in the experimental parameters

(e.g. heating/cooling rate) and the diversity of approaches used to deﬁne the phase

separation temperature, the reader has certainly realized by now that it is not pos-

sible to quantitatively compare experimental data on apparently similar or identical

polymeric systems reported by different researchers.

4.3 Phenomenological Classiﬁcation

To facilitate the description of the phase separation phenomenon of aqueous

polymer solutions, Berghmans and Van Mele proposed the following phe-

nomenological classiﬁcation of their miscibility with water. Type I polymers

[e.g. poly(N-vinylcaprolactam), PVCL] are species that follow the classic Flory–

Huggins behaviour [106,107]: their LCST (i.e. the absolute minimum in the

phase diagram) shifts upon increasing the polymer molar mass towards lower

polymer concentrations. Type II polymers (e.g. PiPAAm [78,108]) are polymers

for which the minimum of the demixing curves is hardly affected by chain length

(see Fig. 1b). For Type II polymers, the architecture has a negligible effect (e.g. the

LCST of star PiPAAms is similar to that of linear polymer [109]), except for poly-

mers with hydrophobic or hydrophilic end-groups [110–112] and polymers with a

high number of arms [113] or spherical brushes [114,115]. Type III polymers [e.g.

poly(methylvinylether),PMVEth] exhibit a bimodal phase diagram, presenting two

critical points for low and high polymer concentrations corresponding to the Type I

and Type II behaviours, respectively [116–119].

4.4 The Hydrophobic Interaction

Water-soluble neutral polymers consist of hydrophilic groups (e.g. amide groups,

ether groups), which are able to interact strongly with water molecules and induce

water solubility, and hydrophobic groups (e.g. vinyl backbone). The formation of

hydrogen bonds between polar groups of the polymers and the water molecules is

the initial driving force for dissolution. The word “hydrophobic” can be misleading.

It implies that the dissolved substance dislikes water, whereas, in fact, the interac-

tion between a hydrophobic molecule and water is attractive due to the dispersion

forces. However, the attraction between the water molecules is much stronger than

the van der Waals forces: water molecules simply “love” themselves too much to

let nonpolar substances interfere with their association. The hydrophobic parts of

the amphiphilic macromolecule organize the surrounding water molecules, leading

44 V. Aseyev et al.

to the formation of an ordered hydration layer. The restructuring of water is en-

tropically unfavourable, and thus the hydrophobic substances are only sparingly

water-soluble, while trying to minimize the entropic loss of the system [120,121].

This feature of hydrophobic molecules in water is known as the hydrophobic effect

[122–129] and it gives rise to the hydrophobic interaction, i.e. to a strong solvent-

mediated “attraction” between hydrophobic molecules in order to minimize the

contact surface between hydrophobes and water. Therefore, an amphiphilic water-

soluble polymer experiences bothrepulsive and “attractive” forces. The sum of these

forces determines the solubility of the amphiphile in water and thus the value and

the sign of the experimentally obtained A2in solution. For readers interested in un-

derstanding the unique properties of liquid water and its solutions, we recommend

the most recent book by Arieh Ben-Naim [129].

The LCST transition in aqueous systems reﬂects ﬁrst of all a local structural

transition involving water molecules surrounding the polymer. At low temperature,

the polymer is hydrophilic and the water molecules are bound to its polar groups

and to each other via hydrogen bonds. Infrared spectroscopy studies on PiPAAm

showed the existence of the amide I (C=O···HN, C=O···H2O) and the amide

II (N–H···O=C, N–H···OH2)hydrogen bonds as well as non-hydrogen-bonded

C=O and N–H groups [130–135]. The polymer molecules adopt an extended coil

conformation. The relative magnitude of the hydrophobic effect increases with tem-

perature. At higher temperatures, water molecules are released in bulk, allowing

associative contacts between the newly exposed hydrophobic monomer units [136].

Thus, during the demixing of PiPAAm, the bound water molecules are liberated,

resulting in the formation of intramolecular hydrogen bonds between the carbonyl

and amine functions of the N-isopropylamide side residues [137]. A negative total

entropy change upon heating controls the system over the enthalpy of the hydrogen

bonding, and the change in the free energy of the mixing becomes positive, causing

chain contraction and, eventually, phase separation. In some cases, it leads to a sol–

gel transition: a sol state (a random coil conformation) below Tsol−gel and gelation

above Tgel−sol.

4.5 Cooperativity of the LCST Transition

The high-temperature collapse of a non-ionic single chain in water has been de-

scribed using concentration-dependent interaction parameters. Although the average

radius of gyration of a chain decreases at high temperature according to phe-

nomenological parameters, the molecular origin of the temperature inversion can

only be understood if one considers the molecular property of polymer–water in-

teraction. Tanaka F et al. developed a description of the phase separation with a

closed loop miscibility gap that takes place in aqueous solutions of poly(ethylene

oxide) (PEO) [138]. The authors explicitly included the hydration [139]inorder

Non-ionic Thermoresponsive Polymers in Water 45

to ﬁnd the molecular origin of the high-temperature collapse. In this description,

the model assumed random and independent hydrogen bonding (referred to as H-

bonding) between PEO and water molecules along the chain. It was adequate to

describe the experimental phase diagrams of PEO. This hydration mechanism was,

however, unable to describe the sharp collapse of PiPAAm chains. The concept

of cooperative hydration has allowed the theoretical derivation of the ﬂat cloud-

point curves of the LCST type observed in aqueous PiPAAm solutions [140]. The

cooperativity in hydration is caused by a positive correlation between neighbour-

ing bound water molecules due to the presence of the large hydrophobic isopropyl

side groups. If a water molecule succeeds in forming an H-bond with an amido

group on a chain, a second water molecule can form an H-bond with the chain

more easily than the ﬁrst one because the ﬁrst molecule causes some displace-

ment of the isopropyl group, thus creating more access space for the next molecule.

As a result, consecutive sequences of bound water appear along the chain, which

leads to a pearl-necklace-type chain conformation [140,141]. When the solution is

heated, each sequence is dehydrated as a whole, resulting in the sharp collapse of

the chain. This concept of cooperative hydration has successfully been applied to

describe theoretically the phenomenon of co-nonsolvency of PiPAAm in a mixed

solvent of water and methanol or other alcohols [142]. The concept of coopera-

tive hydration has also allowed derivation of a uniﬁed model of the association-

induced LCST phase separation in aqueous solutions of telechelic PEO and PiPAAm

(Fig. 3)[143].

Fig. 3 Sequential hydrogen bonds formed along the polymer chain due to the cooperative inter-

action between the nearest neighbouring bound water molecules. The average length of sequences

sharply reduces as temperature approaches Tcp from below. The random-coil parts (thin circles)are

collapsed near Tcp. Reprinted with permission from the American Chemical Society [140]

46 V. Aseyev et al.

4.6 Elastin-Like Polymers

Protein-based polymers are composed of repeating peptide sequences, where the

repeating unit can be asfew as two or as many as hundredsof residues [144]. Among

them, elastin-like polymers (ELPs) are multiblock synthetic copolymers consisting

of the pentapeptides VPGXG, where V stands for L-valine, P for L-proline, G for

glycine, and X represents any natural amino acid except proline[145,146]. ELPs are

water-soluble at temperatures lower than their demixing temperature and precipitate

at higher temperatures. However, ELPs are usually described in the literature not as

LCST type polymers but as polymers that exhibit an inverse solubility temperature

(ITT) in water. The Tdem of ELPs depends on their composition. The hydrophobicity

scale for the amino acid residues X and Tcp of the corresponding ELPs is presented

in [144]. The design of EPLs with a desired Tdem within Tdem =0−100◦Chas

recently been reviewed [44,147].

Strictly speaking, the mechanism of the reversible temperature-modulatedphase

transition of ELPs differs from the transition of the thermosensitive polymers such

as PiPAAm. First of all this isbecause some of the ELPs may either be non-ionic

or weakly charged. However, a number of common features of aqueous solutions

of ELPs and of PiPAAm are evident. For example, kinetic studies on solutions

of poly(VPGVG) showed that the phase separation process is faster than the pro-

cess of redissolution. This behaviour is similar to the thermal hysteresis reported

for PiPAAm [78,95,102] and has been veriﬁed using temperature-modulated dif-

ferential scanning calorimetry (TM-DSC) [44,78,148], a technique capable of

separating phenomena that overlap thermally but present a different time response.

TM-DSC uses a periodically alternating heating programme superimposed on the

constant heating rate and allows differentiating between overlapping phenomena.

Thus, the endothermic peak for aqueous poly(VPGXG) solutions was found to be

a sum of two processes. The ﬁrst endothermic process corresponds to the destruc-

tion of the ordered hydrophobic hydration structures surrounding the polymer chain.

The other, exothermic, process arises from the chain folding into a β-spiral struc-

ture. The hydrophobically driven association of β-spirals results in the formation

of ﬁlaments composed of three-stranded dynamic polypeptide β-spirals that grow to

several hundred nanometers in length and gradually segregate from the solution. The

phase-separated poly(VPGXG) above Tdem contains 63 wt% of water and 37 wt% of

polymer [44], which is surprisingly close to the mass fraction of polymeric material

within single chain globules and mesoglobules formed by fully amorphous synthetic

polymers having high Tg, such as PiPAAm [55]. For comparison, the thermal hys-

teresis reported for PiPAAm was interpreted as partial vitriﬁcation of the polymeric

material in the polymer-rich phase [78].

Non-ionic Thermoresponsive Polymers in Water 47

5 Self-Organization versus Steric Stabilization

5.1 Colloidal Stability

For polymer solutions, a decrease in the solvent thermodynamic quality tends to

decrease the polymer–solvent interactions and to increase the relative effect of

the polymer–polymer interactions. This results in intermolecular association and

subsequent macrophase separation. The term “colloidally stable particles” refers

to particles that do not aggregate at a signiﬁcant rate in a thermodynamically

unfavourable medium. It is usually employed to describe colloidal systems that

do not phase separate on the macroscopic level during the time of an experi-

ment. Typical polymeric colloidally stable particles range in size from ∼1nmto

∼1μm and adopt various shapes, such as ﬁbres, thin ﬁlms, spheres, porous solids,

gels etc.

Any system, if left alone, ﬁnally adopts its stable state. The time required for

that process to occur is determined by the magnitude of the activation energy bar-

riers, which separate the stable and metastable states. A system under a given set

of conditions is called thermodynamically metastable if it is in a state correspond-

ing to a local minimum of the appropriate thermodynamic potential for speciﬁed

constraints imposed upon the system, e.g. constant temperature and pressure [71].

If this system can exist in several states, the state of the lowest free energy is

called the thermodynamically stable state. Thus, the coil conformation corresponds

to the lowest minimum of the chain free energy and, therefore, is thermodynami-

cally stable. In contrast, the globular conformation of a single chain is a metastable

state for the polymer in solution. Globules of single chains tend to associate and

adopt a new phase of energy lower than the sum of the energy of individual glob-

ules dispersed in the solvent. Colloidally stable particles are thermodynamically

metastable.

Standard colloid chemistry strategies have been developed over the years in or-

der to prevent or at least minimize interparticle contacts. We review them brieﬂy

here since they help in understanding the properties of the aggregates formed in

aqueous solutions of thermosensitive polymers heated above their Tcp. In highly

dilute polymer solutions, the rate of the globule–globule contacts is slow, which

limits macroscopic phase separation. The stability of more concentrated polymer

dispersions in water is enhanced either electrostatically or sterically. Electrostatic

stabilization is typically realized using either ionic initiators or ionic surfactants or

dissociating co-monomers in the polymer syntheses conducted in emulsions. Par-

ticles are obtained, which repel each other due to the entropic (osmotic) pressure

caused by the counterions between the surfaces. Interactions of the charged sur-

faces are usually explained by the Derjaguin–Landau–Verwey–Overbeek, (DLVO)

theory, which combines short-range attractive van der Waals and long-range electro-

static double-layer forces. The strength of the repulsion force between the particles

and the thickness of the electric double layer may be altered by changing the ionic

48 V. Aseyev et al.

strength of the aqueous medium [149]. At high electrolyte concentrations, the re-

pulsion between the particles vanishes and the coagulation of the particles is fully

diffusion controlled [150,151].

