2292 Chem. Commun., 2012, 48, 2292–2294 This journal is c The Royal Society of Chemistry 2012

Cite this: Chem. Commun., 2012, 48, 2292–2294

Mirror symmetry breaking and chiral amplification in foldamer-based

supramolecular helical aggregatesw

Simon Azeroual,aJamie Surprenant,

aThomas D. Lazzara,

aMarta Kocun,

aYe Tao,

a

Louis A. Cuccia*ab

and Jean-Marie Lehn*b

Received 8th October 2011, Accepted 5th January 2012

DOI: 10.1039/c2cc16266k

Spontaneous asymmetric generation of supramolecular chiral

fibers was observed in the folding induced self-assembly of a

lock-washer shaped foldamer. A secondary nucleation growth

mechanism is proposed to explain the observed chiral amplification

or deracemization of these supramolecular fibers.

There are numerous examples of achiral or dynamically

racemic molecules that generate chirality in one-, two-, or three-

dimensional crystals, polymers, liquid crystal or supramolecular

assemblies.1–4 Such systems are particularly attractive for

investigating asymmetric induction (i.e. mirror symmetry

breaking) and chiral amplification.5 These conglomerate forming

systems typically yield a stochastic mixture of left- and right-

handed entities. Ideal examples are achiral molecules that

crystallize to form equal numbers of enantiomorphous conglo-

merate crystals from solution.6 However, under certain

conditions, slight and often unperceived, chiral imbalances

can be amplified to homochirality.7,8 The generation of chirality in

supramolecular systems generally involves helical self-assembly

and requires a chiral influence in the form of a chiral solvent, a

chiral additive9 (e.g. the sergeant in the sergeant-and-soldiers

principle10), polarized light11 or a clockwise/counter-clockwise

vortex12 or spin coating direction.13 There are unsurprisingly few

examples of undirected chirogenesis. For example, Fukushima,

Aida and co-workers recently reported the synthesis of polymeric

ortho-phenylenes with a helical conformation. In solution, the

helices rapidly interconvert, but form conglomerate crystals with

observed mirror symmetry breaking enhanced by stirring.14

Lehn and co-workers have observed the induced chirality of

a helical oligopyridinedicarboxamide molecular strand using chiral

solvation with either diethyl D-tartrate or diethyl L-tartrate.15

A related alternating pyridine/pyridazine strand, 1, has a

propensity to fold into a helical lock-washer motif with twelve

heterocycles per turn with an outside diameter of about 25 A,

and undergoes hierarchical self-assembly into helical fibers in

dichloromethane and pyridine (Scheme 1).16,17 A predominance

of fibers bearing one helicity over the other (i.e. mirror symmetry

breaking) was observed in preliminary TEM images of a dichloro-

methane gel.18

Herein, we describe a more detailed investigation of the

chirality in this supramolecular system. A key observation was

the gradual increase of the CD signal with time starting from a

dilute sonicated sample of 1 in CH2Cl2 (Fig. 1a).w This

induced chirality is believed to be governed by an autocatalytic

secondary nucleation process, where the conformationally

labile foldamer preferentially feeds one of two possible

‘conglomerate’ supramolecular fibers.19 In this case, ‘lock-

washer’ stacking decreases the conformational flexibility of 1 and

facilitates helical growth and chiral amplification where optimal

p–p stacking between aromatic rings is only possible when two

(or more) foldamers of the same chirality interact (Scheme 1).20

This is analogous to crystallization-induced deracemization

(i.e. an ‘asymmetric transformation of the second kind’).21,22

In an example of mirror symmetry breaking during the

formation of J-aggregates from amphiphilic dye monomers,

it was suggested that ‘‘the presence of some heredity mechanism

from a seeding aggregate nucleus transfers its chirality to

the majority of the later-formed aggregates’’.23 In our case,

the biased growth mechanism is thought to be initiated by the

Scheme 1 (a) Structure of foldamer 1 (R: -S-nPr). (b) Lock-washer

cartoon representation of 1 (M-helicity). (c) Homochiral lock-washer

stacking (P-helicity).

aDepartment of Chemistry & Biochemistry, Concordia University,7141 Sherbrooke St. West, Montreal, Quebec, Canada H4B 1R6.E-mail: louis.cuccia@concordia.ca

b Laboratoire de Chimie Supramoleculaire, ISIS, 8 allee GaspardMonge BP 70028, F-67083, Strasbourg Cedex, France.E-mail: lehn@unistra.fr

w Electronic supplementary information (ESI) available: Samplepreparation, instrumental techniques, and supporting CD spectra,SEM, TEM and AFM images. See DOI: 10.1039/c2cc16266k

