Towards understanding, control and application of layered double
hydroxide chemistry{
Gareth R. Williams and Dermot O'Hare*
Received 4th April 2006, Accepted 26th May 2006
First published as an Advance Article on the web 15th June 2006
DOI: 10.1039/b604895a
Layered double hydroxides (LDHs) have a vast number of potential applications in fields as
diverse as separation chemistry, polymer additives and catalysis. They are facile and cheap to
prepare, and are environmentally friendly. In this paper, some of the most exciting recent
developments in LDH chemistry are discussed, with an emphasis on how we can control their
chemistry and how in situ techniques can provide enhanced understanding of the nanoscopic
processes involved in intercalation reactions.
1. Introduction
Layered double hydroxides (LDHs) are an unusual family
of layered materials consisting of positively charged layers
with charge balancing anions between the layers. The
latter can be replaced by other species through an anion
exchange process. Most LDHs may be represented by
the formula [M2
2+
M3+
(OH)6]+
X1/n
n2
?yH2O, for instance
[Mg2Al(OH)6]NO3?yH2O and [Ca2Al(OH)6]NO3?yH2O.1,2
These materials have a number of attractive properties
including shape-selective ion exchange,2­6
and catalytic
activity.7­9
Several excellent reviews on LDH chemistry have
recently been published, and the interested reader is referred to
these for more background information.9­12
At present, little is known about the nanoscopic processes
involved in intercalation. This is because few methods have
been developed to monitor solid-state reactions in situ.
Quenching studies (in which an aliquot of the reaction
suspension is removed and the solid product recovered
through filtration) have frequently proved to be unreliable.
The material isolated is often atypical of the reaction matrix as
a whole, having been affected by the quenching process. A
non-invasive probe which can interrogate a typical intercala-
tion process is required. It is also necessary to employ rapid
data collection times in order that kinetic information may be
obtained. X-Ray powder diffraction is a highly appropriate
tool. It is non-invasive, and is a powerful characterisation
technique when used in combination with ex situ analyses.
For in situ studies, the technique of energy dispersive X-ray
diffraction (EDXRD) is employed. This allows the simulta-
neous observation of a wide range of d-spacings in as little
as 10 s, even with small sample sizes. The simultaneous
observation of the host material, any intermediate phases, and
the product is possible. From these data, both qualitative
and quantitative information regarding the mechanism and
kinetics of a reaction can be obtained. A wide variety of
reactions have been monitored using EDXRD,13­19
including
the intercalation reactions of LDHs. Full details of the
Chemistry Research Laboratory, Department of Chemistry, University
of Oxford, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: dermot.ohare@chem.ox.ac.uk; Fax: +44 1865 285131;
Tel: +44 1865 285130
{ The HTML version of this article has been enhanced with colour
images.
Gareth Williams received
an MChem degree from
Pembroke College, Oxford,
having spent the final year of
this course performing a
research project in the lab
of Professor O'Hare. He
remained in the group for a
DPhil (PhD) degree on the
subject of intercalation chemis-
try, which was completed in
October 2005.
Dermot O'Hare studied at
Oxford University were he
was awarded a BA in 1982
and a DPhil in 1985. Following his DPhil he was awarded a
Royal Commission of 1851 Fellowship. After a year at CR&D
Dupont, he returned to Oxford
in 1987, being appointed to a
permanent University position
and fellowship at Balliol
College in 1990. In 1998 he
became a Professor. He has
won a number of awards,
including the Royal Society
of Chemistry Sir Edward
Frankland Fellowship, the
Exxon European Chemical
and Engineering Prize and the
RSC Corday Morgan Medal
and Prize. His scientific
interests are wide ranging,
including synthetic organo-
metallic chemistry, intercalation chemistry, in situ diffraction
studies and the synthesis of meso- and micro-porous solids.
Gareth Williams Dermot O'Hare
FEATURE ARTICLE www.rsc.org/materials | Journal of Materials Chemistry
This journal is ß The Royal Society of Chemistry 2006 J. Mater. Chem., 2006, 16, 3065­3074 | 3065
EDXRD method, and of the models generally used to describe
solid-state reaction processes, have been discussed in a recent
review.12
In this Feature Article, some highlights from recent research
into LDHs will be showcased, with particular reference to how
these data have afforded us an increased understanding of
LDH chemistry, and how this may be exploited and controlled
for advanced applications.
2. New synthetic methodologies
The exploration of new synthetic routes to produce novel
LDHs and to gain morphological control of the LDH particles
produced will be discussed in this section.
2.1 Forcing conditions
LDHs are generally synthesised via a coprecipitation route,
involving the combination of mixtures of metal salts with pH
control. In contrast, the family of LDHs [LiAl2(OH)6]X?yH2O
(LiAl2-X) is generally synthesised by the direct reaction of
concentrated solutions of Li salts with Al(OH)3. Use of the
gibbsite polymorph of Al(OH)3 yields an LDH in which the
layers are stacked in an aba sequence (the hexagonal form,
h-LiAl2-X). Use of the bayerite or nordstrandite polymorphs,
however, produces a rhombohedral form of the LDH
(r-LiAl2-X) with an abca layer stacking sequence.20­23
It will
be seen later that this difference in layer stacking sequences is
surprisingly important in the chemistry of the LiAl2-X systems.
It proved very difficult to intercalate cations other than Li
into Al(OH)3. However, Fogg et al. recently showed that
gibbsite may be activated by grinding in a ring or ball mill.