Stabilizing repulsive forcesmay also arise from speciﬁc chemical and/or physical

properties of the particle surface. It is often suggested that the high hydrophilicity

of a surface could lead to interparticle repulsion, even if the surface does not pos-

sess any electric charge or repulsive polymer layer. This type of repulsion has been

ascribed to a force, the hydration or structural force, which arises as a consequence

of the speciﬁc structure of the hydrogen-bonded water layer on the particle surface.

It has been suggested that the overlap of two structurally modiﬁed boundary layers

gives rise to the hydrophilic repulsion [152–154]. The existence of such hydration

forces remains the subject of debates. It has been argued that, in most cases, the

short-range non-DLVO forces may simply be repulsive forces, such as the undula-

tion or protruding forces, especially when the surface is rough [155,156].

Steric stabilization is achieved via grafting the particle surface with water-soluble

polymers, e.g. PEO. The repulsive force has an entropic origin; when two grafted

surfaces approach each other they experience a repulsive force once the grafted

chains begin to overlap and the mobility of the chains decreases [149,150]. Steric

stabilization by non-ionic hydrophilic polymers is independent of the medium

ionic strength, assuming that the added electrolyte does not drastically change the

thermodynamic quality of the aqueous solvent. PEO has been shown to be an effec-

tive steric stabilizer, even at high electrolyte concentrations, as long as the molecular

mass of PEO is high [157]. The use of PEO is often also considered advantageous

because PEO largely prevents the adsorption of proteins onto polymer surfaces and,

thus, increases the biocompatibility of the polymer [158].

5.2 Hydrophobic Self-Association

Although we limit the review to thermoresponsive homopolymers, a discussion

of the self-association and the colloidal stability of thermoresponsive and non-

thermoresponsive amphiphilic copolymers is unavoidable. Thermally responsive

polymers, which undergo changes in solubility with changes of the solution tem-

perature, are an alternative to the polymers carrying hydrophobic moieties, i.e. the

repeating units that are not soluble in water at T=0−100◦C and normal pres-

sure. Similar to the low-molar-mass surfactants, amphiphilic non-thermoresponsive

block, graft and telechelic copolymers self-organize into diverse micellar struc-

tures in the block-selective solvents above a certain concentration, which is either

called the critical micellization concentration (CMC) or the critical aggregation

concentration (CAC). The advantages of the amphiphilic block copolymers over

the classical detergents lie in the low CAC, in the highly tuneable composition and

architecture, as well as in the dependence of the micellization on selective solvents.

The shape and the size of these self-assemblies are governed by the balance between

Non-ionic Thermoresponsive Polymers in Water 49

three major forces acting on the system, reﬂecting the constraints between the

core-forming blocks, the interaction between the chains in the corona (steric or elec-

trostatic), and the surface energy between the solvent and the core [159]. The most

commonly observed morphologies are spheres, cylinders and vesicles [41,160–

162]. Block, graft and random copolymers are known to form unicore or multicore

micelles in selective solvents [163]. In addition, a variety of other structures have

been reported, including toroids [164], helices [165], disks [166], nanotubes [167]

and multicompartment micelles [168]. Such complex self-assemblies have rarely

been observed for classical low-molar-mass surfactants.

The characteristic feature of neutral thermoresponsive polymers showing the

LCST behaviour in water is an increased hydrophobicity at elevated temperatures.

This feature may lead to the coagulation of the colloidal dispersion. Therefore, in

order to avoid macroscopic phase separation above Tdem, the surface of the hy-

drophobic particles needs to be adjusted, either by using amphiphilic additives

(e.g. detergents) or by careful chemical modiﬁcation of the surface (e.g. using PEO

blocks or grafts). In the latter case, the thermoresponsive backbones or segments

collapse and associate upon heating, thus leading to the formation of colloidally

stable core–shell structures. The demixing temperature of the modiﬁed polymers

varies, depending on the fraction of hydrophilic or hydrophobic moieties. The size

of the aggregates can be altered either by changing the polymer concentration or

its chemical composition in the case of copolymers. PEO-grafted copolymers form

less dense particles than homopolymers or block copolymers, due to the unavoid-

able incorporation of a fraction of the PEO grafts in the aggregated phase [169].

The role of the amphiphilic grafts or blocks on the colloidal stability of microgels

or aggregates formed above the LCST has recently been reviewed [55,170,171]

(see Table 1).

The chains within the polymeric micelles may exhibit retarded mobility (slow ki-

netics), depending on the Tgof the core-forming blocks, which results in the forma-

tion of either equilibrium or non-equilibrium metastable supramolecular structures

[160,172–175]. For thermoresponsive polymers, the formation of the equilibrium

morphologies is easily controlledby adjusting the heating rate and the polymer con-

centration, in comparison to the non-thermoresponsive polymers, upon their direct

dissolution in water [54,55]. If the core-forming block exhibits a high Tg, micel-

lar exchange can become suppressed for the block copolymers [41], so that frozen

micelles are formed and no chain exchange between micellesis possible [176]. Poly-

mers containing blocks with high Tgform aggregates with a compact glassy core,

and either show very low CAC or cannot be directly solubilized in aqueous media.

In the latter case, copolymers are ﬁrst dissolved in a solvent common for both blocks

and then transferred into the aqueous medium.

Actually, the term “micelle” refers to the equilibrium structures and, therefore,

the non-equilibrium structures prepared at T<Tgof the core should be called

“micelle-like aggregates”. However, the term “micelle” is extensively used in litera-

ture. If dynamic systems are aspired, it is therefore advisable to employ amphiphilic

block copolymers, which bear a hydrophobic block with a low Tg.

50 V. Aseyev et al.

5.3 Protein-Like Copolymers

Protein-like copolymers are a special case of thermosensitive copolymers capable

of forming small colloidally stable aggregates in solutions heated above their LCST

[177–182]. In globular proteins, the hydrophilic units mainly cover the water-

exposed surface of the globule, thus preventing interprotein association, whereas

hydrophobic units mainly form the core of the globule. Amphiphilic copolymers can

mimic the behaviour of biopolymers and, in certain cases, that of globular proteins.

The theoretical model of protein-like copolymers ascribes the term “memory” to

amphiphilic copolymers, stating that a polymer chain tends to reassume the confor-

mation in which it was synthesized, due to the unique distribution of repeating units

along this chain. The synthesis of protein-like copolymers from typical synthetic

monomers is difﬁcult, and only few reports on successful synthesis are available

[181,182]. PiPAAm-graft-PEO copolymers in water close to the demixing temper-

ature of the backbone turned out to be able to remember the original conformation

in which they had been grafted [183,184].

5.4 Mesoglobules of Homopolymers

When a homopolymer in solution encounters a situation in which the thermo-

dynamic quality of the solvent is poor, individual chains of the homopolymer

undergo a coil-to-globule collapse. The globules associate immediately,and macro-

scopic phase separation seems unavoidable. However, it has been reported that a

number of polymers in water or in organic solvents form equilibrium globules,

i.e. single chain globules that remain isolated in solution without immediate as-

sociation and precipitation. We have presented in a recent review a compilation

of homopolymers reported to exhibit this behaviour in water [55], forming sta-

ble single chain globules or multimolecular aggregates, termed “mesoglobules”

[185,186]. Mesoglobules of thermosensitive polymers that are formed beyond Tdem

are spherical in shape and monodispersed in size and typically have a radius on

the order of 50–200 nm. Various thermoresponsive polymers and their derivatives

form colloidally stable suspensions instead of the expected macrophase separation

upon heating of their dilute aqueous solutions above Tdem, including homopoly-

mers such as PiPAAm [55,187], PVLC [55], and poly(methylvinyl ether), PMVEth

[55,188,189]. The fact that mesoglobules are metastable structures can be demon-

strated experimentally. For example, when a phase-separated PiPAAm solution is

subjected to centrifugation at 4000 rpm at elevated temperature above Tcp,itformsa

two-phase system consisting of a transparent liquid and a white gel [190]. Nonethe-

less, in a wide range of conditions the mesoglobules remain colloidally stable.

The properties of the mesoglobules depend on factors related to the intrinsic

properties of the polymers and to experimental protocols. Thus, increasing the

Non-ionic Thermoresponsive Polymers in Water 51

content of hydrophobic comonomer leads to a lowering of Tdem of aqueous PiPAAm

and concomitant decrease in the size of the mesoglobules [54,187,191]. Rapid

heating and lowering the polymer concentration have a similar effect. We should

add here that the same phenomenon takes place in organic solvents. For example,

the precipitation time of PS globules formed by polymers of high molar mass is

essentially longer (tens of minutes or even hours) than that of the shorter chains in

the solution of the same polymermass concentration [192]. This suggests a possible

general mechanism responsible for the colloidal stability of mesoglobules formed

by homopolymers in either organic or aqueous media [55].

Various mechanisms have been proposed to account for the stability of mesoglob-

ules [54,55,188,189]. One such mechanism is the viscoelastic effect, which was

introduced by Tanaka H for colloidally stable droplets of PMVEth [188,189].

Accordingly, a collision of two mesoglobules is not effective as long as the time of

their contact is shorter than the time required for establishing a permanent chain en-

tanglement via the chain reptation. Fluorescence spectroscopy allowed us to conﬁrm

the contributions of the viscoelastic effect and also of the partial vitriﬁcation of the

polymer to the mechanism underlyingthe stability of PiPAAm mesoglobular phases

[187]. It also led us to observe directly for the ﬁrst time that PiPAAm mesoglobules

undergo a gradual conversion from ﬂuid-like particles into hard spheres within a

narrow temperature window, Tdem <T<36◦C, a phenomenon that had been in-

ferred, but not proven, by light scattering data. Mesoglobules grow in size and mass

within this temperature range. We suggested that changes in the hydration layer

surrounding the PiPAAm chains and the exchange of water–polymer H-bonds for

interchain H-bonds are involved in the process. For temperatures higher than Tdem,

vitriﬁcation of the mesoglobule core can occur, enhancing particle stability and the

resistance towards merging [78]. The results of our experiments suggest that this

process is indeed signiﬁcant, but only for T>36◦C, a temperature ∼6−7◦Cabove

Tdem. Also, the possibility that electrostatic effects contribute to the stabilization

of PiPAAm mesoglobules cannot be excluded [55,193]. Since our previous re-

view [55], some new fascinating and important evidence has appeared, including

experimental [54,194–203] and theoretical [204–206] aspects of the mesoglobu-

lar phase.

6 List of Thermoresponsive Homopolymers

In this section we outline the publications and selected features of neutral thermore-

sponsive homopolymers exhibiting the LCST phase separation in aqueous media,

see Tables 2and 3, and also those whose properties drastically change upon cool-

ing, see Table 4. We will utilize the deﬁnitions for transition temperatures used by

the authors. Due to the huge number of polymers of this type, some biopolymers

such as polysaccharides will not be described here.

