Engineering functional materials by halogen bonding

HIGHLIGHT

Engineering Functional Materials by Halogen Bonding

PIERANGELO METRANGOLO,1 GIUSEPPE RESNATI,1 TULLIO PILATI,2

ROSALBA LIANTONIO,1 FRANCK MEYER1

1Laboratory of Nanostructured FluorinatedMaterials (NFMLab), Department of Chemistry,Materials, and Chemical Engineering ‘‘Giulio Natta’’, Politecnico di Milano, I-20131Milano, Italy

2Institute of Molecular Science and Technology, CNR, Department of Chemistry,University of Milan, I-20133 Milano, Italy

Received 15 June 2006; accepted 19 June 2006DOI: 10.1002/pola.21725Published online in Wiley InterScience (www.interscience.wiley.com).

ABSTRACT: Engineering fu-

nctional materials endowed with un-

precedented properties require the ex-

ploitation of new intermolecular inter-

actions, which can determine the

characteristics of the bulk materials.

The great potential of Halogen Bond-

ing (XB), namely any noncovalent

interaction involving halogens as

electron acceptors, in the design of

new and high-value functionalmateri-

als is now emerging clearly. This

Highlight will give a detailed over-

view on the energetic and geometric

features of XB, showing how some of

them are quite constant in most of the

formed supramolecular complexes

(e.g., the angle formed by the covalentand the noncovalent bonds around the

halogen atom), while some others

depend strictly on the nature of the

interacting partners. Then, several

specific examples of halogen-bonded

supramolecular architectures, whose

structural aspects as well as applica-

tions in fields as diverse as enantiom-

ers’ separation, crystal engineering,

liquid crystals, natural, and synthetic

receptors, will be fully described.VVC 2006 Wiley Periodicals, Inc. J Polym Sci

Part A: PolymChem 45: 1–15, 2007

Keywords: halogen bonding;

molecular recognition; self-as-

sembly; structure-property rela-

tions; supramolecular structures

Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 45, 1–15 (2007)VVC 2006 Wiley Periodicals, Inc.

Correspondence to:P.Metrangolo (E-mail: [email protected]) orG.Resnati (E-mail: [email protected])

1

Giuseppe Resnati (left) was born in 1955 in Monza (Italy) and

obtained his Ph.D. in Industrial Chemistry in 1986 at the University of

Milan. After two years in pharmaceutical companies, he moved to the

Politecnico di Milano where initially he was a researcher of the

National Research Council, then associate professor (1998), and finally

full professor (2001). Since 2001, he has been a member of the Edito-

rial Board of the Journal of Fluorine Chemistry. He has been a NATO

Fellow at the University of Clemson (USA, 1990), a visiting Professor

at the Universite Paris XI (France, 1993), a Fellow of the Japan Soci-

ety for the Advancement of Science, Nagoya University (Japan, 2001).

He is the author and co-author of more than 165 original research

papers and 10 reviews or book chapters. His research interests are flu-

orine chemistry, synthetic methodologies, and self-assembly processes.

Franck Meyer (right) was born in 1972 in Pontoise (France) and

obtained his PhD in Organic Chemistry in 2000 at the local university.

After two years of temporary position in a pharmaceutical company

(2001–2003), he moved to the Politecnico di Milano in 2004 for a

postdoctoral appointment under the supervision of Prof. Resnati (EU

fellow). Since 2005, he has been appointed as a research assistant pro-

fessor at the Politecnico di Milano. His research interests are in the

synthesis of fluorinated tectons for recognition processes.

Tullio Pilati was born in 1946 in Muggio (Italy). He obtained his Lau-

rea in Chemistry in 1971 at the University of Milan. He is a Senior

Researcher of the National Research Council at the University of Mi-

lan. His research interests are in the crystallography of perfluorocar-

bon-hydrocarbon hybrid materials and bioactive compounds.

Pierangelo Metrangolo (left) was born in 1972 in Lecce (Italy). He obtained

his Laurea in Pharmaceutical Chemistry and Technology at the University of

Milan (1997), a master in Synthetic Organic Chemistry (1999), and then the

Ph.D. in Industrial Chemistry at the Politecnico di Milano (2002). Since

2002, he has been an assistant professor at the Politecnico di Milano where

he was promoted to associate professor in 2005. He was a recipient of the

2005 ‘‘G. Ciamician’’ medal of the Organic Chemistry Division of the Italian

Chemical Society and of the 2005 ‘‘Journals Grants for International

Authors’’ of the Royal Society of Chemistry. He has been a EU Fellow at the

University of Toulouse (France, 2001), and visiting Professor at the Univer-

sity of York (UK, 2005). He is the author and co-author of more than 60

original research papers and 6 book chapters. His research interests are in the

field of supramolecular and material chemistry.

Rosalba Liantonio (right) was born in 1973 in Palo del Colle (Italy) and

obtained her Laurea in Pharmaceutical Chemistry and Technology at the

University of Bari (1999). Then, she moved to the Politecnico di Milano in

2001 where she obtained her PhD in Industrial Chemistry in 2005. Since

2005, she has been appointed for postdoctoral work at the Politecnico di

Milano under the supervision of Prof. Resnati. Her research interests are in

the field of self-assembly processes by using halogen bonding.

TULLIO PILATI

PIERANGELOMETRANGOLO (left) AND

GIUSEPPE RESNATI(right)

ROSALBALIANTONIO (left)

ANDFRANCK MEYER (right)

2 J. POLYM. SCI. PART A: POLYM. CHEM.: VOL. 45 (2007)

Journal of Polymer Science: Part A: Polymer ChemistryDOI 10.1002/pola

INTRODUCTION

The physical and chemical properties of bulk materials

are not the cumulative result of the properties of the par-

ticles they are compounded of. Some characteristics of

the bulk spring out of its nano- and microscopic archi-

tecture and are related to the noncovalent interactions

that determine the architecture. Materials with unprece-

dented characteristics can thus result from the availabil-

ity of new intermolecular interactions.

