Synthetically accessible, tunable, low-molecular-weight oligopeptide organogelators

Article abstract of DOI:10.1039/c0cc01449d

We report a synthetically simple approach to effective and tunable low molecular weight gelators based on amine-initiated oligomerisation of an amino acid N-carboxyanhydride.

Full text of DOI:10.1039/c0cc01449d

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Synthetically accessible, tunable, low-molecular-weight oligopeptide
organogelatorswz
Cecile Lagadec and David K. Smith*
Received 17th May 2010, Accepted 31st July 2010
DOI: 10.1039/c0cc01449d
We report a synthetically simple approach to effective and
tunable low molecular weight gelators based on amine-initiated
oligomerisation of an amino acid N-carboxyanhydride.
To demonstrate this approach we used Ne-(benzyloxycarbonyl)-
L-lysine N-carboxyanhydride ( NCA), as we have previously
shown that well-defined peptides constructed from Z-protected
lysine can form effective gels.12 Compound NCA was synthesised
in 84% yield via cyclisation of Ne-(benzyloxycarbonyl)-L-lysine
with triphosgene under argon in anhydrous THF (see ESIw).13
We then explored the reaction of NCA using a range of
amines which can initiate ring opening oligomerisation
of a peptide chain (Scheme 1). A 1 : 6 initiator : NCA ratio
was employed to target relatively short peptide oligomers.
Initiators 1–6 (Scheme 1, for other initiators see ESIw)
were investigated using a parallel reaction station, with
the crude products being dissolved in a minimum of DMF
and the desired oligomers precipitated by the addition of
diethyl ether.
Self-assembling nanostructured gels, in which non-covalent
interactions between molecular building blocks assemble a
nanoscale ‘solid-like network’ suspended within a ‘liquid-like’
solvent phase, are of intense interest.1 The components used to
assemble such materials can either be small molecules or
polymers. However, there has been relatively little overlap
between researchers in these distinct areas.2 Peptides are
capable of mutually complementary hydrogen bond interactions,
and there has therefore been considerable interest in using
peptides to assemble gels.3 The diversity of amino acid side
chains, combined with their biocompatibility, opens a variety
of applications.4 Low molecular weight peptides, often
incorporating hydrophobic amino acids, have been widely
employed, as organogelators.5 The peptides aggregate through
hydrogen bonding whilst the apolar groups maintain the
solubility in the organic solvent and avoid precipitation.
Polymeric peptides have also been assembled into physical
organogels. For example, poly(g-benzyl-L-glutamate) forms
organogels in toluene due to aggregation between polypeptide
helices.6 Polypeptides have been incorporated into block
co-polymers which can form gels at low loadings.7 Amino
acids have also been attached to polymers, either as side
chains, or on the termini, in order to provide the polymers
with greater propensity to self-assemble into gels.8 For some
time, we have investigated gelators which are intermediate
between low and high molecular weight, working extensively
with dendritic peptides,9 and gaining a good understanding of
their assembly.10 However, dendrimers are relatively complex
and require multi-step syntheses. We therefore became interested
in developing alternative approaches to gelator structures of
intermediate size. The preliminary results are reported here.
We decided to apply ring opening oligomerisation using an
amino acid N-carboxyanhydride to yield relatively small
oligopeptides.11 Clearly, the products will not be as well-
defined as traditional low molecular weight gelators, but the
ease of synthesis is highly attractive. We were interested to
know whether the polydisperse crude products from this type
of reaction could still support gelation.
Electrospray mass spectrometry (ESMS) showed that, in
most cases, the crude solid products formed from initiators
1–6 had succeeded in growing an oligolysine chain to give the
desired I–Lysn. Typically, between two and six lysine units
were attached to the initiator (Table 1). However, the products
obtained in some cases also had ESMS peaks for unattached
oligo-lysine ( Lysn, Fig. S1, ESIw)—oligomerisation was
initiated with adventitious water, possibly because these
initiators were difficult to dry fully. Two initiators ( 1 and 4)
did not produce any unattached oligo-lysine, but initiator 6
mainly gave Lysn, with a smaller amount of I–Lysn.y
The gelation of the crude oligopeptide products was then
studied in a range of solvents. Pleasingly, most compounds
formed gels in 1,2-dichlorobenzene (DCB, Table 2). The
exception to this was 6-Lys—interestingly, the product which
was primarily unattached Lysn—suggesting that this peptide
does not assemble into effective gels, and may even suppress
gelation. Only 1–Lys formed gels in toluene (TOL), and only
3–Lys gelated trichloroethylene (TCE), with 1–Lys forming a
viscous liquid in TCE. This demonstrates that the choice of
initiator directly impacts on gelation ability.