52 V. Aseyev et al.

Tab l e 2 Neutral thermoresponsive homopolymers exhibiting LCST-type phase separation

behaviour in water

Structure Properties

I. Polymers bearing amide groups

N-Substituted poly(acrylamide)s and poly(methacrylamide)s

Poly(N-alkyl(meth)acrylamide)s or N-monosubstituted and N-disubstituted

poly(acrylamide)s (1a) and poly(methacrylamide)s (1b), where R1=H,

CH3,C

2H5etc. and R2=CH3,C

2H5,C

3H7,etc

Homopolymers with R1=H, CH3and R2=CH3do not show the LCST

behaviour in water in the temperature range of 0 <T<100◦C

Homopolymers with R1=H, CH3,C

2H5and R2=C2H5,C

3H7,

excluding two pairs of R1=CH3or C2H5with R2=C3H7(propyl,

isopropyl or cyclopropyl), show the LCST behaviour in water in the

temperature range of 0 <T<100◦C

Homopolymers with other R1and R2are insoluble in water under normal

conditions

Poly(N-ethylacrylamide) PEAAm [207–212]

72.8<LCST <85.5◦C for 3300 <Mn<7400 g/mol upon heating; phase

diagram based on Tcp (0 <c<10 wt%); LCST of the linear PEAAm is

between 1 and 3 wt% and increases with decreasing M[210]; estimated

Tcp =74◦Cforc=1wt%[207]; Tmax =82◦Cforc=5−20 wt% [211]

Hysteresis, the effect of the heating/cooling rate on the phase diagram [210]

Chemically crosslinked hydrogel shrinks upon heating [207]; Tcp =62◦C

[210]; Tmax =78.2◦C[213]

Tcp of solutions and gels increases with increasing SDS content and

decreases with increasing KCl content or crosslinker [210]

Solubility of PEAAm in various solvents [210]

Tg=138.6◦CforMw=204,000 g/mol, PDI =3.3[207]

LCST type copolymers with styrene, 20◦C<Tcp <75◦C[207]; other LCST

type copolymers of PEAAm [211]

Poly(N-ethylmethacrylamide) PEMAAm [207,214–217]

Structural isomer of PiPAAm

Tcp =58◦C[207]; TΘ=67◦C (phase equilibria) [215]; TΘ=70.5◦C

(Mw→∞from 61,000 <Mw<2,040,000 g/mol, 1.7 <PDI <4.5,

studied using viscometry) [217]; Tcp =70◦C[214]

Thermosensitive microgels functionalized with phenylboronic acid [215]

Poly(N,N-ethylmethylacrylamide) PEMAAm [218–222]

Structural isomer of PiPAAm

TDSC =73.8◦C(Mn=18,100 g/mol, PDI =1.12, c=0.1wt%)[220];

Tcp =70◦C(M=10,000 g/mol, c=0.1 wt%) [218];

58 <Tcp <68.8◦C inversely depending on 5400 <Mn<36,500 g/mol

and c=0.05–5 wt% [221]; Tcp =56◦C[210]

Tacticity [223]; ATRP and RAFT polymerizations result in PEMAAm of

similar stereochemistry [221]

Presence of a carboxyl end group instead of an alkyl one elevates Tcp by

3–4◦C[221]

Block copolymers with PiPAAm and PnPAAm; hysteresis [219]

(continued)

Non-ionic Thermoresponsive Polymers in Water 53

Tab l e 2 (continued)

Structure Properties

Poly(N,N-diethylacrylamide) PDEAAm [49,207,211,224–237]

Phase diagrams and concentration dependences [226,228–231]

25◦C<Tcp <36◦C[207,224,226]; Tcp =29◦C, Mw=124,000 g/mol,

c=0.2 wt% [238]; Tcp =30.5◦C, Mw=91,000 g/mol,

c=0.5 wt% [239,240]; Tcp =32◦C, M=10,000 g/mol,

c=0.1 wt% [218]; Tmax =32◦Cforc=5–20 wt% [211]

Decrease in the Tcp with increasing M[226,231]

Chemical crosslinks of PDEAAm decrease Tcp for 3–4◦C in comparison

with the linear polymer [227]

Addition of salt decreases Tcp [103]

Tacticity: syndiotactic and isotactic polymers [223,230,235,236];

isotactic PDEAAm is soluble in water (Tcp =31◦C), but syndiotactic

PDEAAm is insoluble [223]

Copolymers [211,241–244] and hydrogels [233,234,245]

Tg≈90◦C, estimated from [211]

Poly(N-n-propylacrylamide) PnPAAm [130,131,218,237,246–249]

Structural isomer of PiPAAm

Precise analysis of molecular parameters; for A2=0and

Mw=(13.3–159) ×104g/mol: Tθ=22.54 ±0.01◦C[249]

Tcp =25◦C, M=10,000 g/mol, c=0.1wt%[218]; Tcp =25◦C

(M=14,400 g/mol, PDI =1.1, c=0.1wt%)[219]; Tcp =24◦C

[246,247]; Mw=361,000 g/mol: Tcp =23.2◦C(c=0.002 wt%),

Tdem =23.0◦C, Tmax =24.5◦C(c=17,100 unit mol/g) [130]

Thermoresponsive gels [130,250–252]; Tcp =25◦C[247]

Syndiotactic PnPAAm with various racemo diad contents: the high

cooperativity results from the local formation of ordered structures

(presumably helical) in the dehydrated state [253]

Block copolymers with PiPAAm and PEMAAm; hysteresis [219]

Poly(N-n-propylmethacrylamide) PnPMAAm [130,254–256]

Tcp =28◦C[256]; Mw=602,000 g/mol: Tcp =27.2◦C

(c=0.002 wt%), Tdem =26.9◦C, Tmax =28.0◦C

(c=1.70 ×10−4unit mol/g) [130]

Complete resolubilization at 25◦C, transition is very slow (h) and takes

place in a wide range of T[254,255]

Thermoresponsive gels [130]

Poly(N-isopropylacrylamide) PiPAAm, but generally abbreviated as

PNIPAM [45,49,55,86,101,130,207,257–265]

Detailed reviews on synthesis and properties of homo- and copolymers

[21,30,43,45,49,53,260]

LCST =27–32◦C, phase diagram [78,101,108,266]; phase diagram of

nanosized gel particles [267]; Mw=553,000 g/mol: Tcp =31.2◦C

(c=0.002 wt%), Tdem =30.9◦C, Tmax =32.1◦C

(c=2.10 ×10−4unit mol/g) [130]

Cooperative hydration [140]

(continued)

54 V. Aseyev et al.

Tab l e 2 (continued)

Structure Properties

Tcp decreases by 2◦CwhenMnincreases from 5400 to 160,000 g/mol

[103]; Tcp is independent of Mif M>105g/mol [78,266]

No intermolecular aggregates are detected at ambient temperature [55]

Colloidally stable mesoglobules above 50◦C[54,55,194–203]

Density of polymeric material within a fully collapsed single chain

globule or a mesoglobule is 0.3–0.4 g/mL [54,55,95,187], close to

0.40 g/cm3predicted on the basis of a space-ﬁlling model [268];

fractal dimension of the collapsed state is 2.7 [55,187]

Hysteresis understood as limited diffusion of water into the hydrophobic

aggregates above the LCST that retards PiPAAm rehydration

[95,269]

Tg=130◦C[270]; Tg=140◦C[78]

Effect of tacticity [271,272]

Effect of salt follows the Hofmeister series [273,274]

Addition of SDS increases Tcp: low SDS concentrations – dispersion of

colloidal particles, high SDS concentrations – a solution of

“necklaces” by SANS [275]; the coil–globule transition in solutions

of SDS Tcp =34◦C[276]

Addition of a saccharide decreases Tcp [277]

Oligomers show opposite thermal properties when they are freely

dissolved or bound to a gold nanoparticle [278]

Brushes grafted to latex particles [279,280]; polymer-protected gold

nanoparticles [281,282]; various copolymers [45,49,55,259]; drug

delivery, tissue engineering [45], thermoresponsive gels [130]

Poly(N-isopropylmethacrylamide) PiPMAAm, but generally named

PNIPMAm [86,104,130,257,283,284]

For Mn=57,000 g/mol, Mw/Mn=1.7, c=2 wt% and heating rate of

1◦C/min, Tcp =48◦C and complete resolubilization upon cooling at

38◦C, [284]; for fractions 3000 <Mw<11,000 g/mol and

c=0.05 wt%, 61 >Tcp >48◦C[103]; for c=1 wt% and heating

rate of 1◦C/min, Tcp =43◦C and complete resolubilization upon

cooling at 35◦C[86]; Mw=420,000 g/mol: Tcp =41.2◦C

(c=0.002 wt%), Tdem =41.8◦C, Tmax =42.0◦C

(c=1.81 ×10−4unit mol/g) [130]

Tcp =43–44◦C at normal pressure and 10 <Tcp <50◦C at high pressure

(0.1–200 MPa) induced coil–globule transition of anthracene-labelled

PiPMAAm (50,000 and 140,000 g/mol, PDI =1.4–1.6,

c<0.001 wt%); pressure–temperature phase diagram [97]

Kinetics: transition is very slow and takes place in a wide range of T;

hysteresis is more pronounced than in the case of PiPAAm [86,284]

Copolymers, effect of NaCl and other cosolutes [103]

Thermoresponsive gels [130,285–288]

Tg=176◦C[289]

(continued)

Non-ionic Thermoresponsive Polymers in Water 55

Tab l e 2 (continued)

Structure Properties

Poly(N-cyclopropylacrylamide) PcPAAm [131]

Tcp =47◦C, Mw=211,000 g/mol, PDI =4.4, 1 wt% [229];

Tcp =49◦C, Mn=700,000, 0.5 wt%[131]; Tcp =57◦C[207,229]

Thermoresponsive copolymers [290]

Tcp =30◦C for copolymer with 5 mol% pyrene side groups used for

stabilization of carbon nanotubes in water [291]

Tcp =48◦C for PcPAAm-protected gold nanoparticles [292]

Continuous volume change for thermoresponsive gels, Tcp =40–50◦C

[247]

Poly(N-(L)-(1-hydroxymethyl)propylmethacrylamide), abbreviated to

P(L-HMPMAAm) [293]

P(L-HMPMAm) shows optical activity; polymer chains may form packed

structures and hence a low hydration state in water

Tcp =30◦C, Mw=58,700 g/mol, 0.4 wt%; above Tcp, forms solid

precipitates; the turbidity of supernatant is not affected by further

heatingupto55

◦C

Upon cooling the turbidity starts to decrease at 21◦C; hysteresis is

explained by the low hydration state in water due to the compact

structure of the polymer

Size distributions of P(L-HMPMAm) are bimodal below Tcp (6◦C)

P(DL-HMPMAm) is optically inactive; possesses better solubility in

water than P(L-HMPMAm); it exhibits some degree of turbidity at

34◦C, but the transmittance does not decrease to 0%; no hysteresis

P(DL-HMPMAm) forms a clear coacervate above 34◦C; forms no solid

precipitate; steric hindrance between the side chains (racemic

monomers) results in relatively expanded structures of polymeric

chains above 34◦C

No intermolecular aggregates of P(DL-HMPMAm) below Tcp (6◦C)

Poly(N-acryloylpyrrolidine) [207,237,294–298]

Tcp =51◦CforMn=15,000 g/mol, cp=1wt%[294]; Tcp =52◦C

[237]; Tcp =56◦C[298]; no intermolecular aggregates were detected

at ambient temperature [294,297]

Hydrophobic end-groups of the RAFT agent decrease Tcp:

e.g., Tcp =55–56◦CforMn=17,000 g/mol and PDI =1.84,

whereas Tcp =48◦CforMn=5000 g/mol and PDI =1.47

(cp=3wt%)[297]

A small hysteresis between the heating and cooling runs [297]

Tcp decreases upon increasing NaCl concentration [297]

Chemically crosslinked hydrogel shrinks upon heating

Tcp ≈50−60◦C; collapse is not abrupt [207]

Tacticity [223]

Self assembling thermosensitive copolymers, e.g., block copolymers with

poly(butyl acrylate) [294–297]

Tg=142◦C[295]

(continued)

56 V. Aseyev et al.

Tab l e 2 (continued)

Structure Properties

Poly(N-acryloylpiperidine) PAOPip [237,299,300]

PAOPip is soluble below Tcp =4–6◦C in the basal buffer (pH 7.0) and

completely insoluble above 8◦C[237,299]