The focus of this Highlight is on halogen bonding

(XB), which is the attractive interaction where halogen

atoms work as electron density acceptors. The functional

properties of materials exerted by the presence of these

interactions will also be discussed. The formation of do-

nor–acceptor complexes between halogens, or halocar-

bons, and lone pair-possessing atoms or anions, was

seminally emphasized by O. Hassel in his Nobel lecture.

In recent years, the use of haloperfluorocarbons as elec-

tron acceptor species allowed the successful engineering

of crystalline systems to be achieved.1 This boosted the

awareness of the great potential of interactions wherein

halocarbons work as electron density acceptors, and use-

ful applications in fields as diverse as organic semicon-

ductors, liquid crystals, and substrate–enzyme binding

optimization are appearing.

The term halogen bonding (XB) was introduced to

name any D��X��Y interaction in which X is the halo-

gen (Lewis acid, XB-donor), D is any donor of electron

density (Lewis base, XB-acceptor), and Y is carbon,

nitrogen, halogen, etc. (Chart 1). This term stresses the

numerous similarities existing between this interaction

and hydrogen bonding (HB).2 Indeed, most of the ener-

getic and geometric features found in hydrogen-bonded

complexes are encountered in halogen-bonded com-

plexes as well.

GENERAL CHARACTERISTICS OF XB

The term XB comprehensively encompasses a vast class

of noncovalent interactions, from the weak

C��X1��X2��C interaction (so named type-I halogen-

��halogen contacts)3 to the very strong I��I2 interaction(forming the tri-iodide anion). It is thus not surprising

that XB interaction energy spans over a very wide range

of values, from 5 to 180 kJ/mol. In particular, the

strength of D��X XB increases with the electron density

on D; this is the reason why anions are usually stronger

XB-acceptors than neutral species. Conversely, the

strength of D��X interactions increases with the

decrease of electron density around X. As a result of

this, the tendency to form strong interactions decreases

moving from C(sp)��X to C(sp2)��X to C(sp3)��X

groups. Fluorine atoms and perfluorinated residues are

very strong electron-withdrawing groups; for this rea-

son, haloperfluorocarbons (halo-PFCs) are stronger XB-

donors than corresponding halocarbon parents. The

tendency to form strong interactions decreases moving

from iodo- to bromo- to chlorocarbons and only occa-

sional reports describe the possible involvement of also

fluorocarbons in XB interactions. As a consequence of

their effectiveness in giving strong XB, iodo-PFCs will

be used as the unifying motif around which this High-

light is organized, whereas other XB-donors will be

considered only within examples of particular rele-

vance.

Both p and n electrons can be involved in the forma-

tion of XB and usually the former give weaker interac-

tions than the latter.4 Nitrogen (e.g., amine and pyridine

derivatives) gives stronger XB than oxygen and sulfur

(e.g., ethers and thioethers). However, a very rigorous

scale wherein XB-donors (or acceptors) are listed

according to their strength cannot be filed as pairing of

complementary sites after HSBA theory is favored so

that the effectiveness of a given XB-donor (or acceptor)

may also depend on the used XB-acceptor (or donor,

respectively).

The attractive nature of XB causes nonminor inter-

penetration of donor and acceptor orbitals. D��X distan-

ces are between the sum of van der Waals radii and

covalent bonds, the stronger the interaction is the shorter

the D��X distance is. Consistent with the n (or p) ? r*nature of this interaction, the X��Y covalent bond

lengthens on XB formation. The angle between covalent

and noncovalent bonds around the halogen in D��X��Y

is approximately 1808.5 This is consistent with the theo-

retical prediction that the anisotropic distribution of

electron density around the halogen atom has a mini-

mum along the extended C��X bond axis. The shorter

the XB is, the more linear the angle is (Fig. 1).

When n electron-donors are used, XB occurs along

the axis of the orbital containing the donor lone-pair

(Scheme 1).

Chart 1. Schematic representation of halogen bonding.

Donors (D) are neutral or anionic species while acceptors (X)

are halogen atoms linked to a wide variety of molecular scaf-

folds (Y). [Color figure can be viewed in the online issue,

which is available at www.interscience.wiley.com.]

HIGHLIGHT 3


SUPRAMOLECULAR FLUORINATEDPOLYMERS

The self-assembly of diiodo-PFCs (bidentate XB-donors)

with naked iodide anions (multidentate XB-acceptors)

typically affords highly crystalline noncovalent copoly-

mers. From a structural point of view, the halogen-

bonded architecture of these materials consists of mono-,

di-, or tridimensional networks depending on the specific

nature of the used modules and the crystallization pro-

cess. For instance, the diiodo-PFC, the anion, and the

solvent remaining unchanged, the dimensionality of the

resulting network changes depending on the cation,

whose size and shape heavily affects the topology of the

adduct crystal packing. Alternatively, the diiodo-PFC,

the anion, and the cation remaining unchanged, different

solvents can or cannot be included in the crystal matrix

yielding networks of different architecture.

Structural Aspects

When a,x-diiodoperfluoroalkanes are challenged with

chelated potassium iodide, infinite chains6 or honey-

comb-like layers7 [Fig. 2(a)] are obtained depending on

the chelating module used to dissociate the ion pair and

to boost the electron-donor ability of the iodide anion.

These ‘‘primary structures’’ of the halogen-bonded net-

work further organize into ‘‘secondary structures’’. Hon-

eycomb-like sheets entangle into Borromean links [Fig.