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 2292–2294 2293

ultrasound-induced break-up of mother fibers, with successive

and gradual growth of daughter fibers of the same chirality.24–27

The first level of chirality in 1 is a result of molecular folding

into either an M- or P-helix, which subsequently acts as

a template for supramolecular self-assembly. Although a

pseudoracemic28 mixture of M- and P-derived assemblies is

expected, in most cases (ca. 75%) a biased growth of one

helical sense over the other was observed during the maturation

process. The amplification of both positive and negative CD

signal assemblies has been observed (mirror image spectra;

Fig. 1b), but our results are clearly non-stochastic with

negative CD signals observed 30 times and positive CD signals

observed only 3 times. The magnitude of the CD signal at 330 nm,

used as a measure of chiral amplification, varied from 4 to

48 millidegrees with growth plateaus ranging from 5 to 48 days

(Fig. 1a).w The initial chiral bias in our system may simply

originate from residual chirality of the solid starting material

prior to dissolution.29,30 This was confirmed with the observation

of a positive CD signal of solid 1 in KBr from the same stock

which yielded at least two of the three positive CD signal

assemblies.w Such non-stochastic behaviour has been reported

previously22 and is generally attributed to a cryptochiral

environmental effect.31,32

Electron microscopy and atomic force microscopy were

used to probe the rich supramolecular self-assembly of 1

(Fig. 2).w Within the same prepared sample, several different

levels of fiber formation were often observed,28 likely because

solvent evaporation during sample preparation can influence

the fiber morphology. The extended fibers, often ribbon-like,

were usually in the range of 30–50 nm in diameter with a

helical pitch of ca. 10 nm. We believe that the observed fibers

are comprised of bundles of molecular-scale fibrils, i.e., the

one-dimensional stacked lock-washer assembly previously

reported, with a diameter of ca. 25 A (Scheme 1c).16,17 These

tubular fibrils were observed and found to further assemble into

2D arrays on carbon coated TEM grids (Fig. 2a). Hierarchical

chirality was sometimes observed in larger diameter fibers,

however, the difficulty in observing single fiber helicity in most

of our images prevented our attempts to correlate helical sense

with the sign of the Cotton effect observed (Fig. 2b). Most

images where helicity was observed showed fibers with a

majority of one helical sense which, when considered together

with our CD chiral amplification results, strongly suggests a

molecular chirality/helical handedness correspondence.

The formation of mature fibers was also associated with an

increase in viscosity and turbidity of the mixture. No appreciable

conversion of fibers from one chiral sense to the other was

observed when an equal or unequal mixture of mature fibers

(day 112) of opposite chirality was mixed together. This is an

indication that once helicity is established in mature fibers,

there is no driving force for chiral inversion and strongly

suggests that the process relies on an initial chiral imbalance

that is amplified with time.

Chirality was directed in this system via the addition of

chiral additives, in this case, diethyl L-tartrate or diethyl D-tartrate.

Diethyl L-tartrate directed the formation of aggregates displaying

a negative CD signal at 330 nm while diethyl D-tartrate

directed the formation of aggregates displaying a positive

CD signal at 330 nm (Fig. 3a). An important observation

here is that in the presence of an additive, the CD signal

amplifies much faster than in the absence of an additive

(i.e. 15-minute-old solutions with additive gave a signal with

magnitude equivalent to a ‘day 5’ fiber solution prepared

without additive). This suggests that the chiral additive interacts

with 1 at the molecular level to promote only M- or P-helicity

leading to the dominant formation of supramolecular fibers

with one helical sense. This directed mirror symmetry breaking

experiment was repeated seven times, where in one case,

addition of diethyl D-tartrate was unable to overcome the

strong bias towards a negative CD signal amplification. CD

signal inversion from negative to positive, which is attributed

to helix inversion, was observed once upon addition of 5% diethyl

D-tartrate only after sonication of the sample for ca. 10 minutes.

This is a remarkable process where sonication provides enough

energy to not only influence, but also reverse the helical sense of

the aggregates.30

Assemblies of 1 are held together by supramolecular non-

covalent interactions resulting in the formation of a fibrous

Fig. 1 (a) CD spectra of 1 with increasing time (ca. 0.15 mg mL�1 in

CH2Cl2; 2 mm path length). (b) CD spectra of 1: day 26 (�CD signal),

day 19 (+CD signal) and a ‘pseudoracemic’ mixture of both solutions

gives zero CD signal (ca. 0.15 mg mL�1 in CH2Cl2; 1 mm path length).