Puriﬁcation of thermolabile proteins from a crude solution by afﬁnity

precipitation [43]

Tacticity [223]

Poly(N-vinyl amide)s

Poly(N-vinyl caprolactam) PVCL [52,55,170,260,301–306]

Detailed reviews on synthesis and properties on homo- and copolymers

[52,55,170]; no reports have been found on the controlled radical

polymerization

Phase diagram: LCST =31◦C, M

=470,000 g/mol [307]; LCST 30◦C

[116]; if Mw<105g/mol then LCST depends on M

Intermolecular aggregates are formed by the Mw<104g/mol samples

even below Tcp [55]

Tcp =38◦C, Mn=3200 g/mol, PDI =2–2.5, c=10−2wt%:

coil–globule transition by ﬂuorescence technique [194]

Colloidally stable neutral mesoglobules above 50◦C[55]

Tcp decreases with increasing NaCl concentration [308]

Tcp increases with increasing SDS [308,309] and cetylpyridinium

Chloride concentration [309]

Tg=190◦C[107]

Poly(N-vinyl propylacetamide) [307]

Phase diagram: LCST =40◦C, Mη=30,000 g/mol

Poly(N-vinyl-5-methyl-2-oxazolidone) [124]

Tcp =40◦C[124]; Tcp =65◦C[303]

Effect of cosolute on LCST [124]

Poly(N-vinyl isobutyramide) PViBAm [310–313]

Structural isomer of PiPAAm (reversed amide linkage): differences in the

properties have been analysed using microcalorimetry [314],

pressure-dependent solubility analysis [315] and light scattering [316]

Tcp =35–39◦C[310,313]

Used to prepare poly(vinylamine) by hydrolysis of the side chain

[312,317]

Polymer-protected Pt nanoparticles [318]

Copolymers [311,312,319,320]

Protein related polymers

18 Synthetic Protein-based polymers are composed of repeating peptide sequences

polypeptides ITT-type phase transition: although the transition resembles the LCST

type, these polymers usually form helical structures in precipitated

state

(continued)

Non-ionic Thermoresponsive Polymers in Water 57

Tab l e 2 (continued)

Structure Properties

An overview of modern synthesis and self-association of homo- and

block/graft copolypeptides can be found in [321–327];

peptide-based amphiphiles [328]

Selected examples of neutral homopolypeptides are discussed below

19 Poly(VPGXG): V,

L-valine; P, L-proline;

G, glycine; X, any

natural amino acid

except proline

Elastin-like synthetic biopolymers or “elastic protein-based

polymers”: consist of repeating pentapeptides

[44,50,144,322,329–344];

ITT-type transition; detailed reviews [44,144,331]

0◦C<Tcp <100◦C depending on X: above Tcp a random coil turns

into a β-spiral and precipitate

Tcp is dependent on pH and the ionic strength

Hydrophobicity and conformational preferences of the constituent

amino acids deﬁne the LCST behaviour: Tcp of the peptides could

be adjusted by replacing valine residues by more hydrophobic

isoleucine, leucine or phenylalanine residues [329]

Example: Tcp =25◦C for (GVGVP)251 at 0.7 wt% and

M=100,000 g/mol [144]

TM-DSC on elastin-like biopolymers reveals two simultaneous

processes representing chain collapse (endoterm) and β-spiral

formation (exoterm); above Tcp

Elastin-like biopolymers fold and assemble, due to the periodicity of

repeating sequences[44,344]

Short chains based on GVGVP pentad sequence: effects of M,

chemical composition, and salt concentration on the secondary

structure and Tcp [329]

Methacrylate-functionalized poly(VPGVG) prepared by RAFT [345]

Poly(L-proline) PPro [346,347]

Precipitated polymer is in the ordered crystalline state; theoretically

predicted TΘ=100◦CforMn=53,000 g/mol using temperature

dependence of the second virial coefﬁcient [346]

Helical structure of oligoprolines [348,349]

MeO

Poly(N-acryloyl-L-proline methyl ester) PAProMEs [350–355]

Tcp =14◦C[350,351]

Tcp =17.5◦CforMn=12,200 g/mol, Mw/Mn=1.26 [353]

15◦C<Tcp <20◦C, depending on the tacticity

4000 <Mn<17,000 g/mol, Mw/Mn<1.22 [352,353]

15◦C<Tcp <43.5◦C, random copolymers with

N,N-dimethylacrylamide [352]

Synthesized using RAFT polymerization [352,353]

MeO

Poly(N-acryloyl-4-trans-hydroxy-L-proline methyl ester) PAHProMEs

[353]

Tcp =49.5◦CforMn=11,000 g/mol, Mw/Mn=1.29 [353]

Synthesized using RAFT polymerization [352,353]

(continued)

58 V. Aseyev et al.

Tab l e 2 (continued)

Structure Properties

Poly(methyl 2-alkylamidoacrylate)s

Poly(methyl 2-alkylamidoacrylate)s [356]

R1: poly(methyl 2-acetamidoacrylate), water-soluble

R2: poly(methyl 2-propionamidoacrylate), thermosensitive

R3: poly(methyl 2-isobutyracrylate), thermosensitive

R4: poly(methyl 2-n-butyramidoacrylate), insoluble in water

Poly(methyl 2-propionamidoacrylate) [356–359];

LCST =49–50◦C, M

=670,000 g/mol, PDI =2.7: the phase

diagram (Tcp vs. c,0.1<c<10 wt%) is ﬂat above 4 wt%; below

4wt%,Tcp decreases with the increasing c;c=0.5 wt%: sharp

transition at Tcp =51◦C, no hysteresis [356,357]

Shows no endotherm during the phase transition; the difference with the

iPr-containing polymer results from the size of the hydrophobic group

[356]

Tcp decreases with salt concentration in line with the Hofmeister series

[356,357]

Poly(methyl 2-isobutyracrylate) [357]

Tcp =19◦C: c=0.5 wt%, sharp transition, no hysteresis [357]

Shows endotherm during the phase transition [357]

Poly(oxazoline)s

Poly(2-substituted-2-oxazoline)s are polymeric non-ionic tertiary

polyamides obtained from 2-substituted oxazolines via living cationic

ring-opening polymerization [64,360–365];

Poly(2-methyl-2-oxazoline), PMOz, is soluble in water at

0◦C<T<100◦C; polyoxazolines with ethyl, propyl and isopropyl

pendants show the LCST behaviour; the transition is sharp with fast

responsivity in comparison to PiPAAm; transition is reversible, and

shows no noticeable hysteresis; no polyoxazolines with four or more

carbon atoms have been reported to be soluble in water

[362,366–370]; poly(2-alkyl-2-oxazoline)s with 1–7 pendants are

crystallizable and form oriented crystalline ﬁlaments [365,371–376];

while those with 6–11 reveal glass transition temperatures [365]

Poly(2-ethyl-2-oxazoline) PEOz [366,367,370,377–383]

Phase diagram and LCST [377,383]

Tcp >100◦C(Mn<10,000 g/mol) [383]; Tcp >90◦C(Mn=8000 g/mol,

PDI =1.02, c=1wt%)[366,367]; Tcp =90.6◦C(Mn=6700 g/mol,

PDI =1.15, c=5 g/l) and Tcp =69.3◦C(Mn=37,300 g/mol,

PDI =1.6, c=5 g/l) [382]; 78◦C>Tcp >66◦C (9200 g/mol

<Mn<40,000 g/mol, c=5 g/l) [383]; 60◦C<Tcp <78◦C

(M>20,000 g/mol) [370,377–379]

(continued)

Non-ionic Thermoresponsive Polymers in Water 59

Tab l e 2 (continued)

Structure Properties

Effect of crosslinks: Tcp =68◦C of PEOz hydrogel is lower than the

Tcp =73◦C of the linear polymer with comparable molecular mass

[381]; this is similar to PiPAAm hydrogels [382]

Effect of salt [377]

-AtpH<3.5 forms a H-bonded complex with poly(methacrylic acid)

PMAA [385], this is similar to PiPAAm/PMAA complexation (pH <6.3)

[386]

Tg=60◦C[371]; Tm=149◦CforMn=14,920 g/mol, PDI =1.2 [365]

Poly(2-n-propyl-2-oxazoline) PnPOz

Structural isomer of PiPAAm (reversed amide linkage with N in the main

chain and propyl instead of isopropyl pendant)

Tcp =23.8◦C(Mn=12,000 g/mol, PDI =1.04, c=1wt%)[366];

Tcp =25◦C(Mn=3068 g/mol, PDI =1.13, c=2wt%)[387];

Tcp =42.9◦C(Mn=3100 g/mol, PDI =1.1, c=5 g/l) and

Tcp =22.5◦C(Mn=18,000 g/mol, PDI =1.46, c=5 g/l) [382]

Tg=40◦C[371]; Tm=145◦CforMn=12,160 g/mol, PDI =1.3 [365]

Poly(2-isopropyl-2-oxazoline) PiPOz [64,366,388–390]

Structural isomer of PiPAAm (reversed amide linkage with N in the

main chain)

Tcp =36◦C(Mn=16,700 g/mol) [370]; Tcp =38.7◦C

(Mn=9700 g/mol, PDI =1.02, c=1wt%)[366]; Tcp =47◦C

(Mn=3907 g/mol, PDI =1.09, c=2wt%)[387];

45◦C<Tcp <63◦C, Tcp decreases with increasing Mn

(1900 <Mn<5700 g/mol, PDI ≤1.05, c=0.1 wt%) [388]

Telechelic and heterotelechelic with hydroxy, amine or acetal groups: Tcp

is highly concentration-dependent [389]; hydrophobic methyl,

n-nonyl, piperidine, piperazine as well as hydrophilic

oligo(oxyethylene) end groups decrease the LCST; the effect of the

end group polarity on Tcp is stronger than with PiPAAm [390]

Insoluble aggregates of PiPOz are formed when the precipitated polymer

is kept for 24 h above Tcp =65◦C; precipitated polymer is ﬁbrous

[372,373,387]

Tg=70◦C[372]

II. Poly(ether)s

Poly(oxide)s

Polyoxide is a polymer with oxygen atoms in the main chains [124];

polyoxides with x=1, 3 (except PPO), 4, 5, etc. are not soluble in

water at any temperature

Poly(ethyleneoxide) or poly(ethylene glycol) PEO or PEG

[124,391–394]

One LCST-type critical temperature of TΘ=106◦C (estimated at

3 MPa) and two critical temperatures corresponding to the UCST

behaviour: TΘI=−12 ±3◦C (estimated in supercooled state) and

TΘII =115◦C (estimated at 3 MPa) [124,395]

(continued)

60 V. Aseyev et al.

Tab l e 2 (continued)

Structure Properties

LCST-type behaviour: Tcp =96◦CforMn=20,000 [396],

TΘ=96 ±3◦C[124]

Addition of salt decreases TΘ[124,396–400]: TΘ=90◦C, 2 M LiCl;

TΘ=82◦C, 2 M CaCl2;TΘ=80◦C, 2 M MgCl2;TΘ=76◦C, 2 M

NH4Cl; TΘ=73◦C, 2 M SrCl2;TΘ=60◦C, 2 M CsCl; TΘ=60◦C,

2MNaCl;TΘ=57◦C, 2 M KCl; TΘ=56◦C, 2 M RbCl [397]

TΘ=35◦C, 0.45 M K2SO4and TΘ=45◦C, 0.39 M MgSO4[124]

Crystallizable, −65◦C<Tg<−20◦C depending on Mand crystalline

content [124,401]

Poly(propyleneoxide) or poly(propylene glycol) PPO

[103,124,125,402]

M≤400 g/mol is water-soluble at room temperature; M=1200 g/mol is

soluble up to 2 wt%; solubility of M≥2000 g/mol PPO is less than

0.1 wt% [103,124,125]

For c=0.05 wt%: Tcp =15◦CforM=3000 g/mol and Tcp =35◦Cfor

M=1200 g/mol [403]; estimated TΘ=−53◦CforM=∞[124]

For c=4.15 g/L, Mn=1,000 g/mol: 35◦C<Tcp <40◦C, broad

transition with Tmax =40.9◦C[103], transition enthalpy is

1.4 kcal/mol of repeating units, similar to the values observed for

PiPAAm and PMVEth

Limited solubility is suggested to result from spiral folding of the chain

into tightly coiled disks in aqueous solution [402]

Crystallizable, Tg=−75◦C for high M [124]

Poly(vinylether)s

OOR

Polyether is a polymer with oxygen atoms in the main or side chain.