2(b)],8 while infinite chains bend into zigzag pathways

Figure 1. Scatterplot derived from a Cambridge Structure

Database (CSD) search (version 5.27 November 2005, 355.

064 crystal structures; only error free and nonpolymeric

structures containing single-bonded iodine atoms and show-

ing no disorder with R < 0.06 are considered) reporting the

N��I��C angle versus N��I distance for intermolecular

N��I��C interactions. Red full circles correspond to crystal

structures involving iodoperfluorocarbons.

Figure 2. (a) Ball-and-stick view of the (6.3) honeycomb-like network formed by K.2.2.2. KI

and I(CF2)4I. For the sake of clarity, the cryptate molecules and the fluorine atoms are omitted.

Color code: C, gray; I, purple; I��I interactions are black dashed lines; (b) Space-fill view

(down the crystallographic c-axis) of the Borromean links present in the complex formed by

K.2.2.2. KI and I(CF2)8I. Three different colors have been used for highlighting the Borromean

ring topology. The yellow and red honeycomb-like networks are not interlinked as they can be

separated without any XB breakage; it is only the addition of the blue network that ties them all

together. This holds also for any other ring colors pair.



[Fig. 3(a)]6 or roll up into infinite helixes, which, in their

turn, may pair into homochiral double helixes9 [Fig.

3(b)]. A similar behavior is observed when dibromoper-

fluoroalkanes are used as XB-donors.10

The poor affinity perfluoroalkane derivatives for or-

ganic and inorganic compounds determines have mod-

ules’ segregation, which contributes substantially to the

arrangement of formed architectures organized into hier-

archic structures over different length scales. Separate

hydrocarbon (HC) and PFC domains are formed where

the cations are embedded in the HC domains while

anions are at the interface and bind by XB the perfluori-

nated modules. In these examples, XB and nanophase

separation operate in tandem in producing materials in

which structuring at the molecular level (Angstrom

length scale) grows up to supramolecular assemblies

(nanometer length scale). Perfluoroalkanes are endowed

with useful and unique properties (e.g., particularly low

dielectric constants, refractive indexes, surface tensions

and quite high density, and compressibility). Materials

possessing PFC-HC phase-separated domains can thus

be endowed with unique electrical, optical, and elec-

tronic properties.

Bromide, chloride, and fluoride anions are less prone

than iodide anions to give rise to halogen-bonded

adducts but their behaviors are similar.11 The bromide

anion/dibromo-PFCs self-assembly allowed a useful

application to be realized. Racemic 1,2-dibromohexa-

fluoropropane (1) was challenged with (�)-sparteinium

bromide (2), yielding the 1:1 crystalline adduct 3, made

up of 2 and (S)-1, exclusively.10a Each bromide ion

bridges a primary and a secondary bromine of two dis-

tinct and following dibromo-PFC units 1, each of which

is well ordered through bonding to two bromide ions.

Enantiopure, infinite twofold helices are formed and 1 is

resolved into the pure (S) enantiomer; thanks to its

highly specific inclusion in a chiral crystal with a halo-

gen-bonded helical arrangement (Fig. 4). This process

maximizes the transfer of information from the HC to

the PFC units.

The resolution of chiral and racemic protic acids with

chiral and enantiopure bases through HB-driven forma-

tion of diastereomeric salt is a well-established protocol.

The example discussed earlier shows how XB may be

equally effective in driving enantiomer resolution pro-

cesses. This is but an example of the opportunities

opened by this kind of interaction.

Conformational Aspects

Perfluoroalkanes have a very poor tendency to form

crystals suitable for single crystal X-ray analysis as a

consequence of the weak intermolecular interactions

perfluoroalkyl chains give rise to. This accounts for the

high disorder that characterizes perfluoroalkyl chains

also in the solid state. A lack of structural information

on perfluoroalkane molecules and polymers thus ensues.

When long-chain iodo- and bromo-perfluoroalkanes are

halogen-bonded to anionic or neutral lone-pair possess-

ing species, highly crystalline materials develop and sin-

gle crystal X-ray diffraction methods can be used rou-

tinely for their analysis. This has helped in filling the

above-mentioned lack of information on the structural

properties of PFCs. For instance, it was proven that PFC

chains undergo a nonminor widening of the C��C��C

angles (mean value 116.2, mean 6 SE 0.2) and a less re-

markable narrowing of the F��C��F angles (mean value

110.7, mean6 SE 0.3). Other interesting pieces of infor-

mation concerning the preferred conformation of PFC

chains were obtained. While the helical distorted-trans

conformation is most frequently encountered in long-

chain diiodoperfluoroalkanes, the zigzag all-trans is not

Scheme 1. Geometric features shown by a selection of hal-

ogen-bonded complexes involving a variety of N and O elec-

tron donor species. The D��I��C angles (D¼¼N, O) remain

close to 1808 and almost independent on the nature of the

donor species. (a) Supramol Chem 2002, 14, 47–55; (b) Tet-

rahedron 2000, 56, 5535–5550; (c) Chem Commun 2004,

1492–1493; (d) Tetrahedron 2002, 58, 4023–4029; (e) Acta

Crystallogr 2003, E59, o1332–o1333; (f) J Am Chem Soc

2001, 123, 11069–11070; (g) J Mol Struct 2005, 737, 103–

107. [Color figure can be viewed in the online issue, which

is available at www.interscience.wiley.com.]

HIGHLIGHT 5


so uncommon. Moreover, in a single PFC molecule, the

helical arrangement always has the same handedness

(Fig. 5).