When the activated Al(OH)3 is treated hydrothermally with a
highly concentrated solution of a metal (M = Co, Ni, Cu and
Zn) nitrate (10 M), a new family of LDHs is produced.24
These
are structurally similar to the h-LiAl2-X LDHs, except that
only half the octahedral vacancies in the Al(OH)3 layers are
filled after reaction: the new materials have the unprecedented
composition [MAl4(OH)12](NO3)2?yH2O (MAl4-NO3). There
are ordered cation vacancies in the layers (Fig. 1). The ion
exchange chemistry of these materials has been thoroughly
investigated, and is found to be similar to, but distinct from,
that of the LiAl2-X systems.25,26
2.2 Morphological control
Modifying the traditional coprecipitation method of LDH
synthesis is of interest, since this method produces an
inhomogeneous distribution of particle sizes and shapes.
Reverse micelle/microemulsion systems have been used to
produce LDHs with novel particle morphologies.27,28
When a
surfactant such as sodium dodecyl sulfate (NaDDS) is
added to an organic solvent (e.g. isooctane), spherical reverse
micelles will form with the hydrophobic chains pointing
out into the solvent, and the hydrophilic heads clustered
together. The addition of water causes the reverse micelles
to swell, with water droplets trapped inside the polar core.
These can be utilised as `nanoreactors'. Hu and O'Hare27
discovered that by dispersing a solution of Mg nitrate,
Al nitrate, Na nitrate and NaOH into an isooctane/1-
butanol/NaDDS system led to the synthesis of Mg2Al
LDHs with a novel `nanoplatelet' morphology [Fig. 2(a)].
Modification of the synthesis by adding a triblock copolymer
[HO(C2H4O)n(C3H6O)m(C2H4O)nH] at different stages of the
reaction caused further changes in the morphology of the
particles produced. Addition of the polymer at the start of
the reaction led to structures with a belt-like morphology
[Fig. 2(b)], whereas adding it after heating for 24 h produced
rod-like structures [Fig. 2(c) and (d)].
From elemental microanalysis and EDX analysis, all three
different morphologies were found to have the approximate
formula [Mg2Al(OH)6](DDS)?yH2O. The X-ray diffraction
patterns were all consistent with the DDS anions being inter-
calated between the layers, giving an interlayer separation of
ca. 26 A° . The nanoplatelets consist of 3­4 monolayers stacked
together, and are approximately 200­500 A° in diamater. These
platelets stack together into larger blocks without a specific
morphology. The belt structures are a few hundred microns
along the long axis; the cross-sectional dimensions are
Fig. 1 The idealised structure of the MAl4-NO3 LDHs. M atoms are
shown in white and the interlayer N atoms in black. Reproduced with
permission from J. Mater. Chem. 2004, 14, 2369. E Royal Society of
Chemistry, 2004.
Fig. 2 (a) TEM image showing Mg2Al nanoplatelets; (b) SEM image
showing a belt-like structure; (c) SEM and (d) TEM images of the
rod-like structures. Reproduced with permission from J. Am. Chem.
Soc. 2005, 127, 17 808. E American Chemical Society, 2005.
3066 | J. Mater. Chem., 2006, 16, 3065­3074 This journal is ß The Royal Society of Chemistry 2006
ca. 10 6 3 mm. The LDH layers are stacked perpendicular to
the long axis. The rod-like structures are a few tens of microns
in length, and a few hundred nanometres perpendicular to the
long axis. The rods feature layers stacked along the long axis.
The belts in particular can be easily exfoliated.
The control of particle size and morphology is potentially
of high importance for the production of nanocomposites,
where one requires a stable, uniform dispersion of the
inorganic component in the polymer matrix.
Several authors have achieved this by intercalation of
macromolecules, and then exfoliation of the LDH. However,
this can be difficult owing to the strength of the interactions
between LDH layers.29,30
By modifying the ratios of the
reactants used in the reverse microemulsion synthesis, O'Hare
and co-workers have successfully synthesised LDH mono-
layers.31
These exist as particles of ca. 15 A° in height, and
diameters of approximately 400 A° (Fig. 3).
The monolayers have the formula [Mg2Al(OH)6](DDS)?
yH2O. This suggests that the particles observed by AFM
consist of single LDH layers coated in DDS anions to balance
the charge. The monolayers can easily form stable dispersions
in acrylate monomers. Hence, the development of homo-
genous LDH­polymer nanocomposites with improved pro-
perties should be possible.
Duan and co-workers adopted a different approach in their
attempt to control LDH particle sizes and morphologies.32­34
A colloidal mill (Fig. 4) was employed to synthesise LDHs
with separate nucleation and aging steps (SNAS). In the SNAS
method, the different metal salts are mixed very rapidly in the
mill (,2 min). The resultant slurry is subsequently aged. Thus,
all the particles begin to form at the same time, and the growth
time is the same for all particles. This is in contrast to standard
coprecipitation methods, in which the solutions of the two
metal salts are combined slowly: in this method the particles
precipitate out at different times, and hence a range of particle
sizes and morphologies are produced.
The SNAS method produces LDHs {e.g. [Mg2Al(OH)6]2-
CO3?yH2O} with high crystallinity, and a much narrower
range of particle sizes and shapes than those produced via a
traditional coprecipitation approach.
3. Understanding intercalation
In order that we can begin to control reactions, tailoring
the conditions to give desired outcomes, it is necessary to
understand the intimate processes involved in intercalation.
The EDXRD technique has been successfully employed to
gain these insights.