Considering the solvent Kamlet–Taft parameters
(Table 2),14 gelation only occurred if the a parameter was
zero, i.e., hydrogen bond donor solvents such as acetonitrile
(ACN) and nitromethane (NM) disrupt gelation. Of those
solvents with an a parameter equal to zero, only DCB and to
some extent TCE and TOL supported gelation, whereas
decane (DEC) and mesitylene (MES) did not. It is likely that
gelation occurred best in DCB because it has quite high p*
(polarisability) and b (hydrogen bond acceptor) values—
which are required in order to solubilise the moderately
polar oligopeptide. If the p* and b values are too low
(e.g. DEC and MES), then the oligopeptides will not
dissolve, hence preventing gelation from taking place.
We reason that TCE and TOL are somewhat intermediate
Department of Chemistry, University of York, Heslington, York,
YO10 5DD, UK. E-mail: dks3@york.ac.uk
w Electronic supplementary information (ESI) available: Experimental
and assay procedures, sample mass spectra, SEM images and full MS
characterisation data. See DOI: 10.1039/c0cc01449d
z This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
c
340 Chem. Commun., 2011, 47, 340–342
This journal is The Royal Society of Chemistry 2011

View Article Online
Scheme 1 Amine-initiated oligomerisation of Z-protected lysine N-carboxyanhydride. Initiators 1–6 were tested in this reaction.
Table 1 Mass spectrometric peak intensities associated with different
oligomeric products from the parallel synthesis (normalised to the
largest peak in each case)
very impressive gelation at such low loading and compares
very favourably to other gels. Typically, peptide organogels3,5,9,10
have MGC values of 40.2 wt/vol% at room temperature—
often significantly more. Importantly, this clearly demonstrates
that the polydisperse nature of compound 1–Lys does not
inhibit its ability to act as an effective organogelator.
Compounds 2–Lys and 3–Lys were also investigated (Fig. 1).
These gelators also had low MGC values—the MGC of 3–Lys
was ca. 0.15 wt/vol%, whereas 2–Lys was less effective
(0.65 wt/vol%). However, these gelators had lower Tgel values
than 1–Lys. Gelator 3–Lys had a higher Tgel value (ca. 40 1C)
than 2–Lys (ca. 35 1C). It is possible that 2–Lys is less effective
due to structural features of the initiator, although this may be
a consequence of 2–Lys containing more unattached Lysn,
which is not an effective gelator—and may even inhibit the
gelation process somewhat. Interestingly, 4–Lys (see below)
also gave less thermally stable gels than 1–Lys, even though
it contains no Lysn. This demonstrates that the chemical structure
of the initiator plays an active role in controlling the thermal
properties of the gel. It is possible that the apolarity of initiator 1
enhances gel stability, for example through van der Waals
interactions or solubility modification.12
1 (%)
2 (%)
3 (%)
4 (%)
5 (%)
6 (%)
Lys4
Lys5
Lys6
Lys7
—
39
39
18
6
—
—
18
—
—
—
—
—
—
16
16
11
3
88
100
55
24
6
9
9
4
2
—
—
—
—
100
94
53
56
22
12
44
—
—
—
—
100
60
20
5
Lys8
—
I–Lys2
I–Lys3
I–Lys4
I–Lys5
I–Lys6
I–Lys7
I–Lys8
100
73
40
3
3
—
—
67
58
100
56
22
11
6
100
33
33
42
—
—
—
—
2
—
—
Table 2 Gelation ability (10 mg in 0.5 mL) of the different crude
products in a range of solvents and Kamlet–Taft parameters (a, b and
p*) for these solvents. Ins = insoluble/precipitate; V = viscous fluid;
G = gel
Sola
a
b
p*
1–Lys 2–Lys 3–Lys 4–Lys 5–Lys 6–Lys
DEC 0.00 0.00 0.30 Ins
MES 0.00 0.13 0.41 Ins
TOL 0.00 0.11 0.49 G
TCE 0.00 0.50 0.53 V
DCB 0.00 0.30 0.80 G
ACN 0.19 0.40 0.75 Ins
NM 0.22 0.06 0.85 Ins
Ins
Ins
Ins
Ins
G
Ins
Ins
Ins
G
G
Ins
Ins
Ins
Ins
Ins
Ins
G
Ins
Ins
Ins
Ins
G
Ins
Ins
Ins
Ins
V
Ins
Ins
Ins
Ins
Ins
Ins
Ins
Ins
a
DEC (decane); MES (mesitylene); TCE (trichloroethylene); TOL
(toluene); DCB (1,2-dichlorobenzene); CAN (acetonitrile); NM
(nitromethane).
in terms of their p* and b values and therefore only support
gels for some of the molecular frameworks.