XB-BASED RECEPTORS

As it is the case for HB and other noncovalent interactions,

XB has been effectively used to direct the selective recog-

nition of ions and neutral molecules in solution and in the

solid state.12

Heteroditopic Receptors for Alkali Metal Halides

Anions are effective electron-donors to halogens. XB

can thus be anticipated as a promise in anion binding

processes. The first confirmation of this expectation

came recently from the binding of halide anions by an

iodotetrafluorophenyl substituted receptor designed apriori.13

Ion pairing in a salt can dramatically reduce receptor/

anion binding affinities and alter binding selectivities.14

For this reason a heteroditopic receptor tailored to the si-

multaneous binding of both the ions of alkali halides

was developed. A careful design resulted in the synthesis

of tris-{2-[2-(4-iodotetrafluorophenoxy)-ethoxy]-ethyl}-

amine 4 [Fig. 6(a)], which coordinates selectively

iodide, bromide, and chloride anions in the solid, liquid,

and gas phases.

The polyoxyethylene core mimics the kriptofix1

2.2.2. (K.2.2.2.) moiety and secures cation binding; the

iodotetrafluorobenzene pendants are the motifs for the

XB-based anion recognition. NMR experiments on 4/

NaI solutions showed that the binding constant of 4 for

the sodium cation increases by approximately 20 times

Figure 3. The self-assembly of naked anions with telechelic diiodoperfluoroalkanes gives rise

to infinite halogen-bonded zigzag chains (a) or to infinite supramolecular helixes, which in their

turn pair into homochiral double helixes (b). Color code: F, green; I, purple; I��I interactionsare black dashed lines. [Color figure can be viewed in the online issue, which is available at

www.interscience.wiley.com.]

Figure 4. Space-fill representation, viewed down the crys-

tallographic a-axis, of the enantiopure halogen-bonded heli-

ces 3 made of (S)-1,2-dibromohexafluoropropane 1 and (�)-

sparteinium bromide 2. For the sake of clarity, all the spartei-

nium cations but one per chain have been removed. Color

code: C, gray; H, white; F, green; Br, red; Br��Br interac-

tions are black dashed lines. [Color figure can be viewed in

the online issue, which is available at www.interscience.

wiley.com.]



with respect to its pentafluorophenyl analogue. This

proves the boosting effect of the XB-mediated anion

binding on cation complexation. X-ray analysis of a sin-

gle crystal of the 4/NaI complex showed that the ion pair

of the salt is separated; thanks to the simultaneous bind-

ing of I� and Na+ by the two different recognition arrays

of atoms of 4. Na+ is surrounded by the three arms of the

receptor and is separated by 5.585 A from the nearest I�

anion, which is engaged in strong I��I��C XB

[Fig. 6(b)]. I� anions bridge three iodotetrafluorophenyl

rings of three different podand molecules so that rolled-

up polymeric noncovalent chains are formed. Notewor-

thy, although the 4/NaI complex is composed of intrinsi-

cally achiral components, it crystallizes in the chiral

space group P212121.Crystalline complexes of the receptor with Br� and

Cl� ions were not obtained. This is consistent with the

common observation that in solution the formation of

XB between halide anions and iodo-PFCs becomes dis-

favored moving from I� to Br� to Cl� (the 19F NMR

chemical shift changes shown by iodo-PFCs on XB for-

mation decreases moving from I� to Br� to Cl�). Thegreater affinity of 4 toward iodide than bromide and

chloride ions was also confirmed by mass experiments

(ESI-MS). Competitive experiments were performed by

analyzing, in the negative ion polarity mode, mixtures

containing 4 and equimolar amounts of I�, Br�, or Cl�

anions. The signals of [4 + I�] were particularly strong,

while the signals for [4 + Br�] and [4 + Cl�] complexes

were very weak.

Molecularly Imprinted Polymers

When a monomer with tailored functional groups and a

crosslinker are copolymerized in the presence of an

imprinting agent (namely, a template molecule whose

functionalities are complementary binding sites for the

monomer functional groups), a crosslinked copolymer is

obtained and its architecture contains properly posi-

tioned recognition sites for the imprinting agent.15 In

fact, spontaneous monomer preorganization occurs;

thanks to the formation of monomer/imprinting agent

Figure 6. Schematic (a) and ball-and-stick view (b) of the complex tripodand 4/NaI. The so-

dium cation is embedded in the polyoxyethylene core, while the iodide counterion coordinates

three iodine atoms belonging to three different podand molecules. Color code: C, gray; H, white;

F, green; I, purple; O, red; N, blue; Na, orange.

Figure 5. All-trans distorted helical arrangement of mono-

iodoperfluoro-octane (a) and -decane (b) exhibiting the same

handedness when bound to naked iodide ions. For the sake

of clarity, the ammonium cations and fluorine atoms have

been omitted. Color code: C, gray; I, purple; I��I interac-

tions are black dashed lines. [Color figure can be viewed in

the online issue, which is available at www.interscience.

wiley.com.]

HIGHLIGHT 7


complexes. Copolymerization translates this preorgani-

zation into a rigid crosslinked matrix, which, upon re-

moval of the imprinting agent, presents cavities whose

size, shape, and electronic features are complementary

to the imprinting agent (Fig. 7, top).

Through this approach it is possible to create syn-

thetic receptors that are able to recognize molecules pos-

sessing structural and electronic analogies to the

imprinting agent. This strategy afforded materials quite

useful in many different fields, such as, among others,

enantiomer resolution, sensing, and solid-phase extrac-

tion, as well as in separation science.