3.1 Kinetics and energetics
In favourable instances, intercalation reactions can be
monitored over a range of temperatures and accurately be
described using classical models for solid-state reaction
processes. This is often the case for reactions of LiAl2-X and
of the [Ca2Al(OH)6]NO3?yH2O LDH (Ca2Al-NO3). In con-
trast, [Mg2Al(OH)6]NO3?yH2O (Mg2Al-NO3) is found to react
very rapidly, which precludes the calculation of kinetic
parameters. In situ techniques have been applied to other
LDHs,35,36
but this can be difficult owing to poor crystallinity.
A number of bicyclic and tricyclic carboxylate intercalates
of LiAl2-Cl, Mg2Al-NO3 and Ca2Al-NO3 have recently
been synthesised by Khan and O'Hare,37
and the reaction
mechanisms were probed using in situ EDXRD. Examples of
the guests incorporated are given in Fig. 5. EDXRD data
from the intercalation of 1-AA into h-LiAl2-Cl are given in
Fig. 6. The reaction is seen to proceed directly from the host
(h-LiAl2-Cl) to the product (h-LiAl2-1-NAA). Extent of
reaction, a = (Intensity at time t)/(maximum intensity), for
any given reflection. The data are fitted with the Avrami
equation: a = 1 2 exp(2kt)n
, where k is the rate constant, t is
Fig. 3 AFM image of the LDH monolayers. Individual particles are
marked A­F. Reproduced with permission from Chem. Commun.,
2006, 287. E Royal Society of Chemistry, 2006.
Fig. 4 Schematic diagram of the colloidal mill used by Duan et al.
Fig. 5 Examples of some cyclic carboxylates which have been
intercalated: (a) 1-adamantane acetate (1-AA); (b) 5-norbornene-2-
carboxylate (5-NC); (c) 1,3-adamantane diacetate (1,3-ADA).
This journal is ß The Royal Society of Chemistry 2006 J. Mater. Chem., 2006, 16, 3065­3074 | 3067
time, and n is an exponent providing information on the
reaction mechanism.
By taking double logs of this equation, a plot of
ln[2ln(12 a)] vs. ln t can be generated. This is known as a
Sharp­Hancock plot, and a linear plot is taken to be the
benchmark test showing that the Avrami model is valid, over
the full course of the reaction.
The Sharp­Hancock plot allows calculation of the reaction
exponent, n (from the gradient), and the rate constant, k
(from the intercept). A plot of ln k vs. 1/T (Fig. 7) easily
allows the activation energy, Ea, to be determined, via the
Arrhenius relationship. In this case Ea is calculated to be
68.4  4.7 kJ mol21
.
The exponent gives information on the reaction mechanism.
In this case 1.5 ( n ( 2. This is suggestive that the reaction
mechanism is nucleation-controlled. The rate-determining step
of the reaction involves the expansion of the interlayer space
to accommodate the new guests. Similar calculations have
now been peformed for a wide range of LDH intercalation
reactions; a recent review has dicussed these in detail.12
The intercalation of a number of organic carboxylate (e.g.
1,4-benzenedicarboxylate) and sulfonate (e.g. 1,5-naphthala-
nedisulfonate) species into the novel MAl4-NO3 LDHs has
been investigated using EDXRD.25
It was discovered that in
all cases bar one the reaction proceeds directly from the host
to the product. The carboxylates were observed to react
very quickly, with the products being formed within a few
minutes at room temperature. The intercalation of maleate
into CuAl4-NO3 proceeded via a more hydrated intermediate;
once this had formed some water was subsequently extruded to
give the final product.
For MAl4-NO3 (M = Zn, Cu, Co), the intercalation of
sulfonates occurred much more slowly, taking ca. 30­60 min
to reach completion at 50 uC. In contrast, the reactions of
NiAl4-NO3 with the organic sulfonates occurred much more
rapidly, at similar rates to carboxylate intercalation.
Furthermore, the reaction mechanisms were found to be
very different. In the M = Zn, Cu and Co systems, nucleation
control is operational, and the rate-limiting step is the
expansion of the interlayer spaces to accommodate the new
guests. In the M = Ni case, the reaction is diffusion-controlled.
As soon as the guest species reach the host they can intercalate:
the reaction barrier being observed is that inhibiting movement
of guests through the solvent (water).
3.2 Divergent mechanisms
In a number of cases, intercalation reactions occur too rapidly
to be modelled using the Avrami equation. In such cases, one
may still follow the reaction in situ by adding a solution of the
guest dropwise to a suspension of the host. This limits the rate
of reaction to the rate of addition, and therefore no kinetic
parameters may be calculated. However, mechanistic informa-
tion may still be obtained. In fact, it turns out that a number of
these rapid reactions are interesting mechanistically.
The energy barrier to an intercalation reaction may be
reduced by a process known as staging. This is a phenomenon
in which some interlayer regions are completely vacant while
other regions are fully or partially occupied. The number of
layers between successively filled or partially filled layers
defines the order of staging. The traditional models describing
staging involve the layers having a degree of flexibility.38,39
LDHs have relatively rigid layers,40
and so staging is rare.
Drits et al.41
have reported a hydrotalcite-based mineral found
in a saline deposit in Soviet Central Asia that has interlayers
which alternately contain SO4
22
and CO3
22
.