Among them, thermoresponsive poly(vinylether)s have oxymethylene

and/or oxyethylene pendants in their side chains [30,124,404–406]

Phase separation temperature of vinyl ethers can be controlled by varying

the number of the pendant oxyethylene units and/or the

hydrophobicity of an ω-alkyl group, R

Tcp measurements typically reveal an abrupt reversible transition within

ΔT=1◦C; no hysteresis

Homopolymers of ethyl vinylether and higher alkyl vinylethers are

insoluble in water

Poly(methylvinylether) PMVEth [30,32,55,103,188,260,407–416]

Bimodal phase diagram [188,417,418]

Colloidally stable droplets of PMVEth [188]

LCST1 =32–33◦C(c<30 wt%) and LCST2 ≈28◦C(c>30 wt%)

[116–119,417,418]; intermolecular aggregates exist below Tcp [55]

DSC: broad endothermic peak typically has a low ΔCp shoulder on the

lower temperature side [103,417,418]

Addition of salt decreases Tcp [103,407]

Polymer-protected gold nanoparticles [413]

Time-limited colloidal stability; stable droplets [188]; mesoglobules

above 50◦C; liquid–liquid macrophase separation within a month [55]

(continued)

Non-ionic Thermoresponsive Polymers in Water 61

Tab l e 2 (continued)

Structure Properties

Isotactic PMVEth is crystallizable, −19 <Tg<−40◦C

[118,119,124,417,418]

Copolymers [30,414,419–422]

Poly(2-methoxyethylvinylether) PMOVEth [405,423,424]

Tcp =63◦C[405]; Tcp =70◦C(Mn=20,000 g/mol, PDI =1.11,

1wt%)[405]

Tcp decreases by 5◦CasMnincreases from 10,000 to 20,000 g/mol;

further increase in Mnhardly affects Tcp [405]

No hysteresis [405]

Gradient, random and block copolymers with PEOVEth [424]

Poly(2-ethoxyethylvinylether) PEOVEth [404,423,424]

Tcp =20◦C(Mn=22,000 g/mol, PDI =1.13, 1 wt%) [405]

No hysteresis [405]

Gradient EOVEth-co-MOVEth undergo gradual thermally induced

association above Tcp =20◦C, forming micelles with a hydrophobic

core of EOVE-rich segments. The size of the micelles decreases

monotonously with further increasing solution temperature, whereas

block copolymers reveal two-step transition, and random copolymers

one-step transition [424]

Block copolymers with poly(hydroxyethyl vinyl ether), PHOVEth:

sol–gel transition at 20.5◦C, c=17 wt% [423,425]

Poly(2-(2-ethoxy)ethoxyethylvinylether) [426]

Phase diagram c<50 wt% [427]; the Tcp curve is ﬂat except in a very

dilute region

Tcp =40◦C[428]; LCST =40.0–40.5◦C(Mn=20,000 g/mol,

PDI =1.33 and Mn=34,000 g/mol, PDI =1.26) [427]

Thermoresponsive copolymers [420,428]

OOH

Poly(4-hydroxybutylvinylether) [30,420,429]

Tdem ∼42◦C

Derived from a silyloxy-protected pendant counterpart

Polymers with shorter or longer –(CH2)– spacers are soluble or insoluble

in water, respectively

Alkylglycidylethers: poly(methyl glycidyl ether), poly(ethyl glycidyl

ether), poly(ethoxyethyl glycidyl ether) [430–432];

14.6◦C<Tcp <57.7◦C is strongly affected by the length and structure of

the alkyl chain [430,431]

Anionic ring-opening polymerization

Ether bond in the main and side chain

Temperature-dependent sol–gel transitions

Copolymers of glycidyl methyl ether with ethyl glycidyl ether

to adjust Tcp [432]

(continued)

62 V. Aseyev et al.

Tab l e 2 (continued)

Structure Properties

III. Polymers bearing phosphate groups

Poly(phosphoester)s

Poly(phosphoester)s are polyphosphates obtained through ring-opening

polymerization of cyclic phosphoester monomers;

poly(2-methoxy-2-oxo-1,3,2-dioxaphospholane), or poly(methyl

ethylene phosphate), is not reported to show the LCST behaviour;

poly(phosphoester)s are biodegradabile and biocompatible [433–438]

Poly(2-ethoxy-2-oxo-1,3,2-dioxaphospholane) or poly(ethyl ethylene

phosphate [437,439,440]

Tcp =38◦C(Mw=14,600 g/mol, PDI =1.25, c=1wt%)[440]

Transition is thermoreversible with small hysteresis

Gold nanoparticles [438]

Poly(2-isopropoxy-2-oxo-1,3,2-dioxaphospholane) or poly(isopropyl

ethylene phosphate) [437,439,440]

Tcp =5◦C[440]

Linear copolymers [437,440]; addition of NaCl decreases Tcp; transition

is thermoreversible with small hysteresis

Gold nanoparticles [438]

Tab l e 3 Selected examples of thermoresponsive neutral polymers based on amphiphilic balance

and showing the type of LCST behaviour

Structure Properties

Poly(N-methylacrylamide) PMAAm [207]

Estimated Tcp >100◦C

Tg=178.5◦C, Mw=185,000 g/mol, PDI =3.6

LCST-type copolymers with styrene, 20◦C<Tcp <100◦C

Poly(N,N-dimethylacrylamide) PDMAAm

[195,207,222,236,454–456];

LCST: estimated Tcp >100◦C[207,454], Tcp ≈200◦C[195]

Chemically crosslinked hydrogel shrinks upon heating [207]

Tg=125.7◦C, Mw=156,000 g/mol, PDI =3.4[207];

Tg=122◦C[454]; Tg=105◦C[295]

Tacticity [223]; isotactic PDMAAm is highly crystalline and

only partially soluble in water [457,458]; however, in [223]

PDMAAm samples are reported to be soluble in water

regardless of the tacticity

LCST type copolymers with styrene, 20◦C<Tcp <100◦C

[207] and with 2-methoxyethylacrylate, 9◦C<Tcp <80◦C

[454]; AB diblock copolymers [455]

(continued)

Non-ionic Thermoresponsive Polymers in Water 63

Tab l e 3 (continued)

Structure Properties

45 Poly(N-

alkyl(meth)acrylamide)s

bearing hydroxyl groups

N-monosubstituted and N-disubstituted poly(acrylamide)s and

poly(methacrylamide)s [459]

The precursor polymers, e.g.

poly(N-2-hydroxypropylmethacrylamide),

poly[N,N-bis(hydroxyethyl) acrylamide] and

poly(N-[tris(hydroxymethyl)-methyl] acrylamide): the Tcp

is tailored by varying the acylating agent (acetylation and

cinnamoylation) or by varying the extent of acylation

Poly(vinylpyrrolidone) [303,460,461]

Phase separation and solubility behaviour [124,461]

Estimated and measured TΘ=140 ±5◦C[124], TΘ=160◦C

[303]

Salt and aromatic cosolutes decrease Tcp :Mw=78,000 g/mol,

27◦C<Tcp <77◦C[462–465]

TΘ=28◦C, Mn=99,000–457,000 g/mol in 0.55 M Na2SO4

[461]

Tg=86±1◦C[124]

Poly(N-acryloylmorpholine) pAOM

RAFT polymerization [300,466–468]

Well soluble in water; Tcp is probably 100◦C

36 <Tcp <80◦C thermosensitive ﬂuoroalkyl-end-capped

pAOM homo- and co-oligomers [469,470]

Tacticity [223]

Poly(N-tert-butylacrylamide) [471,472]

LCST: theoretical Tcp =−5◦C; Tg=108◦C

Tcp =27◦C for random

poly[(N-tert-butylacrylamide)-co-acrylamide] with 50:50

molar ratio of N-tert-butylacrylamide/acrylamide

0.2 mm thick ﬁlm made of chemically crosslinked random

poly[(N-tert-butylacrylamide)-co-acrylamide], with 27:73

molar ratio of repeating units, reversibly swells and

contracts in the range of 6–80◦C

Poly(2-substituted-2-oxazoline)s

Copolymers with adjusted Tdem by changing the comonomer

composition and molecular weight [382,473,474];

gradient or random copolymers of POz and either iPOz or

EOz 23.8◦C<Tcp <75.1◦C[366,367]; gradient

copolymers of iPOz with 2-N-propyl-, 2-N-butyl-, and

2-N-nonyl-2-oxazoline, 9◦C<Tcp <46◦C[387]

Block copolymers and thermoresponsive micelles [475];

cylindrical molecular brushes [476]; comb and graft shaped

poly(oligoEOz methacrylate)s [477]; polyion complex

micelles stabilized with PiPOz [478]

Poly(2-ethyl-2-oxazoline)-block-poly(

-caprolactone):

thermally reversible sol–gel transition [479,480]

(continued)

64 V. Aseyev et al.

Tab l e 3 (continued)

Structure Properties

Effect of salt: NaCl lowers the LCST [367]

A variety of amphiphilic random, block and star copolymers of

2-methyl-2-oxazoline with 2-oxazoline-bearing pendant

hydrophobic moieties (LCST behaviour was not studied)

[371,481–484]

50a

50b

(50a) Poly(vinylalcohol) PVAl

(50b) Poly(vinylacetate) PVAc [303,485–490]

PVAl: estimated TΘ=125◦C[303]

PVAl is obtained from PVAc by alcoholysis, hydrolysis or

aminolysis [485]; PVAl–PVAc with the degree of

hydrolysis below 83% shows the LCST behaviour between

0 and 100◦C; Tcp decreases with increasing VAc content

[124,491–493]

Properties of aqueous PVAl–PVAc solutions are affected by the

degree of hydrolysis, temperature, pressure, addition of

electrolytes; H-bonds are disrupted at T=54 −67◦C[491]

PVAl is highly crystallizable: needs to be heated above 70◦Cto

solubilize

PVAl with the degrees of hydrolysis above 87% are not soluble

at all

For PVAl–PVAc, 50% of VAc, TΘ=25◦C[494]

PVAl–PVAc: TΘ=97◦CforMw=13,500, 34,400,

74,100 g/mol [397,487]

Tg=70−99◦C[124,401]

51a

51b

(51a) Poly(ethyleneoxide) PEO

(51b) Poly(propyleneoxide) PEO

Copolymers, PEO–PPO–PEO block copolymers, Pluronics or

Poloxamer, Tetronics [45,49,51,392,495–503]

PEO37–PPO56–PEO37: micellization at 12–18◦Cand

Tcp =91◦C of LCST type [499]

Hydrophobically end-capped poly(EO-co-PO): Tcp is in the

range of 18–71◦C depending on the end group,

c=0.5wt%; sharp phase transition within 3◦Candsmall

hysteresis; two liquid phases above Tcp;Tcp is linearly

decreases with increasing concentration of salts (Na2SO4

and Na3PO4)[504]

52a

OOR

52b

OOR

Self-assembling polymers containing PEO in the side chain

form a class of thermoresponsive polymers based on

amphiphilic balance [49]; R is ω-alkyl group or H

Substituting the hydrophilic groups that make the polymer

water-soluble with hydrophobic groups, one can convert a

polymer, originally soluble in water at all temperatures, into

a polymer soluble in water only below a given temperature

and vice versa [207]