We investigated 1–Lys in more detail and monitored the
gelation ability of this compound as a function of concentration,
using a vial inversion method to record Tgel values (Fig. 1).
The Tgel value rose to 4120 1C at approximately 3 mg mLꢀ1
(0.3 wt/vol%) in DCB. The minimum gelation concentration
(MGC) at room temperature was ca. 0.15 wt/vol%. This is
Fig. 1 Thermal behaviour of gels formed from 1–Lys, 2–Lys and
3–Lys in 1,2-dichlorobenzene as solvent.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 340–342 341

View Article Online
Notes and references
y MS peak height does not necessarily correlate directly with product
composition. However, for comparison of structurally related
compounds it provides useful insight into product composition. For
diamines, it is hard to say whether the growth of the oligomer occurs
on both amines simultaneously or only on one.
1 Molecular Gels: Materials with Self-Assembled Fibrillar
Networks, ed. P. Terech and R. G. Weiss, Springer, Dordrecht,
2006.
2 M. Suzuki and K. Hanabusa, Chem. Soc. Rev., 2010, 39,
455–463.
3 F. Fages, F. Vogtle and M. Zinic, Top. Curr. Chem., 2005, 256,
¨
77–131.
4 A. R. Hirst, B. Escuder, J. F. Miravet and D. K. Smith,
Angew. Chem., Int. Ed., 2008, 47, 8002–8018.
5 For selected examples: (a) J.-H. Fuhrhop, D. Spiroski and
C. Boettcher, J. Am. Chem. Soc., 1993, 115, 1600–1601;
(b) K. Hanabusa, R. Tanaka, M. Suzuki, M. Kimura and
H. Shirai, Adv. Mater., 1997, 9, 1095–1097; (c) S. Bhattacharya
and S. N. G. Acharya, Chem. Mater., 1999, 11, 3121–3132;
Fig. 2 Thermal behaviour of gels formed from 4–Lys-A and 4–Lys-B
in 1,2-dichlorobenzene as solvent.
The influence of oligomerisation was studied in more detail
using initiator 4 with different 4 : NCA molar ratios—1 : 2,
1 : 4 and 1 : 10. The 1 : 2 ratio led to a product which could
not be precipitated—it was assumed that any oligomers
obtained were too short. The other reactions produced solid
products. ESMS indicated that the compound formed from
the 1 : 4 ratio reaction ( 4–Lys-A) had 2 or 3 lysines linked to
the initiator, with the major peak being for 2 lysines and with
no Lysn being observed (Fig. S3, ESIw). On the other hand, the
crude product from the 1 : 10 reaction ( 4–Lys-B) exhibited
ESMS peaks for longer oligomers having 2–5 lysine units
attached to the initiator, with the major peaks for 3 and 4
lysine repeat units—however, some peaks were also observed
for Lysn (Fig. S4, ESIw). Clearly, when larger amounts of
NCA were used, the oligomer chain length increases, but so
does the chance of oligomerisation initiated by adventitious
water. Compound 4–Lys-A formed moderately stable gels
with a maximum Tgel value around 35 1C (Fig. 2). Compound
4–Lys-B had a lower thermal stability (o25 1C). Clearly, the
presence of longer oligomers does not benefit gel stability—
indeed, relatively short oligo-lysines attached to the initiator
appear sufficient to enable efficient self-assembly and avoid the
formation of Lysn. Scanning electron microscopy (SEM)
performed on the xerogels indicated that although both these
gels had a fibrillar nature (Fig. S5 and S6, ESIw), similar to
related low molecular weight well-defined peptide gels,10
4–Lys-A had a more nanostructured appearance.