Fogg et al. discovered that the intercalation of a variety of
carboxylic acids into h-LiAl2-Cl proceeds via a then-unprece-
dented second-stage intermediate. This features alternate
interlayer regions occupied by Cl2
and carboxylate anions
[seen later in Fig. 11(b)].42
Similar results have also been
observed for the intercalation of some phosphonate anions
into this LDH.43,44a
Data for the intercalation of methyl-
phosphonate (MPA) at pH 8 are shown in Fig. 8. Methyl-,
ethyl- and benzylphosphonate all intercalate via this two-stage
mechanism, whereas phenylphosphonate intercalates in a
direct, one-step mechanism. However, for the rhombohedral
analogue, r-LiAl2-Cl, a one-step mechanism is operational for
the intercalation of all four phosphonate anions.
Fig. 6 In situ EDXRD data for the intercalation of 1-NAA into
h-LiAl2-Cl: extent of reaction vs. time plots at 40 (&), 45 ($), 50 (m),
and 55 uC (.).
Fig. 7 Arrhenius plot for the intercalation of 1-AA into h-LiAl2-Cl.
3068 | J. Mater. Chem., 2006, 16, 3065­3074 This journal is ß The Royal Society of Chemistry 2006
Data for MPA are given in Fig. 9(a). Experiments were also
performed with other LiAl2-X materials (X = NO3 and Br). It
was observed that staging intermediates are never seen where
X = NO3 [Fig. 9(b) and (c)], but where X = Br, second-stage
intermediates are formed with certain organic anions [MPA,
fumarate and succinate in particular: Fig. 9(d)]. Therefore,
both the interlayer anion and the stacking sequence of the
layers play a profound role in determining the mechanism of
the reaction.44b
Generally speaking, staging intermediates are metastable
species, which makes them hard to isolate, even though
they can be observed by in situ experiments. A rare example
of a thermodynamically stable heterostructured material
resulting from the intercalation of 4-nitrophenolate (4-NP)
into h-LiAl2-Cl has been synthesised.45
This is structurally the
same as second-stage materials. Alternate interlayer spaces
are occupied by Cl and 4-NP, giving a phase with the com-
position [LiAl2(OH)6]2Cl(4-NP)?yH2O. However, second-stage
intercalates have only previously been seen to occur as
intermediates during intercalation reactions that happen very
rapidly at room temperature. In contrast, the 4-NP hetero-
structure is not seen as an intermediate during the ion
exchange of Cl by 4-NP. This material is only isolated when
h-LiAl2-Cl is reacted with a small excess of 4-NP in ethanol at
elevated temperatures (>70 uC).
In situ EDXRD studies have been performed to investigate
this material: it was found that the formation of a second-stage
product has a higher activation energy than the direct conver-
sion of h-LiAl2-Cl to the first-stage product, h-LiAl2-4-NP
(ca. 70 and 42 kJ mol21
respectively). This demonstrates
unequivocally that the 4-NP heterostructure is a thermo-
dynaically stable species, and that the alternating distibution
of interlayer anions might be more properly described as
interstratification rather than staging.
A recent collaboration between Leroux, Taviot-Gue`ho and
O'Hare has aimed to explore the chemistry of some second-
stage materials.46
It was previously noted by Pisson et al. that
second-stage intermediates are formed during the intercalation
of succinate and tartrate into Zn2Al-Cl, Zn2Cr-Cl and
Cu2Cr-Cl.35
After an in situ study, it proved possible to isolate
the second-stage materials using a quenching approach. The
chemistry of some second-stage intercalates of Zn2Cr-Cl
(Zn2Cr-Cl/succ. and Zn2Cr-Cl/tart.) was then investigated.
In situ EDXRD was used to monitor the reactions of these
systems with solutions of adipate and fluoride ions. A remark-
able segregation effect was observed. When Zn2Cr-Cl/succ. or
Zn2Cr-Cl/tart. were reacted with adipate, the adipate first
replaces the organic succinate (tartrate) anions, forming a new
second-stage intermediate, Zn2Cr-Cl/adip. Upon continued
addition of adipate, the Cl anions are replaced, and the
product retrieved from the reaction is the first-stage adipate
intercalate. This is shown in Fig. 10.
Experiments were also performed in which the second-stage
Zn2Cr-Cl/succ. and Zn2Cr-Cl/tart. materials were reacted
with a solution of F2
ions. It was seen that the F2
ions
initially replace the chloride anions in the interlayer space,
before replacing the organic species. These results are sum-
marized schematically in Fig. 11. A remarkable segregation
between the organic and inorganic ions is operational here.
A similar segregation phenomenon is observed for the 4-NP
heterostructure; reaction of this with stoichiometric amounts
of some carboxylates (e.g. phthalate) leads to the isolation of
the h-LiAl2-Cl/carboxylate second-stage intercalate.
4. LDHs for advanced applications
4.1 Bionanohybrids as storage and delivery matrices
Much of the interest in LDHs arises because of their potential
in industrial applications. One principal area that has been the
focus of intense research in recent years is the use of LDH host
matrices as storage and delivery devices for biologically
important species. A number of important bioactive species
are based on carboxylic acids, and hence are suitable for
intercalation into LDHs. Furthermore, the wide variety of
cations that can comprise an LDH mean that it is facile to
produce biocompatible materials.
Fig. 8 Time-resolved in situ EDXRD data showing the course of the
ion exchange reaction between h-LiAl2-Cl and MPA at pH 8: (a) 3D
stacked plot and (b) extent of reaction vs. time plot showing the
host 002 (&), intermediate 004 (m) and product 002 ($) reflections.
Reproduced with permission from Chem. Commun., 2003, 1816. E
Royal Society of Chemistry, 2003.