Example: grafted polymethacrylates (molecular brushes)

[30,505–515]

(continued)

Non-ionic Thermoresponsive Polymers in Water 65

Tab l e 3 (continued)

Structure Properties

Polymers show reversible cloud points with no hysteresis;

Tcp of these polymers depends on chemical composition and

can be adjusted between 20 <T<90◦C

Tcp is strongly dependent on the lengths of PEO chain

Tcp is not dependent on c, ﬂat phase diagram

Typically Tg<0◦C; longer ﬂexible PEO side chains

decrease Tg[516]

Poly[2-(2-ethoxyethoxy)ethylacrylate] PEEO2A [297]

Tcp =9◦CforMn=17,500 g/mol, PDI =1.66 at c=1wt%;

Copolymers with oligo(ethylene glycol) methyl ether acrylate

9<Tcp <49.9◦C; no hysteresis

Poly[2-(2-methoxyethoxy)ethylmethacrylate)] PMEO2MA

[297,509,512]

Tcp =28◦CforMn=16,700 g/mol, PDI =1.72, c=3wt%

[512]

Tcp in water is around 26–27◦C, Mn=10,000–37,000 g/mol,

PDI <1.1, c=0.2wt%[509]; Tcp decreases with

increasing the Mn

Very weak hysteresis [509,512]

Tg=−40◦C[509]

Effect of tacticity [509]

Block copolymers with PS [509]

Poly(2-[2-(2-methoxyethoxy)ethoxy]ethylmethacrylate)

PMEO3MA [509]

Tcp =49–52◦C, Mn=10,000–37,000 g/mol, PDI <1.1,

c=0.2wt%; Tcp decreases with increasing the Mn

Very weak hysteresis

Tg=−47◦C

Effect of tacticity

Block copolymers with PS and PMEO2MA

8-9

Poly[oligo(ethyleneglycol)methacrylate] POEGMA with side

chains of eight or nine ethylene oxide units [294,512]

Tcp =83◦CforMn=15,000 g/mol, PDI =1.08, c=1wt%

[294]; Tcp =90◦CforMn=10,000 g/mol, PDI =1.18,

c=3wt%[512]

Very weak hysteresis for homo- and copolymers [294,512];

Copolymers P(MEO2MA-co-OEGMA): ﬂat phase diagram;

measured Tcp were in the range of 28–90◦C;

Tcp =28+1.04 ×DPOEGMA [512]; self-assembling block

copolymers [294]

57a

~20%

57b

~80%

mixture of isomers

Poly(2-hydroxypropylacrylate) PHPA, mixture of isomers

[207,517]

Strong concentration dependence of Tcp :Tcp =16◦Cat

c=10 wt% [207]; Tcp =18.3◦Catc=1.5wt%,

Tcp =21.4◦Catc=1.0wt%, Tcp =26.7◦Catc=0.5wt%,

Tcp =33.3◦Cat0.25wt%(Mn=11,100 g/mol,

PDI =1.21) [517]

For dilute solutions, the phase transition is broad and it is

broader upon dissolution than upon precipitation [517]

(continued)

66 V. Aseyev et al.

Tab l e 3 (continued)

Structure Properties

For dilute solutions, redissolution of PHPA upon

cooling occurs at higher temperatures than

precipitation upon heating [517], i.e. hysteresis is

reversed to the hysteresis observed PiPAAm [95]

Tg=21.7◦C(Mn=11,100 g/mol, PDI =1.21) [517]

Random copolymers [207,517]

Poly(2-hydroxyethylmethacrylate) PHEMA [518–524]

Mw/Mn<1.25, c=0.50 wt%: for Mn<10,900 g/mol

Tcp >100◦C, for 10,900 <Mn<14,300 g/mol

39 >Tcp >28◦C, Mn>14,300g/mol is insoluble;

range of transition temperature is very broad ∼15◦C;

enhanced water solubility of these PHEMA at pH

2.2 is due to protonation of the terminal morpholine

groups derived from the ATRP initiator [518]

Copolymers [518], hydrogels [519,524]

Urea raises the degree of swelling of PHEMA gels:

Mη=(1−50)×105:TΘ=10◦C in aqueous 4 M

urea, TΘ=27.2◦C in 6 M urea, and TΘ=52.5◦Cin

8Murea [523]

Isotactic PHEMA: TΘ=15.3◦Cfor

Mη=39,000 −816,000 [522]

HEMA copolymers are biocompatible and blood

compatibility [525,526]

(CH

)

NH (CHOH)

N-substituted polymethacrylamides with

alkylaldonamide side chains

Phase diagram for the polymer with x=10 and

c>20 wt%; thermotropic and lyotropic properties;

Physical gel melts upon heating and consequently

adopts a birefringent glassy lamellar phase, lamellar

phase, and isotropic solution [527]

(CH

)

NH O

(CH

)

Poly(amidohydroxyurethane) PAmHU [528,529]

Tcp =57◦CforMn=18,700 g/mol, cp=1–3 w/wt%

The molecular architecture of studied polymer suggests

a coil-to-micelle demixing scenario

PAmHU is crystalline

22◦C<Tcp <57◦C of PAmHU/water/ethanol mixture

61 Hyperbranched polyethers (61a) 1,4-butanediol diglycidyl ether with triols such as

trimethylolethane and trimethylolpropane [530]

19.0<Tcp <40.3◦C: (c=1.0wt%) is adjustable

depending on the hydrophilic/hydrophobic balance

of 1,4-butanediol diglycidyl ether and triols

(61b) 1,2,7,8-diepoxyoctane with ethylene glycol,

di(ethylene glycol), tri(ethylene glycol),

1,2-propanediol, and glycerol [531]

23.6<Tcp <67.2◦C: (c=1.0wt%) is adjustable

depending on the composition

−48.8<Tg<−29.7◦C; highly branched polyethers are

ﬂexible polymers

(continued)

Non-ionic Thermoresponsive Polymers in Water 67

Tab l e 3 (continued)

Structure Properties

62 Oligo(ethylene oxide)-grafted

polylactides

Glycolides with pendent oligoEO monomethyl ether

substituents [532]

One or two EO units: more hydrophilic than polylactide

but insoluble in water

Three EO units: Tcp =19◦C, Mn=59,800 g/mol,

PDI =1.16, c=1.5wt%

Four EO units: Mn=10,600 g/mol, PDI =1.12,

c=1.5wt%: Tcp =37◦C

63 Methoxy-terminated

dendronized polymethacrylates

PG1: Tcp =62.5–64.5◦C(c<4wt%, Mindependent, no

speciﬁc morphologies for aggregates is observed

above Tcp, aggregation is dependent on heating rate

and concentration, and also differs for heating and

cooling

PG2: Tcp =64.2–65.7◦C(c<2 wt%, uniform spherical

aggregates above Tcp, uniformity is independent of

heating rate and concentration)

Tg<−80◦C for both

Thermoresponsiveness results from the entire

branch-work and not from just a peripheral

decoration

Change methyl for ethyl groups at the periphery of the

polymers has a pronounced effect on LCST [533]

64 Isobutyramide-terminated

poly(amidoamine) dendrimers

Dendrimers of generation G3, G4, and G5 (32, 64, and

128 terminal VIBAm groups) showed Tcp of 76, 60

and 42◦C, respectively, in 10 mM phosphat e buffer

(1.0 wt%, pH 9.0); phase diagram for c<1wt%

Tcp increases with increasing urea concentration

Tcp decreases with increasing hydrophilicity of

generations; this ﬁnding was rationalized in terms of

densely packed structures, which facilitate the

dehydration process (impact of steric hindrance on

LCST) [534–536]

OCH

y2-x

Poly(organophosphazene)s with two side groups of

poly(ethylene oxide) and amino acid esters, where

R1=H, CH3, COOR2,CH

2COOR2,

CH2CH2COOR2,CH(CH

3)CH2CH3and

R2=CH3,C

2H5,CH

2C6H5[30,49,303,537–542]

50◦C<Tcp <93◦C, depending on the structure of the

side groups

Biodegradable thermosensitive polymer [543]

Reversible sol–gel transition upon heating [540]

68 V. Aseyev et al.

Tab l e 4 Neutral thermoresponsive homopolymers, for which the solubility in water decreases

upon cooling

Structure Properties

Poly[6-(acryloyloxymethyl)uracil] [544]

UCST type of transition: Tcp ≈60◦Cforc=0.1wt%

Since NH and C=O groups of uracil act as donors and

acceptors, interpolymer complexes are formed upon

decreasing temperature and increasing the strength of the

hydrogen bonds

Phase transition is shifted to lower temperatures upon addition

of urea or adenosine (complementary nucleic acid base to

uracil) preventing the complex formation in cold water

Poly(ethyleneoxide) PEO

Two critical temperatures corresponding to the UCST

behaviour

TΘI=−12±3◦C, estimated in supercooled state [124]

PEO shows UCST behaviour (TcpII =115◦C) above its LCST

(Tcp =106◦C) under pressure of 3 MPa, between 106 and

115◦C PEO demixes (immiscibility island); phase

behaviour studied using SANS [395]

Hydrostatic pressure lowers both the LCST and the UCST

[395]

Poly(methylvinylether) PMVEth

Two UCSTs are theoretically predicted for the low and high

polymer concentrations using thermodynamic perturbation

theory of Wertheim for saturation interactions

(i.e. hydrogen bonds) [545–547], adapted to the lattice

model [417]

One UCST <−15◦C has been experimentally observed at

c>80wt% [418]

Poly(methacrylamide) PMAAm [124,548–551]

The second virial coefﬁcient and the intrinsic viscosity were

found to increase with increasing temperature; highly

concentrated PMAAm solutions form gel upon heating

[548]

TΘ=6◦C, Mw=320,000g/mol (Tdependence of the second

virial coefﬁcient) [548]; TΘ>30◦C, Mw=78,000g/mol

[549]; TΘ>100◦C[550]

Effect of salts (perchlorates, thiocyanates, chlorides, sulphates

of uni- and bivalent metals); electrophoretic measurements

suggests that both anions and cations are bound on the

polymer chain; salting-in effect of cations (increasing with

increasing surface charge density); the effect of anions is

unfavourable to dissolution [551]

Tg>100◦C[124]

(continued)

Non-ionic Thermoresponsive Polymers in Water 69

Tab l e 4 (continued)

Structure Properties

70a

70b

(70a) Poly(vinyl alcohol) PVAl

(70b) Poly(vinyl acetate) PVAc [493]

PVAl–PVAc gels form upon cooling; prepared by freeze/thaw

cycling [552,553]; the gel–sol transition for physically

crosslinked PVA hydrogels is 55–70◦C[554]

Both the LCST and the UCST behaviour in an aqueous mixture

of 99–89% hydrolysed PVAl (DP =1,700, c>15 wt%)

NH2

Poly(N-acrylylglycinamide) [124,555–561]

Aggregation of chains occurs in solutions with c≤1wt%

Physical thermoreversible gels are formed from solutions

annealed below room temperature; gels melt upon heating

above their Tm

Tmincreases with molar mass (23.5◦C<Tm<78.6◦Cfor

27,600 <Mn<944,000 g/mol) and with polymer

concentration (67.4◦C<Tm<87.0◦Cfor3<c<7)

Effect of added reagents on gelation; [η] of PAG solution

containing 2 M NaCNS is higher than that of pure aqueous

solution

Tg=182±2◦C[557]

ONH NH

Poly(N-methacrylylglycinamide) [555,561]

Physical thermoreversible gels: gels melt upon heating;

Solubilities and properties of PMG and PAG are similar, but

higher cand/or Mare required for PMG, and Tmof gels are

lower than for PAG

Tg=226◦C[561]

Tab l e 5 Structural isomers of PiPAAm

Isomer of PiPAAm Abbreviation Tcp (◦C)