In the first example of an XB-based molecularly

imprinted polymer (MIP),16 4-dimethylaminopyridine

(DMAP, 5) was selected as the imprinting agent; thanks

to its two N functionalities, which are known to work as

effective XB-acceptor sites. 2,3,5,6-Tetrafluoro-4-iodos-

tyrene (6) was chosen as the monomer, being comprised

of a strong XB-donor site (electron poor iodine atom)

and of a polymerizable unit (vinyl group). The binding

and selectivity characteristics of different DMAP-

imprinted polymers toward selected analytes were eval-

uated (Fig. 7, bottom). The weakest affinity was

observed toward analytes having a single XB-acceptor

Figure 7. Top, (a) selection of suitable monomer (violet arrowed olefin) and imprinting agent

(sky blue oval); (b) self-assembly of the complex monomer-imprinting agent in solution; (c) po-

lymerization reaction; (d) removal of the imprinting agent from the MIP by washing with an or-

ganic solvent. Bottom, left: chemical drawings of the imprinting agent (DMAP, 5) and the

monomer 6 of the first XB-based MIP. Right: histogram showing the binding abilities of the

MIP for DMAP and related compounds: 1, DMAP; 2,4-(N,N-dimethyl)aniline; 3,4-methylpyri-

dine; 4,4-aminoaniline; 5, aniline; 6, pyridine; 7,2-aminopyridine; 8,2-methylpyridine; 9,1-amino-

naphtalene; 10, quinoline; 11,8-aminoquinoline. [Color figure can be viewed in the online issue,




site (e.g., aniline and its N,N-dimethyl derivative, 1-

naphthylamine, pyridine, 2- and 4-picoline, quinoline).

The binding affinity increased when the analyte pre-

sented two binding sites (e.g., DMAP, 2- and 4-amino-

pyridine, 8-aminoquinoline). Molecular recognition

being affected by the matching between analyte shape

and MIP cavity shape, the binding abilities of 4-substi-

tuted derivatives were larger than those of 2-substituted

analogues. Noteworthy, 4-aminopyridine showed the

strongest binding to DMAP-imprinted polymers (even

stronger than DMAP).

Biological Receptors

The relevance of XB in the context of natural systems

can be easily predicted. Thousands of halogen-contain-

ing bioactive compounds, vancomycin and chloram-

phenicol, just to name two of them, are currently

known17 and XB may contribute to their binding at the

receptor sites. Forceful signals in this direction come

from the thyroid hormones, which are naturally occur-

ring compounds containing iodine.18 A great number of

short I��O contacts from thyroxine and its derivatives to

their associated proteins have been identified.

When 5-bromouridine substitutes for uridine or thy-

mine in a DNA sequence, a four-stranded Holliday junc-

tion substitutes for the standard duplexes because of

short Br��O contacts (3.0 A, 12% shorter than the sum

of their van der Waals radii for Br and O).19 An ultra-

high resolution structure (0.66 A) of the enzyme aldose

reductase complex with a halogenated inhibitor revealed

Br��O contacts of similar length.20 Moreover, the X-ray

crystallography of some tubulin-bound brominated tax-

anes revealed a role played by XB in the association

with the protein (Fig. 8).21 The potential role of halogens

in taxane-tubulin binding suggests novel possibilities for

the design of other microtubule-stabilizing compounds.

All these results have prompted quantum mechanical

calculations to compare the polarizability of halogen

atoms within the context of functional groups relevant to

biological molecules. A survey of short C��X��O inter-

actions in proteins and nucleic acids data base revealed

clearly the potential significance of XB in ligand binding

and recognition, as well as in molecular folding. The

survey also demonstrated that the XB geometries in bio-

logical systems conform generally to those seen in small

molecules. A similar survey involving p electron-donor

sites in proteins is also available.22

SOLID-STATE SYNTHESIS

Supramolecular photochemistry23 in the solid state pro-

vides an efficient way for accessing stereo- and regio-

controlled syntheses. The advantages of this approach

come from the preorganization of the reacting modules

in the crystal matrix, but the engineering of such a preor-

ganization remains a challenge. Different strategies have

been explored to control modules’ topochemical

arrangement by using in a rational way the noncovalent

interactions they can give rise to. HB,24 p��p stacking,25

and metal–ligand interactions26 were all used success-

fully.

[2 + 2] Template-Assisted Photodimerizationof Olefins

The requirements for the [2 + 2] photocyclization in the

solid state to occur, as identified by Schmidt,27 entail

that two double bonds are oriented in a parallel manner

and 3.5–4.2 A away from each other. Self-organization

and template-assisted organization of the olefins (Chart

2) are the two main strategies used to meet these require-

ments.

The latter strategy requires that olefinic substrate(s)

are organized around linear templates by means of

directing noncovalent interactions. The preorganization

of the template dictates the alignment of the double

bonds to meet the Schmidt’s requirements. The supra-

molecular control in the covalent bond-formation pro-

cess has been recently achieved through the organization

of olefinic modules by XB-based templates.28 The sys-

tem consists of a tetratopic XB-donor module, which

works as the template, and a ditopic XB-acceptor, as the

olefinic substrate. The pentaerythritol ether 7, carrying

four iodotrafluorophenyl rings, was challenged with

trans-1,2-bis(4-pyridyl)ethylene (8), a ditopic XB-

acceptor. The N��I XB being quite a strong interaction,

the template 7 and the substrate 8 cocrystallized in a 1:2

ratio to maximize the formation of halogen bonds. Infi-

nite 1D halogen-bonded ribbons were formed (Fig. 9).

In these ribbons the four arms of 7 points two by two to

opposite sides and the tetrafluorophenyl rings lying on

the same side of the molecule are paired in a quasi-paral-

lel fashion; thanks to face-to-face p��p intramolecular

interactions. Particularly, strong and directional N��Ihalogen bonds (N��I distances 2.795–2.819 A, N��I��C

angles 177.09 and 176.728) transfer this topochemical

information to the olefinic substrates 8 that are pinned in

the ribbons in a parallel fashion with a distance of less

than 4.5 A between the olefins’ centroids. Irradiation of

the powdered cocrystal afforded the corresponding tetra-

kis(4-pyridyl)cyclobutane with only the rctt stereochem-

istry in quantitative yields.