This journal is ß The Royal Society of Chemistry 2006 J. Mater. Chem., 2006, 16, 3065­3074 | 3069
A variety of drugs, including those in Fig. 12, have been
incorporated into LDHs.47­50
It is a long-term goal of
pharmaceutical scientists to develop so-called `controlled
release formulations' (CRFs). These are advantageous over
current methods of drug delivery: instead of taking doses of
the drug regularly at given time intervals, CRFs allow the
patient to take only one tablet far less frequently. Delivery of
the drug is slow and sustained, and an effective and non-toxic
concentration of the drug may be retained in the body over a
long period of time.
With traditional formulations, the drug concentration is in
the effective region for a relatively short period of time, either
side of which the concentration may be dangerously high or
ineffectively low.
O'Hare and co-workers investigated drug intercalates of the
h-LiAl2-Cl, Mg2Al-NO3 and Ca2Al-NO3 materials as CRFs
for release into the bowel.49,51
It was discovered that the host
used had a profound effect on the release profile. The release
of 4-biphenylacetic acid (4-Bip2
) at pH 7.5 is shown in Fig. 13,
and a summary of the release data for several drugs is given
in Table 1.
Fig. 9 EDXRD showing the intercalation of MPA into (a) r-LiAl2-Cl; (b) h-LiAl2-NO3; (c) r-LiAl2-NO3 and (d) h-LiAl2-Br. Reproduced with
permission from Chem. Mater., 2005, 17, 2632. E American Chemical Society, 2005.
Fig. 10 EDXRD showing the intercalation of adipate into Zn2Cr-Cl/
succ. The initial replacement of the succinate, followed by replacement
of the Cl anions by adipate may be clearly seen. AEC is a theoretical
anion exchange capacity. When AEC = 1, exactly enough of the new
guest has been added to replace the initial guest.
3070 | J. Mater. Chem., 2006, 16, 3065­3074 This journal is ß The Royal Society of Chemistry 2006
Release occurs very much faster for Mg2Al-4-Bip than for
the Ca-containing analogue. The effect of the host may also be
seen in Table 1.
Choosing the right combination of host and guest allows
the release time to be varied between 0.5 and 35 min. It is
important to note that it is difficult to determine trends; the
release data cannot be easily corellated to the charge density of
the layers or to the size of the drug molecule. A number of
competing factors are operational, and deconvoluting these is
non-facile. However, the data do suggest that by employing
the right combination of host and guest, release times in the
order of hours (which is the target for these systems to be
practically useful) could be attained.
Choy et al. have made very significant contributions to this
area. Mg2Al-NO3 was successfully employed to intercalate
folic acid and methotrexate (MTX), both commonly used to
treat cancer sufferers.50
An in vitro bioassay was used to
demonstrate that in the initial stages after administration
of the drug, Mg2Al-MTX has a significantly higher efficacy
Fig. 12 Some of the drug molecules which have been intercalated into LDHs: (a) 4-biphenylacetic acid; (b) Diclofenac; (c) Gemfibrozil;
(d) 2-propylpentanoic acid.
Fig. 13 Profiles for the release of 4-Bip2
from Ca2Al-4-Bip (&) and
Mg2Al-4-Bip ($) into simulated intestinal fluid (pH = 7.5).
Fig. 11 Schematic diagram illustrating the selective intercalation chemistry of the Zn2Cr-Cl/succ. material. (a) Zn2Cr-Cl/adip., synthesised
through reaction of Zn2Cr-Cl/succ. with adipate; (b) Zn2Cr-Cl/succ.; (c) Zn2Cr-Fl/succ., produced via the reaction of Zn2Cr-Cl/succ. with fluoride.
Table 1 Release data for selected drug ions at pH 7.5. The data given
are the time (min) taken for 90% of the intercalated drug to be released
Drug, X LiAl2-X Mg2Al-X Ca2Al-X
Diclofenac 4 22 6
Gemfibrozil 5 12 35
Ibuprofen 2.5 13 12
Tolefenamic acid 21 0.5 20
Naproxen 9 2.5 5.5
4-Biphenylacetic acid 2 2 15
This journal is ß The Royal Society of Chemistry 2006 J. Mater. Chem., 2006, 16, 3065­3074 | 3071
against tumor cells than MTX alone. This could be because the
LDH matrix allows MTX to pass through the cell membrane
more effectively, and also prevents decomposition of the drug
in the cell plasma. However, it is not clear exactly how this
could occur. The LDH is not simply acting as a delivery
matrix, but is also improving the efficiency of the drug. A
novel recent development is the synthesis of LDHs intercalated
with b-cyclodextrins.52
These bowl-like molecules can be used
to contain lipophilic drug molecules, thereby increasing the
stability, water solubility and bio-availability of these drugs.
Nucleotides and DNA have also been intercalated into
LDHs.53­56
Data from cellular uptake experiments show the
transfer efficiency of the bionanohybrids to be as much as
25-fold greater than that of the nucleotide alone. Further
experiments have shown that vitamins may also be intercalated
and discharged in a controlled fashion.57
In vivo studies
have determined that LDH particles have little systematic
effect at low doses, and thus are likely to be suitable as drug
delivery matrices.58
O'Hare and co-workers have studied the intercalation of a
number of agrochemicals, such as those in Fig. 14.59
Similarly
to the intercalation of drugs, modification of the host and
guest led to widely different release profiles. It was generally
observed that release occurs more slowly from the LiAl2-X
intercalates than from the Mg2Al-X and Ca2Al-X analogues.
Studies are ongoing to optimise the materials for industrial
applications.