Poly(N-ethylmethacrylamide) PNEMAAm 67–71

Poly(N,N-ethylmethylacrylamide) PNNEMAAm 56–74

Poly(N-n-propylacrylamide) PnPAAm 23–25

Poly(N-isopropylacrylamide) PiPAAm 27–33

Poly(N-vinylisobutyramide) PViBAm 35–39

Poly(2-n-propyl-2-oxazoline) PnPOz 22–25

Poly(2-isopropyl-2-oxazoline) PiPOz 36–63

Polyleucine PLeu Insoluble

Polyisoleucine PiLeu Insoluble

7 Some Generalizations

7.1 Structural Effects

As noted above, only a qualitative analysis can be done in view of the different

approaches to deﬁning the Tcp, and, in general, the use of Tcp or Tdem instead

of the LCST as a uniform and unique temperature to deﬁne the phase transition

70 V. Aseyev et al.

of any polymer of a certain molar mass. We highlight in this section important

evidence on the structural features of a polymer chain that affect its thermal

response in water. Thus, Kano and Kokufuta report that the thermally induced

interactions between macromolecules in solution, as well as between polymer

chains and solvent molecules, depend on whether the α-carbon in the back-

bone bears an H atom (AAm) or a methyl group (MAAm) and whether the

N-propyl pendant group is branched (iP) or linear (nP) [130]. From a compar-

ison of Tcp values for PiPAAm and PiPMAAm, one may expect that a methyl

group in the main chain in the α-position increases solubility. This agrees with

the reported molar fraction of the C=O···HN bonds at temperatures near the

demixing temperature: 0.13 for PiPAAm [131] and 0.42 for PiPMAAm [132],

andalso0.30forPnPAAm[131] and 0.40 for PnPMAAm [132]. Based on the

H-bonds fraction, Kano and Kokufuta noted that the solubility order ought to be

PiPMAAm >PnPMAAm >PnPAAm >PiPAAm, which disagrees with their

measurements of Tdem (PiPMAAm >PiPAAm >PnPMAAm >PnPAAm) and

of the endothermic enthalpy (PnPMAAm >PnPAAm >PiPMAAm >PiPAAm)

[130]. Analysis of the highly diverse Tcp values collected in Table 2does not offer

any evident conclusions. This certainly calls for further systematic studies on the

structural effect of the constituent repeating units.

7.2 Structural Isomers of PiPAAm

The structural isomers of PiPAAm with corresponding literature values of Tcp are

given in Table 5.

To the best of our knowledge, the last two structural isomers of PiPAAm are

not soluble in water (PLeu [144,441,442]andPiLeu[144]). Urry deﬁned Leu as

a more hydrophobic residue than iLeu [144]. Small rearrangement of the methyl

group from Leu to iLeu results in a 5◦C rise on the hydrophobicity scale. PLeu

and PiLeu are crystalline polymers. PLeu forms α-helical structures, the so called

leucine zippers, consisting of two parallel α-helices. PiLeu forms fewer α-helices,

favouring the formation of β-structures (Fig . 4)[144,443].

A comparison of the isomers suggests that:

1. PnPAAm vs. PiPAAm and PLeu vs. PiLeu: the solubility is higher (i.e. higher

Tcp)for polymers with an isopropyl pendant in the side chain rather than

n-propyl.

Fig. 4 Chemical structures

of polyleucine (73)

and polyisoleucine (74)73

Non-ionic Thermoresponsive Polymers in Water 71

2. PNEMAAm vs. PNNEMAAm: methyl group in the main chain causes higher

solubility.

3. PViBAm vs. PiPAAm: reversed amide linkage (NH group linked to the main

chain in the case of PViBAm, vs. C=O for PiPAAm) results in better solubility.

4. PiPOz vs. PiPAAm: tertiary amide linkage and N in the main chain enhances

solubility. However, if both N and C=O are in the main chain, solubility decreases

(see PLeu vs. PiPAAm).

5. As an overall tendency, a C=O group positioned closer to the end of the pen-

dant group, and N closer to the backbone, results in an increase in the polymer

solubility.

Structural differences, together with differences in the synthesis, result in consider-

able variations of the physical properties of the PiPAAm structural isomers. Thus,

PiPOz is a crystalline polymer [389] and is able to crystallize from water as a ﬁbrous

material when its solution is annealed for 24 h above Tcp =65◦C[373,387]. Co-

agulated PiPOz particles exhibit hierarchical structures with two levels of ordering

that are micron-sized spherical particles consisting of ﬁbrils with a cross-sectional

diameter of about 30–50 nm and a length of several microns [373]. The densely

packed microspheres formed in dilute solutions are uniform in size and shape and

resemble a ball made of rattan.

7.3 Hysteresis

Hysteresis in the heating/cooling cycles of polymer–water systems featuring an

LCST has been ascribed to the limited diffusion of water into the dense hydropho-

bic aggregates formed above the LCST, which effectively delays the hydration of

the aggregates and the eventual resolubilization of the polymer upon cooling be-

low the LCST [95,269]. In order to increase the rate of response, macroporous

hydrogels have been prepared [444,445]. Macroporous thermoresponsive hydro-

gels allow molecules of water to enter freely within the polymer matrix, and to

leave it quickly, in response to a temperature change. Pore forming agents, foaming

reagents or solvent mixtures are typically used to prepare macroporous hydrogels.

An alternative synthetic procedure, cryogelation, has been introduced recently for

bioseparation [445–448]. Since the pore surface can be functionalized to recognize

target molecules, hydrogels are suitable media for the reversible immobilization

or separation of biomacromolecules. Thus, macroporous PiPAAm-based hydrogels

were used for the reversible adsorption of bovine serum albumin [449,450]and

to concentrate its aqueous solutions [451,452] or to concentrate aqueous solutions

of lignin [453]. PEO-grafted PiPAAm [169] or PEO-grafted PVCL [107]havealso

been used as fast-response polymeric systems, based on the expectation that PEO

chains may provide hydrophilic channels, thus facilitating the diffusion of water

molecules through the collapsed polymer matrix for temperatures above Tdem.

The limited diffusion of water molecules into the collapsed polymer matrix

does not explain why the cooling/heating rates are different for the kinetically fast

72 V. Aseyev et al.

process of hydrophobic hydration/dehydration. A qualitative analysis of the data

listed in Tables 2and 3suggests that the phase transition in water of polymers

with Tgwell below the phase separation boundary show a weak heating/cooling

hysteresis, if any at all. This is the case for thermoresponsive poly(vinylether)s,

poly(phosphoester)s, as well as acrylate- and methacrylate-based copolymers con-

taining PEO in their side chains. The majority of thermoresponsive N-substituted

poly(acrylamide)s and poly(methacrylamide)s, for which the phase transition shows

hysteresis, have a Tgvalue above 100◦C. In this case, the polymer concentration and

the rate of heating/cooling affect the hysteresis. One may assume, consequently,that

this type of hysteresis originates in the kinetically slow exothermic process of par-

tial vitriﬁcation of the phase-separated polymer, which is also responsible for the

stability of the mesoglobular phase [78,108,187]. Polyoxazolines with ethyl and

n-propyl pendant groups also show sharp LCST transitions and faster response to

changes in temperature, compared to PiPAAm. Poly(2-ethyl-2-oxazoline) (PEOz)

has a Tg=60◦C[371]. The Tcp of PEOz takes place for a temperature higher than

Tg.PnPOz(Tg=40◦C[371]) has a Tcp ≈Tg. The transitions are reversible, with no

hysteresis if solutions are heated/cooled with sufﬁciently high rates.

As stated above, the hysteresis of ELPs in the course of the ITT transition results

from the overlap of two kinetically different processes: a fast endothermic process,

which corresponds to the destruction of the ordered hydrophobic hydration, and a

second exothermic process arising from the β-spiral chain folding.

7.4 Effect of Macromolecular Architecture

The polymer architecture affects the demixing behaviour of thermoresponsive poly-

mers [562]. On the basis of theoretical studies it is expected that, as a rule,

branched macromolecules are more soluble than their linear analogues [563–565].

This prediction was conﬁrmed experimentally in the case of a solution of star-like

polystyrene in cyclohexane(an UCST-type phase separation) for which an increase

in the degree of branching resulted in a decrease in the temperature of demixing

[566,567]. On the basis of a review of water-soluble polymers of various shapes by

Aoshima and Kanaoka [30], it appears that water-soluble polymers do not offer a

uniform tendency in their LCST-type phase behaviour.

Xu and Liu recently reported the syntheses of the well-deﬁned 7-arm and 21-

arm PiPAAm stars with a β-cyclodextrin core [278,568] and presented a thorough

analysis of the literature on thermoresponsive stars and polymer brushes tethered

to curved surfaces, such as latex particles [279,280,569], gold nanoparticles

[282] and microgels [570]. A unique feature of these architectures is that they

form a densely packed spherical core and a less-dense outer shell [159]. As a re-

sult of such a non-uniform density distribution, two temperature-induced phase

transitions have been observed experimentallyin several systems based on PiPAAm

[279,280,282,568,569]. One transition has been ascribed to the phase transition

of the inner segments of PiPAAm, whereas the other transition, which is concentra-

tion dependent, was assigned to the collapse of the outer PiPAAm segments [282].

Non-ionic Thermoresponsive Polymers in Water 73

The two-step transition can also be explained in terms of the n-clustering that in-

duces the collapse [571]. Attractive many-body interactions between the polymer

repeating units take place within the most dense regions in the vicinity of the par-

ticle core and result in n-clustering [279,280,568,569]. The collapse of the outer

layer occurs at higher temperatures due to the lower local chain density. Accord-

ing to the n-clustering concept, the n-clustering increases with decreasing polymer

length, i.e. polymer brushes with short chains should have a lower Tcp. This was ob-

served experimentally for surface-adsorbed PiPAAm brushes [279,280,569]. Also,

the Tcp of 7-arm and 21-arm PiPAAm stars increases with increasing the arm length

[568]. Solutions of 21-arm PiPAAm stars with relatively long arms exhibit a bi-

modal DSC curve, which the authors explained on the basis of the two-layer brush

concept used to account for the two-step collapse of PiPAAm brushes grafted on the

gold nanoparticles.

7.5 Cyclic Polymers

There have been a few recent reports on the synthesis of macrocyclic PiPAAms

aimed at exploring the effect of topological constraints on the solution properties

of PiPAAm. The polymers were obtained by “click” intramolecular coupling of

linear heterofunctional α-azido-ω-alkynyl-PiPAAm samples synthesized via RAFT

[572]orviaATRP[573,574] polymerizations. The phase separation of cyclic Pi-

PAAms (c-PiPAAm) and their linear counterparts (l-PiPAAm) in aqueous solution

was monitored by microcalorimetry and turbidimetry. Qiu et al. reported that the

Tdem values of c-PiPAAms were systematically higher than those of the correspond-

ing l-PiPAAm precursors [572]. As the size of PiPAAm increases, the gap in Tdem

between linear and cyclic PiPAAms becomes narrower, implying that as the ring

size becomes larger, the effect of topological constraint on the LCST of cyclic

polymers becomes smaller. It should be noted that the Tdemvalues reported by Ye

et al. [573] followed slightly different trends, which may be attributed to differ-

ences in measurement protocols or in the detailed chemical structure of the coupling

groups. The ring size of the cyclic polymers also exerts a marked effect on the en-

thalpy change during the phase transition. The enthalpy of the phase transition (ΔH)

for l-PiPAAms (6000–19,000 g/mol) remains constant (6.06 and 6.40 kJ/mol per

NIPAM unit), which is consistent with the reported ΔHvalues of 5.5–7.5 kJ/mol

per repeating unit upon phase transition for linear PiPAAm. In contrast, the phase

transition enthalpies of c-PiPAAms are signiﬁcantly lower than those of ordinary l-

PiPAAm, with ΔHvalues of 3.86, 4.47 and 5.38 kJ/mol for c-PiPAAm of molecular

weight 6000, 12,000 and 19,000 g/mol, respectively. In addition, the density of the

mesoglobules formed by c-PiPAAm was lower than that of l-PiPAAm mesoglobules

[573]. The density difference was attributed to the lack of chain interpenetration

and entanglements in the c-PiPAAm mesoglobules. The hydration and dynamic

behaviour of c-PiPAAm in water was investigated by means of high frequency di-

electric relaxation measurements.Additional cooperativity in the molecular motions

74 V. Aseyev et al.

of the amide functional groups of each monomer unit in the polymer chains with a

cyclic topology was observed, compared to l-PiPAAm of similar molecular weight.