With the aim of applying the tools of supramolecular

chemistry to control the solid-state synthesis of complex

heterotopic tectons tailored to XB-based crystal engi-

neering, we have synthesized the 1D self-complemen-

HIGHLIGHT 9


tary tecton 9. Molecules wherein an electron-donor site

and an electron poor halogen atom are linked by an ole-

finic spacer appear promising substrates.29 N,N-Dime-

thylaniline and iodotetrafluorophenyl residues30 were

selected as self-complementary groups for XB and (E)-1-[4-(N,N-dimethylamino)phenyl]-2-(4-iodotetrafluoro-

phenyl)ethylene (9) was prepared (Scheme 2, top).31

It was expected that self-complementary XB induced

the formation of infinite chains, while p��p stacking

interactions between aromatics having opposite quadru-

polar moment paired these chains after a prereactive

arrangement. Single crystal X-ray analysis of 6 thor-

oughly confirmed the expectations. Modules 9 are

assembled head-to-tail and form infinite chains with a

zigzag geometry due to the presence of N��I interactionswith the standard geometrical features. The N��I dis-

tance is 3.093 A (13% shorter than the sum of van der

Waals radii), the N��I��C and C��N��I angles are

169.82 and 97.388, respectively. p��p stacking between

the PFC and HC arenes secures the antiparallel coupling

of the dipolar moments of modules 9 into head-to-tail

dimers while XB connects these dimers into infinite zig-

zag ribbons. As a result of this crystal packing, pairs of

modules 9 in adjacent chains have the double bonds sep-

arated by a distance of 3.761 A (just meeting Schmidt’s

requirements for solid-state photodimerization). A regio-

and stereospecific cycloaddition reaction occurs on the

irradiation of powdered crystals of 9 and the 1,3-bis(4-

iodotetrafluorophenyl)-2,4-bis[4-(N,N-dimethylamino)-

phenyl]cyclobutane (10) having only the rctt stereo-

chemistry is isolated in 80% yield (Scheme 2, bottom).

The packing of this cyclobutane in the crystal is a nice

example of the robustness of the N��I supramolecular

synthon and its ability to prevail over other noncovalent

interactions in directing crystal architecture. The cyclo-

butane 10 possesses two XB-donor sites and two XB-

Figure 9. Single crystal X-ray structure of the complex between pentaerythritol derivative 7,

which functions as the template, and trans-1,2-bis(4-pyridyl)ethylene (8). The distance between

the olefins’ centroids is in the range required for the [2 + 2] photoreaction in the solid state.

Color code: C, black; F, green; N, blue; O, red; I, purple; N��I interactions are black dashed

lines.

Chart 2. Schematic diagram showing the preorganization

of olefins for solid-state photoreaction, as induced by the

self-assembly around linear templates by means of comple-

mentary intermolecular interactions.

Figure 8. O��Br halogen bonds within the tubulin–taxane binding complex. (Courtesy of

Y. Jiang, J.-M. Chen and J. P. Snyder)



acceptor sites and, on crystallization, it forms all possi-

ble N��I halogen bonds. The resulting architecture

shows large columnar voids, which are filled by solvent

molecules, and no p��p stacking occurs (10 could give

up to eight such interactions) (Fig. 10).

Topochemical Polymerization in the Solid State

Like all topochemical reactions, 1,4-polymerization of

diynes requires a precise prealignment of the reactant

molecules within the crystal. Experiments show that the

preferred monomer repeat distances dm is about 4.9 A

and the angle h is 458, so that the distance R1,4 (between

the reacting atoms C1 and C40) is 3.5 A (Chart 3).

Most diacetylenes do not crystallize in accordance to

these precise structural requirements. To circumvent this

limitation, diynes have been assembled by means of non-

covalent interactions with templates that reliably dictate

the formation of complexes with crystallographic features

corresponding to the targeted alignment needed for reac-

tion.32 Specifically, telechelic diiododiynes are good XB-

donors; thanks to the polarizability of iodine atoms and

the strong electron withdrawing ability of the sp-hybri-

dized carbon atom. On the other hand, Fowler, Lauher,

and coworkers have demonstrated that oxalamides form

self-complementary HB networks with a repeat distance

(4.9–5.1 A) that matches well the 4.9 A distance require-

ment for diyne 1,4-polymerization. When bispyridyl oxa-

lamides cocrystallize with telechelic diiododiynes, 1D in-

finite chains are formed wherein the strength and direc-

tionality of N��I XB translates the packing features of

oxalamide units into the packing arrangement of the diio-

dodiynes units [Chart 4(a)]. Some of the obtained com-

plexes display dm and R1,4 distances and alignment angles

h close to the desired values but unfortunately up to now,

all attempts of polymerization in the solid state have

failed. However, from a methanol solution of diiodobuta-

diyne with a bis(nitrile)oxalamide, a unique poly(diiodo-

diacetylene) [Chart 4(b)] has been isolated, probably as a

result of the spontaneous topochemical polymerization of

the starting diiodobutadiyne in solution.33

LIQUID CRYSTALS

XB has proven successful in determining the self-assem-

bly of supramolecular mesogens and forming new fami-

lies of materials showing liquid-crystalline behavior.

The same had already been the case for HB,34 quadrupo-

lar,35 and charge-transfer36 interactions.