4.2 Possibilities in separation science
Interestingly, LDHs have been shown to be highly effective for
separating mixtures of isomeric guest ions. For instance, Fogg
et al. observed that if h-LiAl2-Cl is reacted with an equimolar
mixture of 1,2- 1,3- and 1,4-benzenedicarboxylate (BDC),
1,4-BDC is intercalated with close to 100% selectivity, and
the other anions remain in solution.3
Analogous results were
obtained with a mixture of fumarate and maleate, where the
intercalate contained only fumarate. Additionally, Millange
et al. discovered that Ca2Al-NO3 can also effect the separation
of 1,2- and 1,4-BDC; only the 1,4-BDC anions are inter-
calated.1
In situ EDXRD was used to determine that the
selectivity is governed by thermodynamic factors. Initially,
all the guest isomers intercalate, and subsequently the less
favourable guest(s) are de-intercalated, and replaced by the
thermodynamically favoured species.
Further work has revealed that this selective property is very
general, and LDHs may be used to separate large numbers of
isomeric organic species, including naphthalenesulfonates,4
pyridinecarboxylates, and toluate isomers.5,6
A very recent
study considered all the possible isomers of a variety of
substituted benzoates (XC6H4COO2
, where X = F, Cl, Br,
OH, OMe, NO2, CO2Me, NH2, NMe2). Reactions were
performed with a range of isomeric mixtures, and it was noted
that generally the selectivity series is 4-isomer > 3-isomer >
2-isomer. Molecular modelling was used to determine the
dipole moments of each of the guests; the 4-isomer has the
greatest dipole moment and the 2-isomer the smallest. It is
postulated that the greater the difference in the dipole
moments of the isomeric guests, the higher the selectivity for
the isomer with the greatest dipole moment.60
A greater dipole
moment is likely to lead to stronger electrostatic interactions
between the host and guest.
The new LDHs MAl4-NO3 have been investigated for their
selective properties.26
All four materials show broadly similar
selectivity trends to the related LiAl2-Cl system. 1,4-BDC is
intercalated with almost 100% selectivity over the 1,2- isomer.
Similarly, 2-naphthalenesulfonate (NS) is intercalated almost
exclusively over 1-NS. Reactions were investigated over a
range of temperatures (rt to 100 uC) using several solvent
systems (water, water/acetone and water/THF), which were
shown to cause subtle changes to the selectivity. More
interestingly, the competitive intercalation of 1,5 and
2,6-naphthalenedisulfonate (NDS) was found to be highly
sensitive to the temperature and solvent used for reaction. For
the ZnAl4-NO3 system, in water at room temperature the
intercalate contains ca. 55% 2,6-NDS. However, when the
reaction is performed at 100 uC, the selectivity for 2,6-NDS is
only 27% (Fig. 15). Using a water­acetone mixture (1 : 1) at
100 uC reduces the amount of 2,6-NDS incorporated even
further to 7%. Similar results have been seen for LiAl2-Cl,
Mg2Al-NO3 and Ca2Al-NO3.61
These separations are facile to perform, and the LDHs used
are easy and cheap to make. This approach to separation
Fig. 14 Some of the agrochemicals that have been intercalated:
(a) 1-naphthaleneacetic acid; (b) 3-indoleacetic acid; (c) 2-methyl-4-
chlorophenoxyacetic acid
Fig. 15 Percentage of each guest intercalated in the competition
reaction between 1,5- (&) and 2,6-NDS (#) in water for ZnAl4-NO3.
Reproduced with permission from J. Mater. Chem., 2006, 16, 1231. E
Royal Society of Chemistry, 2006.
3072 | J. Mater. Chem., 2006, 16, 3065­3074 This journal is ß The Royal Society of Chemistry 2006
should be amenable to large-scale application, and is therefore
very attractive to industry. It should be emphasised that the
high degree of separation of the isomers achievable is of great
industrial importance. For instance, the 1,4-isomer of benze-
nedicarboxylate is the monomer used for polyester synthesis.
Benzenedicarboxylates are produced from the oxidation of
xylenes derived from crude oil. These xylenes are produced in
mixtures. The separation of the useful 1,4-isomer from other
species is therefore vital. At the present time, this is normally
achieved by selective crystallisation or adsorption of the xylene
isomers. However, these methods are relatively ineffective.
Naphthalenesulfonates are important organic synthons. They
are produced in a similar way to the benzenedicarboxylates,
and their separation is also very difficult to achieve using
conventional methods.
Another important class of raw materials for industry
which are commonly synthesised as mixtures are nitrophenols
(NPs). These are used in the manufacture of pharmaceuticals,
dyestuffs and agrochemicals, among other applications. It has
recently been demonstrated that h-LiAl2-Cl may be used to
selectively remove 4-nitrophenolate from a mixture of the 2-,
3- and 4-isomers.62
Studies were also performed into the
feasibility of using this system to separate mixtures of 4-NP
and 2,4-dinitrophenolate. The solvent and host LDH used had
a significant effect on the selectivity observed.
4.3 Improved polymers
The desirability of producing LDHs with small, regularly sized
particles was stressed in Section 2.2. It has been found that
LDHs synthesised using the SNAS process are more effective
additives for polymers than those synthesised commercially.