This enhanced cooperativity may contribute to the increase in the LCST of aqueous

solutions of c-PiPAAm, compared to that of l-PiPAAm, in the 10 g/L concentration

domain probed [575].

7.6 Telechelic Amphiphilic Polymers

Polymers that carry a hydrophobic group at one chain end tend to form core–shell

structures in which the hydrophobic core is insulated from the water by a brush-

like corona of PiPAAm chains [576]. Flower-like micelles, consisting of loops of

hydrated polymer chains having both end groups entrapped in the micellar core,

form in solutions of PiPAAm carrying a hydrophobic group at each chain end

[577,578]. The introduction of hydrophobicend-chains affects the phase behaviour

of PiPAAm solutions in two ways. First, the miscibility of the polymer in water be-

comes poorer as a result of direct interactions between water and the alkyl chains.

Second, the mixing entropy of the polymer chains is reduced due to the increase of

their apparent molecular weight via micelle formation. Both factors favour phase

separation, so that LCST tends to shift downwards. However, association of the

end chains does not affect the hydration of the main chains, except for segments

near the micellar core, because they remain exposed to water even when associa-

tion takes place. Therefore, the telechelic PiPAAm/water system is an interesting

example of the coexistence, without competition, of two phenomena: end-chain

association and hydration. These phenomena were monitored experimentally by

microcalorimetry, light scattering [579,580] and small angle neutron scattering

(SANS) [581]. A theoretical study of systems featuring coexisting LCST behaviour

and hydrophobic association via hydrophobic end groups was described by Okada et

al. for systems with “random” hydration (such as PEO) and “cooperative” hydration

(such as PiPAAm) [143].

There have been only a few reports so far on the preparation of telechelic

or semi-telechelic hydrophobically modiﬁed poly(oxazolines). Volet et al.

have described the synthesis and solution properties of semi-telechelic poly(2-

methyl-2-oxazolines) (PMOz) bearing an n-dodecyl- or an n-octadecyl group

at one chain end [475]. Telechelic PMOz with a perﬂuorooctyl group at one

end and a hydrocarbon group 6–18 carbons long were prepared with a view

towards the creation of multidomain micelles containing segregated ﬂuori-

nated and hydrocarbon hydrophobic compartments [582]. Hydrophobically end-

modiﬁed poly(2-ethyl-2-oxazolines) (PEOz) and poly(2-isopropyl-2-oxazolines)

(PiPOz) bearing an n-octadecyl chain on both termini or on one chain end only

were prepared by cationic ring-opening polymerization of 2-ethyl-2-oxazoline

and 2-isopropyl-2-oxazoline, respectively, and subsequent end-group modi-

ﬁcation [583]. The polymers had Mnranging from 7000 to 13,000 g/mol,

a size distribution Mw/Mn<1.20, and end-group functionality >0.97. All

polymers, except the semi-telechelic sample C18-PiPOz (Mn=13,000 g/mol),

Non-ionic Thermoresponsive Polymers in Water 75

formed core–shell micelles in cold water with a hydrodynamic radius (Rh)of

7–12 nm and a core radius (Rc), determined by analysis of small angle X-ray

scattering (SAXS) data, of ∼1.3 nm. Aqueous solutions of all polymers under-

went a heat-induced phase transition detected by an increase in solution turbidity

at Tcp of 32–62◦C, depending on the polymer structure and size. Temperature-

dependent light scattering measurements and ﬂuorescence depolarization studies

with the probe diphenylhexatriene revealed that extensive intermicellar bridg-

ing takes place in solutions heated in the vicinity of Tcp, leading to microgels

(Rh≥1μm). Further heating caused these assemblies to shrink into objects with

Rhof about 300–700 nm, depending on the size and structure of the polymer. Upon

heating aqueous semi-telechelic PiPOz at 65◦C for 24 h, extensive crystallization

occurred, as already noticed for aqueous solutions of the unmodiﬁed PiPOz [584].

Interestingly, telechelic PiPOz samples were shown to resist crystallization from

hot water. This resistance to crystallization was taken as an indication that the loops

formed by polymer chains captured in the ﬂower micelles that exist in cold water,

retain their conformation in the aggregates formed upon heating telechelic PiPOz

samples above their phase transition temperature. This behaviour is rather unique

because other end-modiﬁcations of the PiPOz chains reported so far, for example

grafting onto polysaccharides [585], do not hinder its crystallization from hot water.

7.7 Cononsolvency

The PiPAAm chain exhibits peculiar conformational changes in water upon addition

of a second water-miscible solvent such as methanol, tetrahydrofuran or dioxane.

Although the second solvent is a good solvent for the polymer, the polymer chain

collapses in certain compositions of the mixed solvent, followed by the eventual

reswelling when the second solvent is the major component [586,587]. The ten-

dency for phase separation is also strongly enhanced by the presence of the second

solvent. For instance, the LCST of aqueous PiPAAm solutions shifts to a lower tem-

perature when methanol is added. The temperature drop is the largest, from 31◦C

down to 7◦C, for a speciﬁc molar fraction, 0.35, of methanol. This enhanced phase

separation in mixed good solvents is knownas cononsolvency.Crosslinked PiPAAm

gels are also known to collapse sharply in water in the presence of methanol, at

a speciﬁc molar fraction of around 0.3, and gradually recover their swollen state

with increasing methanol content [588]. There have been efforts to understand co-

nonsolvency by the combination of three parameters [587] and also by the formation

of stoichiometric compounds between the solvent molecules [589]. Without consid-

ering direct hydrogen bonds between polymer and solvent, however, it is difﬁcult to

explain the sharp LCST behaviour. Tanaka F et al. recently derived a polymer expan-

sion factor for PiPAAm in mixed water and methanol as a function of the solvent

composition on the basis of competitive hydrogen bonds between PiPAAm/water

and PiPAAm/methanol [142]. This approach allowed them to model the sharp re-

entrant coil-to-globule-to-coil transition of PiPAAm in mixed water/methanol.

76 V. Aseyev et al.

8 Postscript

Arieh Ben-Naim wrote in his latest book that: “The ﬁeld of aqueous solutions has

become so huge that it is impossible to review the whole ﬁeld in a single book”

[129]. He added that “the behaviour of water and of aqueous solutions of simple

solutes is reasonably well understood”. This review led us to conclude that the

solutions of amphiphilic polymers in water still present mysteries, in spite of the

staggering number of publications on this topic. The literature provides mechanisms

responsible for the phase behaviour of aqueous amphiphilic polymer solutions, yet

most existing theoretical approaches still require proper experimental validation. It

is our hope that the systematic presentation of the experimental data collected for

a great variety of amphiphilic thermoresponsive polymers contained in this review

will help experimentalists and theoreticians in their quest towards a rational under-

standing of the phenomena involved and the intricate relationships among them.

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Mar 2001

Polymeric materials include plastics, gels, synthetic fibres, and rubbers. They are all-important both in industry and in daily life. Unlike liquid water, ice, or sugar solution, polymers are not homogeneous. They are said to consist of two or more phases, and their production and processing, as well as their properties and uses, depend on an understanding of the transitions that take place between these phases. Over the last two decades, phase diagrams of considerably complexity have begun to appear in the polymer literature. Phase transitions occur abundantly in polymer production and processing, are often encountered in poymer research, or are instrumental in laboratory methods of polymer characterization. This new textbook uses fundamental principles to classify phase separation phenomena in polymer systems, and describes simple molecular models explaining the observed behaviour. It supplies insight in the reading and construction of complex phase diagrams, as well as an understanding of the relationships that must exist between different phase transitions. Containing hundreds of diagrams, exercises at chapter ends, and several useful appendices, this text should be useful for anyone teaching or studying a course in polymer science.

Block Copolymers in Solution: Fundamentals and Applications: Hamley/Block Copolymers in Solution: Fundamentals and Applications

Book

Jul 2005

Ian W Hamley

Properties of Polymers

Article

Jan 1990

D.W. Van Krevelen

Physical Chemistry of Macromolecules

Article

Jan 1962

Block Copolymers in Nanocience

Book

Feb 2008

This first book to take a detailed look at one of the key focal points where nanotechnology and polymers meet provides both an introductory view for beginners as well as in-depth knowledge for specialists in the various research areas involved. It investigates all types of application for block copolymers: as tools for fabricating other nanomaterials, as structural components in hybrid materials and nanocomposites, and as functional materials. The multidisciplinary approach covers all stages from chemical synthesis and characterization, presenting applications from physics and chemistry to biology and medicine, such as micro- and nanolithography, membranes, optical labeling, drug delivery, as well as sensory and analytical uses.

Molecular theory of water and aqueous solutions: Part I: Understanding water

Book

Jan 2009

A. Ben-Nairn

The aim of this book is to explain the unusual properties of both pure liquid water and simple aqueous solutions, in terms of the properties of single molecules and interactions among small numbers of water molecules. It is mostly the result of the author's own research spanning over 40 years in the field of aqueous solutions. An understanding of the properties of liquid water is a prelude to the understanding of the role of water in biological systems and for the evolvement of life.The book is targeted at anyone who is interested in the outstanding properties of water and its role in biological systems. It is addressed to both students and researchers in chemistry, physics and biology. © 2009 by World Scientific Publishing Co. Pte. Ltd. All rights reserved.

Phase behavior in PVA/water solution : The coexistence of UCST and LCST

Article

Jan 1997

The presence of both the upper critical solution temperature (UCST) and the lower critical solution temperature (LCST) has been found in poly(vinyl alcohol) (PVA)/water solution, which consists of 99% hydrolyzed PVA. 89% hydrolyzed PVA. and water: the solution had a LCST-type phase boundary at high temperatures and an UCST-type boundary at low temperatures. This immiscibility gap was determined by the cloud point measurement method maintaining the solutions for 2 days at the desired temperatures. The coexistence of the UCST and the LCST was justified by the kinetic analysis of the phase separation. The increase of the apparent diffusion coefficient of spinodal decomposition (Dopp) obtained by the time-resolved light scattering method at high temperature region supports the existence of the LCST. On the other hand, the decrease of Dopp at low temperature region supports the existence of the UCST. The coexistence of both the UCST and the LCST was also supported by the supplemental experiments of temperature-jump and -drop from a two-phase region to a single-phase region.

Properties of Polymers

Article

Jan 2009

This authoritative, widely cited book has been used all over the world. The fourth edition incorporates the latest developments in the field while maintaining the core objectives of previous editions: to correlate properties with chemical structure and to describe methods that permit the estimation and prediction of numerical properties from chemical structure, i.e. nearly all properties of the solid, liquid, and dissolved states of polymers. * extends coverage of critical topics such as electrical and magnetic properties, rheological properties of polymer melts, and environmental behavior and failure * discusses liquid crystalline polymers across chapters 6, 15, and 16 for greater breadth and depth of coverage * increases the number of supporting illustrations from approximately 250 (in the previous edition) to more than 400 to further aid in visual understanding.

Future Outlook and Perspectives

Chapter

Mar 2003

The authors present a discussion of the future outlook and perspectives for conventional radical polymerization (RP) and controlled/living radical polymerization (LRP).

Non-Ionic Thermoresponsive Polymers in Water

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