Halogen-Bonded Low Molar Mass Liquid Crystals

Alkoxystilbazoles have been shown to be versatile mod-

ules for the construction of molecular materials, and in

particular metallomesogens and hydrogen-bonded meso-

gens. A series of liquid-crystalline materials resulted on

HB-driven self-assembly of alkoxystilbazole with vari-

ous substituted phenols, neither starting component

Scheme 2. Schematic diagram showing the preorganization

of olefins for solid-state photoreaction, as induced by the

self-assembly around linear templates by means of complemen-

tary intermolecular interactions. [Color figure can be viewed in the

online issue, which is available at www.interscience.wiley.com.]

Figure 10. Mercury 1.4. view down the crystallographic a-axis of the crystal packing of 1,3-bis(4-iodotetrafluorophenyl)-

2,4-bis[4-(N,N-dimethylamino)phenyl]cyclobutane (10). Color

code: C, gray; H, white; F, light green; Cl, green; I, purple; N,

blue. Space-fill representation has been used for clathrated

chloroform. [Color figure can be viewed in the online issue,


HIGHLIGHT 11


being mesomorphic. Prompted by the striking parallel-

ism between the properties of HB and XB, Bruce et al.

undertook the synthesis of supramolecular complexes of

the range of nonmesomorphic 4-alkoxystilbazoles 11

with iodopentafluorobenzene 12 (Scheme 3).

The single crystal X-ray structure of these complexes

shows that the two modules are held together by a strong

N��I XB and that quadrupolar phenyl/perfluorophenyl

interactions are absent. Despite the nonmesomorphic na-

ture of the starting materials, complexes 11-12 were all

liquid-crystalline.37 The mesomorphism of these halo-

gen-bonded stilbazole complexes is that of a simple,

dipolar mesogen, showing a nematic phase or a SmA

phase when the alkoxy residue is composed of a short or

long alkyl chain, respectively. The work of Bruce dem-

onstrated that XB can be added to the palette of nonco-

valent interactions for inducing the self-assembly of

supramolecular mesogens showing thermotropic liquid

crystallinity.

Supramolecular Liquid-Crystalline Polymers by XB

In the literature it is possible to find examples in which

difunctional proton-donors and difunctional proton-

acceptors (e.g., dicarboxylic acids and bipyridine deriva-

tives) self-assemble via intermolecular HB to generate

supramolecular liquid-crystalline polymers. Keen to fol-

low this approach by using XB, Xu and He have synthe-

sized the difunctional XB-donors 13 by using the stand-

ard protocol described by Metrangolo and Resnati to

prepare 4-iodotetrafluorophenyl ethers.28 The telechelic

XB-donors 13 self-assemble with the dipyridyl-modules

14 to give rise to halogen-bonded supramolecular

copolymers with a 1:1 stoicheiometry. Once again, both

starting materials were nonmesogenic, but the 13-14b

and 13-14c series complexes showed monotropic liquid

crystallinity on cooling.38 In particular, it was found that

the flexible spacer length of XB donors can play a role

in controlling the formation of mesophases. For exam-

ple, 13c series complexes showed nematic phases, 13b

series complexes exhibited highly ordered smectic

phases, and 13a series complexes showed no liquid crys-

tallinity.

On the other hand, the first report proving the ability

of XB to produce supramolecular polymers showing lyo-

Chart 3. Geometrical features required for the trans-1,4-po-lymerization of diynes to occur in the solid state.

Chart 4. (a) Complex between 1,4-diiodobutadiyne and

oxalamide derivative obtained by self-assembly driven by si-

multaneous O��H HB and N��I halogen bonding. (b) Poly(-

diiododiacetylene) obtained upon spontaneous topochemical

polymerization from a methanol solution of diiodobutadiyne

with a bis(nitrile)oxalamide. [Color figure can be viewed

in the online issue, which is available at www.interscience.

wiley.com.]

Scheme 3. Chemical structures of the starting materials

used for the synthesis of halogen-bonded supramolecular

mesogens. [Color figure can be viewed in the online issue,




tropic liquid crystallinity and made by self-assembly of

nonmesomorphic species came as early as in 2002.39

The waxy adducts obtained starting from oligomeric 4-

vinylpyridine and 1,6-diiodoperfluorohexane when stud-

ied under polarized light optical microscope showed

many spherulitic textures with a Maltese extinction cross

dispersed in a birefringent matrix, as typical for a smec-

tic-type liquid crystal. This macroscopic organization

remained unchanged upon heating, suggesting a lyo-

tropic character of this system.

Highly Fluorinated Low Molar Mass LiquidCrystals by XB

It is well known that liquid crystals can derive their mo-

lecular dipole moment from terminal perfluoroalkyl (Rf)

chains. However, the introduction of long Rf chains in

mesogens enhances the smectic character of a liquid

crystal, as a consequence of the microphase separation

that occurs between the Rf chains and HC segments of

the molecule (fluorophobic effect). Considering the abil-

ity of a single XB to form dimeric liquid crystals from

nonmesogenic units and the ability of diiodoperfluoroal-

kanes to work as effective XB-donors, a low molar mass

approach to trimeric liquid crystals was pursued. Specifi-

cally, a diiodoperfluoroalkane modules self-assemble

with two molecules of alkoxystilbazole 11 to give a

range of trimeric adducts 15 (Scheme 4).

Single crystal X-ray diffraction of 15d confirms the

expected 2:1 ratio between the stilbazole and diiodoper-

fluorohexane modules in the crystal. The trimeric adduct

is characterized by a stepped arrangement between the

two stilbazoles consequent on the antiperiplanar arrange-

ment of the perfluoromethylene groups of the XB-donor

(Fig. 11, top).