For instance, in Asia, low density polyethylene is frequently
used in the manufacture of greenhouses. Duan and co-workers
have performed field trials using polymers with different
additives: the mineral talc, a commerically available LDH, and
an LDH prepared using the SNAS method. It was found that
both the daily maximum and minimum temperatures are
significantly higher in greenhouses made using the SNAS LDH
than the other polymers.63,64
Very recent results from the laboratory of O'Hare have
shown that using the LDH monolayers synthesised via a
reverse microemulsion approach as polymer additives confers
much improved properties on the resulting polymers.65
Conclusions
It has been shown that by systematic modification of the
synthesis strategy, LDHs with novel stoichiometries and
particle morphologies and sizes may be formed. This latter
development is of profound importance for the generation of
polymers with improved physicochemical properties. It has
frequently been proven that the composition of the LDH
layers alters the chemistry of the materials, and hence a new
family of LDHs is also of immense importance. The use of
X-ray diffraction to study the intercalation reactions of LDHs
in situ, in real time, has produced some significant insights
into the reaction mechanisms. In general, the reactions proceed
directly from the host to the product, and the rate-limiting step
is the expansion of the interlayer space to accommodate the
new guests. In a few cases where the reaction proceeds
very rapidly at room temperature, however, the reaction
proceeds via an unusual second-stage intermediate. The
stacking sequence of the layers and the initial interlayer anion
are seen to have a profound effect on the mechanism of
intercalation into LiAl2-X systems. The second-stage materials
are of interest for the preparation of multifunctional materials.
Finally, the potential to use LDHs in pharmaceutical and
agrochemical applications, as well as in separation science and
as polymer additives, has been demonstrated.
Acknowledgements
The authors thank the EPSRC for funding, and the CCLRC
for access to Station 16.4 of the UK SRS.
References
1 F. Millange, R. I. Walton, L. X. Lei and D. O'Hare, Chem. Mater.,
2000, 12, 1990.
2 R. Allmann, Chemica, 1970, 24, 99.
3 A. M. Fogg, J. S. Dunn, S. G. Shyu, D. R. Cary and D. O'Hare,
Chem. Mater., 1998, 10, 351.
4 A. M. Fogg, V. M. Green, H. G. Harvey and D. O'Hare, Adv.
Mater., 1999, 11, 1466.
5 L. Lei, F. Millange, R. I. Walton and D. O'Hare, J. Mater. Chem.,
2000, 10, 1881.
6 L. Lei, R. P. Vijayan and D. O'Hare, J. Mater. Chem., 2001, 11,
3276.
7 F. Cavini, E. Trifiro and A. Vaccari, Catal. Today, 1991, 11, 173.
8 M. Chibwe, J. B. Valim and W. Jones, NATO ASI Ser., Ser. C,
1993, 400, 191.
9 A. I. Khan and D. O'Hare, J. Mater. Chem., 2002, 12, 3191.
10 V. Rives, Layered Double Hydroxides: Present and Future, Nova
Science Publishers, Inc., New York, 2001.
11 P. S. Braterman and Z. P. Xu, in Handbook of Layered Materials,
ed. S. M. Auerbach, K. A. Carrado and P. K. Dutta, Marcel
Dekker, New York, 2004, ch. 8.
12 Mechanistic and Kinetic Studies of Guest Ion Intercalation into
Layered Double Hydroxides Using Time-resolved, In-situ X-Ray
Powder Diffraction, G. R. Williams, A. I. Khan and D. O'Hare, in
Structure and Bonding, Vol. 119, Layered Double Hydroxides,
ed. X. Duan and D. G. Evans, Springer, Berlin/Heidelberg, 2006,
pp. 161­192.
13 F. Rey, G. Sankar, J. M. Thomas, P. A. Barrett, D. W. Lewis,
C. R. A. Catlow, S. M. Clark and G. N. Greaves, Chem. Mater.,
1995, 7, 1435.
14 F. Rey, G. Sankar, J. M. Thomas, P. A. Barrett, D. W. Lewis,
C. R. A. Catlow and G. N. Greaves, Chem. Mater., 1996, 8, 590.
15 A. T. Davies, G. Sankar, C. R. A. Catlow and S. M. Clark, J. Phys.
Chem. B, 1997, 101, 10 115.
16 R. I. Walton, T. Loiseau, D. O'Hare and G. Ferey, Chem. Mater.,
1999, 11, 3201.
17 A. J. Norquist and D. O'Hare, J. Am. Chem. Soc., 2004, 126, 6673.
18 R. I. Walton, A. J. Norquist, S. Neeraj, S. Natarajan, C. N. R. Rao
and D. O'Hare, Chem. Commun., 2001, 1990.
19 S. J. Price, J. S. O. Evans, R. J. Francis and D. O'Hare, Adv.
Mater., 1996, 8, 582.
20 A. M. Fogg, A. J. Freij and G. M. Parkinson, Chem. Mater., 2002,
14, 232.
21 A. M. Fogg and D. O'Hare, Chem. Mater., 1999, 11, 1771.
22 K. R. Poppelmeier and S.-J. Hwu, Inorg. Chem., 1987, 26, 3297.
23 G. R. Williams and D. O'Hare, J. Phys. Chem. B, 2006, 110, 10619.
24 A. M. Fogg, G. R. Williams, R. Chester and D. O'Hare, J. Mater.
Chem., 2004, 14, 2369.
25 G. R. Williams, T. G. Dunbar, A. J. Beer, A. M. Fogg and
D. O'Hare, J. Mater. Chem., 2006, 16, 1222­1230.
26 G. R. Williams, T. G. Dunbar, A. J. Beer, A. M. Fogg and
D. O'Hare, J. Mater. Chem., 2006, 16, 1231­1237.
27 G. Hu and D. O'Hare, J. Am. Chem. Soc., 2005, 127, 17 808.
This journal is ß The Royal Society of Chemistry 2006 J. Mater. Chem., 2006, 16, 3065­3074 | 3073
28 J. He, B. Li, D. G. Evans and X. Duan, Colloids Surf., A, 2004,
252, 191.