(d) B. Escuder, S. Martı and J. F. Miravet, Langmuir, 2005, 21,
´
6776–6787; (e) A. Friggeri, C. van der Pol, K. J. C. van Bommel,
A. Heeres, M. C. A. Stuart, B. L. Feringa and J. van Esch,
Chem.–Eur. J., 2005, 11, 5353–5361; (f) I. A. Coates, A. R. Hirst
and D. K. Smith, J. Org. Chem., 2007, 72, 3937–3940;
(g) H.-F. Chow, J. Zhang, C.-M. Lo, S.-Y. Cheung and
K.-W. Wong, Tetrahedron, 2007, 63, 363–373; (h) D. Bardelang,
M. B. Zaman, I. L. Moudrakovski, S. Pawsey, J. C. Margeson,
D. Wang, X. Wu, J. A. Ripmeester, C. I. Ratcliffe and K. Yu, Adv.
Mater., 2008, 20, 4517–4520; (i) A. Banerjee, G. Palui and
A. Banerjee, Soft Matter, 2008, 4, 1430–1437; (j) V. Lozano,
R. Hernandez, C. Mijangos and M. J. Perez-Perez, Org. Biomol.
Chem., 2009, 7, 364–369.
6 (a) T. Korenaga, H. Oikawa and H. Nakanishi, J. Macromol. Sci.
Phys., 1997, 36, 487–501; (b) R. Tadmor, R. L. Khalfin and
Y. Cohen, Langmuir, 2002, 18, 7146–7150.
7 (a) K. T. Kim, C. Park, G. W. M. van der Meulen, D. A. Rider,
C. Kim, M. A. Winnik and I. Manners, Angew. Chem., Int. Ed.,
2005, 44, 7964–7968; (b) M. I. Gibson and N. R. Cameron,
Angew. Chem., Int. Ed., 2008, 47, 5160–5162.
8 (a) H. Ihara, M. Takafuji, T. Sakurai, M. Katsumoto,
N. Oshijima, T. Shirosaki and H. Hachisoko, Org. Biomol. Chem.,
2003, 1, 3004–3006; (b) S. Okabe, K. Ando, K. Hanabusa and
M. Shibayama, J. Polym. Sci., Part B: Polym. Phys., 2004, 42,
1841–1848; (c) M. Suzuki, C. Setoguchi, H. Shirai and
K. Hanabusa, Chem.–Eur. J., 2007, 13, 8193–8200;
(d) J. Hentschel and H. G. Borner, J. Am. Chem. Soc., 2006,
128, 14142–14149.
9 D. K. Smith, Adv. Mater., 2006, 18, 2773–2778.
10 (a) B. Huang, A. R. Hirst, D. K. Smith, V. Castelletto and
I. W. Hamley, J. Am. Chem. Soc., 2005, 127, 7130–7139;
(b) A. R. Hirst, V. Castelletto, I. W. Hamley and D. K. Smith,
Chem.–Eur. J., 2007, 13, 2180–2188; (c) A. R. Hirst, D. K. Smith
and J. P. Harrington, Chem.–Eur. J., 2005, 11, 6552–6559;
(d) A. R. Hirst and D. K. Smith, Org. Biomol. Chem., 2004, 2,
2965–2971.
11 (a) J. Rodriguez-Hernandez, M. Gatti and H.-A. Klok,
Biomacromolecules, 2003, 4, 249–258; (b) I. Dimitrov and
H. Schlaad, Chem. Commun., 2003, 2944–2945; (c) T. Aliferis,
H. Iatrou and N. Hadjichristidis, Biomacromolecules, 2004, 5,
1653–1656.
12 A. R. Hirst, I. A. Coates, T. R. Boucheteau, J. F. Miravet,
B. Escuder, V. Castelletto, I. W. Hamley and D. K. Smith,
J. Am. Chem. Soc., 2008, 130, 9113–9121.
13 R. Wilder and S. Mobashery, J. Org. Chem., 1992, 57,
2755–2756.
This communication demonstrates that oligomerisation of
amino acid NCA derivatives is a simple approach to
generating oligomers, which even in crude form, can be
excellent organogelators. In this case, the use of initiator 1 is
optimal. Structurally perfect small molecules are not,
therefore, a necessary pre-requisite for gelation. Features such
as choice of initiator, and length of oligomer control gel
behaviour, making these materials highly tunable. Future
work will focus on high-throughput screening of further
oligopeptides, minimising water-initiated oligomers, and
exploiting potential applications. For example, we anticipate
that modifying the amino acid, will give rise to a versatile class
of synthetically simple nanomaterials.
14 (a) M. J. Kamlet, J. L. M. Abboud, M. H. Abraham and
R. W. Taft, J. Org. Chem., 1983, 48, 2877–2887; (b) C. Laurence,
P. Nicolet, M. T. Dalati, J. L. M. Abboud and R. Notario, J. Phys.
Chem., 1994, 98, 5807–5816.
We acknowledge EPSRC and Givaudan for funding.
c
342 Chem. Commun., 2011, 47, 340–342
This journal is The Royal Society of Chemistry 2011