The stilbazole and the perfluorinated modules are

bound together by strong N��I XB and stack in separated

columns parallel to the a crystallographic axis, probably

as a consequence of the fluorophobic effect. On heating,

all the trimers 15 melted directly to the isotropic liquid,

but on cooling, a nematic phase forming from the iso-

tropic liquid was seen, as it is evident from its character-

istic schlieren texture (Fig. 11, bottom). Indeed, the sys-

tematic presence of a nematic phase in all of the com-

plexes 15 is quite surprising, as it is an uncommon

feature for liquid crystals containing long Rf chains. The

expected microphase separation associated with per-

fluoroalkyl chains is surprisingly absent.40

PERSPECTIVES IN MATERIALS SCIENCE

Halogen-Bonded Paramagnetic Complexes

Persistent nitroxide radicals interact with 1,4-diiodo-tet-

rafluorobenzene (DITFB) via XB.41 Specifically, 4-phe-

nyl-2,2,5,5-tetramethyl-3-imidazolin-1-yloxyl radical

and 4-amino-2,2,6,6-tetramethyl(piperidin-1-yloxyl)

radical cocrystallize with DITFB giving rise to 1D coor-

dination polymers consisting of alternating electron-do-

nor and acceptor modules in a 1:1 ratio; thanks to direc-

tional NO��I interactions. The occurrence of NO��Iintermolecular interactions also in the liquid phase was

proven by ESR.42 The technique allowed to establish

that the interaction strength is close to that of a strong

HB. For instance, the DH8 of the TEMPO-1-iodoper-

fluorooctane XB is –7.0 6 0.4 kcal/mol.

Halogen-Bonded Organic Semiconductors

As early as 1995, Imakubo and Kato introduced for the

first time the use of XB to direct intermolecular interac-

Scheme 4. Halogen-bonded trimeric complexes formed by

alkoxystilbazoles and a,x-diiodoperfluoroalkanes and showing

liquid crystal behavior. [Color figure can be viewed in the online

issue, which is available at www.interscience.wiley.com.]

Figure 11. Space-fill representation of the stilbazole-diiodo-

perfluorohexane complex 15d (top) and schlieren texture of

the corresponding monotropic nematic phase as obtained on

cooling from the isotropic phase (bottom). [Color figure can

be viewed in the online issue, which is available at www.

interscience.wiley.com.]

HIGHLIGHT 13


tions in crystalline molecular conductors based on tetra-

thiafulvalene (TTF) derivatives.43 In particular, while

XB interactions have been observed only incidentally in

neutral halogenated TTFs, they have been extensively

encountered in their radical cation salts. Since the semi-

nal work of Imakubo and Kato, XB has been fully inves-

tigated as a first choice noncovalent interaction to con-

trol the solid-state structures of organic molecular con-

ductors and hence to influence their electronic

properties.44

XB at the Outer Sphere of Metal–LigandComplexes

Keen to extend his work on the study of the behavior of

inorganic halogen species (Metal-X) as directional

Lewis bases in the formation of hydrogen bonds,

Brammer and coworkers have demonstrated the great

potential of XB in stabilizing the outer sphere of metal–

ligand complexes.45 A clear understanding of the nature

of M��X��X0��C XB provides an impetus for a wide

range of applications to supramolecular construction of

organic–inorganic hybrid materials and has the potential

to yield applications in the control of conformations in

metal complexes, and of substrate binding in catalysis.

CONCLUSIONS

XB is a strong, specific, and directional interaction that

can frequently prevail over other interactions (e.g., HB46,47

and p–p stacking31) in systems of interest to chemical,

biopharmacological, and material sciences. Specific exam-

ples have been discussed where XB plays a key role in

enantiomer separation,10a crystal engineering,1 selective

binding of small molecules to synthetic13,16 and natural17–21

receptors, formation of supramolecular liquid crys-

tals,37–40 and of molecular conductors.43,44 Indeed, XB

impacts in all the fields where the design and manipula-

tion of aggregation phenomena play a key role and seri-

ous problems may arise if its occurrence is neglected.2a

In general, halogen-bonded adducts can be consid-

ered as prereactive complexes (or intermediates) formed

prior to significant charge-transfer or chemical reaction.

The strongest interactions can evolve into different mo-

lecular species if concentration, temperature, solvent po-

larity, or other parameters are changed. In general, com-

plexes between halogens and Lewis bases have been

observed in, or invoked for, many reaction mechanisms

in solution. The 1:1 complex that dihalogen molecules

form with alkenes is a particularly noteworthy case. It

lays on the way to the addition/substitution products’

formation and its evolution depends on the reaction con-

ditions.48 Other well-known examples come from the

chemical reactivity of iodine. This reactivity is generally

greater in solvents that give yellowish solutions (elec-

tron-donating solvents) than in solvent giving violet sol-

utions (noncoordinating solvents).49

Several analytical techniques (solution calorimetry; UV,

IR, and Raman spectroscopy, 1H, 13C, 14N, 19F NMR;

dielectric polarization; nuclear quadrupole resonance; sin-

gle crystal X-ray analysis; ESR) have been used to detect

the formation of XB, to define its nature, to establish its

energetic and geometric characteristics, and to reveal the

striking similarities between XB and HB. All the aggrega-

tion phenomena controlled by HB may have a parallel

under the control of XB. The exploitation of the similarities

between these two interactions can be expected to favor

the flourishing of numerous and successful applications

where the presence of XB is crucial. The molecular struc-

tures of modules that can be involved in self-assembly

processes driven by XB are obviously different from those

involved in HB-driven ones, and this allows new adducts

with new properties to be obtained.

A full utilization of the bottom-up approach to func-

tional materials continuously requires new and effective

noncovalent interactions for assembling molecules into

supramolecular architectures associated with pre-estab-

lished functions. The great potential of XB in the design

of new and high-value functional materials is now

emerging clearly.

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HIGHLIGHT 15


Engineering functional materials by halogen bonding

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