29 F. Leroux and J.-P. Besse, Chem. Mater., 2001, 13, 3507.
30 In-situ Polymerization and Intercalation of Polymers in Layered
Double Hydroxides, F. Leroux and C. Taviot-Gueho, in Structure
and Bonding, Vol. 119, Layered Double Hydroxides, ed. X. Duan
and D. G. Evans, Springer, Berlin/Heidelberg, 2006, pp. 121­160.
31 G. Hu, N. Wang, D. O'Hare and J. Davis, Chem. Commun., 2006,
287.
32 Y. Zhao, F. Li, R. Zhang, D. G. Evans and X. Duan, Chem.
Mater., 2002, 14, 4286.
33 S. Guo, D. Li, W. Zhang, M. Pu, D. G. Evans and X. Duan,
J. Solid State Chem., 2004, 177, 4597.
34 F. Li, X. Jiang, D. G. Evans and X. Duan, J. Porous Mater., 2005,
12, 55.
35 J. Pisson, C. Taviot-Gueho, Y. Israeli, F. Leroux, P. Munsch,
J. P. Itie, V. Briois, N. Morel-Desrosiers and J. P. Besse, J. Phys.
Chem. B, 2003, 107, 9243.
36 C. Taviot-Gueho, F. Leroux, C. Payen and J. P. Besse, Appl. Clay
Sci., 2005, 28, 111.
37 A. I. Khan and D. O'Hare, J. Solid State Chem., 2006, in
preparation.
38 A. Herold, in Intercalated Layered Materials, ed. F. Lévy,
D. Reidel, Dordrecht, Holland, 1979, vol. 6, p. 321.
39 N. Daumas and A. Herold, C. R. Acad. Sci., Paris C, 1969, 268,
373.
40 S. A. Solin, Annu. Rev. Mater. Sci, 1997, 27, 89.
41 V. A. Drits, T. N. Sokolova, G. V. Sokolova and V. I. Cherkashin,
Clays Clay Miner., 1987, 35, 401.
42 A. M. Fogg, J. S. Dunn and D. O'Hare, Chem. Mater., 1998, 10, 356.
43 G. R. Williams, A. J. Norquist and D. O'Hare, Chem. Commun.,
2003, 1816.
44 (a) G. R. Williams, A. J. Norquist and D. O'Hare, Chem. Mater.,
2004, 16, 975; (b) G. R. Williams and D. O'Hare, Chem. Mater.,
2005, 17, 2632.
45 A. Ragavan and D. O'Hare, J. Mater. Chem., 2006, submitted.
46 Y. Feng, G. R. Williams, F. Leroux, C. Taviot-Gueho and
D. O'Hare, Chem. Mater., 2006, submitted.
47 P. A. Bianconi, Adv. Chem. Ser., 1995, 245, 509.
48 J. Portier, G. Campet, N. Treuil, A. Poquet, Y.-I. Kim, S.-J. Kwon,
S.-Y. Kwak and J.-H. Choy, J. Korean Chem. Soc., 1998, 42, 487.
49 A. I. Khan, A. J. Norquist and D. O'Hare, Chem. Commun., 2001,
2342.
50 J. H. Choy, J. Jung, S. J. M. Oh, M. Park, J. Jeong, Y. K. Kang
and O. J. Han, Biomaterials, 2004, 25, 3059.
51 A. I. Khan and D. O'Hare, J. Mater. Chem., 2006, in preparation.
52 J. H. Choy, E. Y. Jung, Y. H. Son and M. Park, J. Phys. Chem.
Solids, 2004, 65, 509.
53 J. H. Choy, S. Y. Kwak, J. S. Park and Y. J. Jeong, J. Mater.
Chem., 2001, 11, 1671.
54 J. H. Choy, S. Y. Kwak, Y. J. Jeong and J. S. Park, Angew. Chem.,
Int. Ed., 2000, 39, 4042.
55 J. H. Choy, S. Y. Kwak, J. S. Park, Y. J. Jeong and J. Portier,
J. Am. Chem. Soc., 1999, 121, 1399.
56 J. H. Choy, J. S. Park, S. Y. Kwak, Y. J. Jeong and Y. S. Han,
Mol. Cryst. Liq. Cryst. Sci. Technol., Sect. A, 2000, 341, 425.
57 J. H. Choy and Y. H. Son, Bull. Korean Chem. Soc., 2004, 25, 122.
58 S. Y. Kwak, W. M. Kriven, M. A. Wallig and J. H. Choy,
Biomaterials, 2004, 25, 5995.
59 A. Ragavan, A. I. Khan and D. O'Hare, J. Phys. Chem. Solids,
2006, 67, 983.
60 L. Lei, A. I. Khan and D. O'Hare, J. Solid State Chem., 2005, 178,
3648.
61 A. I. Khan and D. O'Hare, Chem. Mater., 2006, in preparation.
62 A. Ragavan and D. O'Hare, J. Mater. Chem., 2006, 16, 602.
63 D. G. Evans and X. Duan, Chem. Commun., 2006, 485.
64 G. Xu, C. Guo, X. Duan and C. Jiang, Chin. J. Appl. Chem., 1999,
16, 45.
65 G. Hu and D. O'Hare, 2006, in preparation.
3074 | J. Mater. Chem., 2006, 16, 3065­3074 This journal is ß The Royal Society of Chemistry 2006