Fig. 2 (a) TEM micrograph of 1 with a 2D array of 2.6 nm fibrils

highlighted in the inset (ca. 0.15 mg mL�1 in CH2Cl2; day 14). (b)

Tapping mode AFM phase image of 1 with 24 nm fiber highlighted

(ca. 0.15 mg mL�1 in CH2Cl2; day 4); inset: tapping mode AFM height

image of 1 with a 20 nm height scale (ca. 0.15 mg mL�1 in CH2Cl2; day 7).

Fig. 3 (a) CD spectra of 1 with 5% diethyl L-tartrate, 5% diethyl

D-tartrate or no additive (ca. 0.15 mg mL�1 in CH2Cl2; 15 minutes;

2 mm path length). (b) CD spectra of 1 with cumulative 30 s bursts of

sonication (0.15 mg mL�1 in CH2Cl2; day 48; 2 mm path length).

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2294 Chem. Commun., 2012, 48, 2292–2294 This journal is c The Royal Society of Chemistry 2012

organogel. A detailed investigation of fiber disassembly was

prompted by the requirement of sonication to promote helix-

sense inversion in the presence of a chiral additive. Here, a

‘day 48’ fiber solution was sonicated with sequential 30 second

bursts and a CD spectrum was recorded until a baseline signal

was obtained (ca. 3 minutes; Fig. 3b). This result suggests that

sonicating the sample for 10 minutes should be sufficient to

disrupt the non-covalent interactions holding the fibers together,

thus eliminating their chirality. As expected, supramolecular fiber

denaturation with temperature was also observed (Fig. 4a).

AFM images of a 1,2-dichloroethane solution of 1 also

revealed an extended fiber network, but mirror symmetry

breaking and chiral amplification were not observed in this

solvent. However, after sonication in the presence of a chiral

additive, chiral amplification was observed. Furthermore, in

this case it was found that the chirality of the fibers was

reversed as temperature increased. In the presence of 5%

diethyl L-tartrate a solution of 1 in 1,2-dichloroethane at low

temperature gave a negative CD signal at 330 nm, but at high

temperature a positive and weaker CD signal was observed at

330 nm (Fig. 4b). The opposite was true when using 5% diethyl

D-tartrate as additive.w In the presence of a chiral additive, 1 is

chirally biased such that temperature dependent intermolecular

interactions can affect the distribution of chiral assemblies.33

In summary, solutions of 1 do not form pseudoracemic

mixtures but rather tend to amplify towards one helical sense

upon aging. This is attributed to a secondary nucleation-

governed ripening process. Microscopy reveals that the fibers

are comprised of bundles of one-dimensional molecular-scale

fibrils with a diameter of ca. 25 A and hierarchical supra-

molecular helicity is observed. Directed mirror symmetry

breaking using diethyl L-tartrate or diethyl D-tartrate was able

to reverse the strong bias towards one helical sense observed in

our lab, which is attributed to a cryptochiral environmental

effect. The observed decrease in the CD signal with increasing

temperature or sonication is an indication that the nanoscale

aggregates disassemble to a great extent.28

We are grateful to Kelly Sears, Jeannie Mui and Line

Mongeon at the McGill Facility for Electron Microscopy

Research for their microscopy expertise and assistance. Anne

Petitjean, Fiorenzo Vetrone and Monica Cheung are thanked

for careful proofreading of the manuscript. Pedro Cintas,

Cristobal Viedma and the anonymous referees are thanked

for their insightful comments. NSERC, FQRNT, CFI and

Concordia University are thanked for financial support

and we also acknowledge our membership in the FQRNT-

supported, multi-university Centre for Self-Assembled Chemical

Structures (CSACS).

Notes and references

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Fig. 4 (a) CD spectra of 1 in pyridine with increasing temperature

(ca. 0.2 mg mL�1 in pyridine, initial sample incubated at 12 1C for

5 days; 5 minute equilibration at each temperature; 2 mm path length).

(b) CD spectra of 1 with 5% diethyl L-tartrate and increasing

temperature as indicated (ca. 0.15 mg mL�1 in 1,2-dichloroethane;

15 minutes; 2 mm path length).

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