Templated Synthesis of Knots and Ravels · 9 Inspiration from DNA Knots 15 10 Conclusion 15...

Templated Synthesis of Knots and Ravels

Jean-Pierre Sauvage1 and David B. Amabilino2

1Universite de Strasbourg, Strasbourg, France2Institut de Ciencia de Materials de Barcelona (CSIC), Catalonia, Spain

1 Introduction 12 The Pioneers of Synthetic Chemical Topology 23 Approaches to Molecular Knots 34 Molecular Knots Constructed on Dicopper(I) Helical

Complexes 45 To Molecular Knots by Hydrogen Bonding 76 Molecular Knots Constructed on Octahedral

Complexes 97 Topological Enantiomers and Diastereomers 128 Borromean Rings 139 Inspiration from DNA Knots 1510 Conclusion 15References 15

1 INTRODUCTION

This chapter will detail the synthesis of artificial molecu-lar knots and other complex molecular topologies preparedusing noncovalent interactions between molecular frag-ments. The compounds are a much greater challenge thansimple catenanes (which are dealt with in the chapter titledSelf-Assembled Links: Catenanes, Volume 5) becausethey all contain more than two crossing points. Apartfrom the competing reactions that generate open-chaincompounds or topologically simple macrocycles, when aknot is approached the catenanes are often the possibleby-products.

Supramolecular Chemistry: From Molecules to Nanomaterials.Edited by Philip A. Gale and Jonathan W. Steed. 2012 John Wiley & Sons, Ltd. ISBN: 978-0-470-74640-0.

The relatively simple synthetic links, called catenanes bymolecular chemists, are used to represent extremely chal-lenging chemical targets often through covalent approachesinvolving creativity and luck,1 but nowadays they are rea-sonably accessible2 thanks to both coordination chemistryand supramolecular chemistry based on purely organic frag-ments as well as to new methods of covalent bond forma-tion. The synthesis of knots is motivated by the syntheticchallenge as well as an aesthetic dimension3 and the pos-sible new properties—even at the nanometer scale—thatthese compounds might have as a result of their compacttwisted forms and their topological properties, includingchirality.

1.1 Topology: art to mathematics

Beauty in art is a personal and intangible thing, but complexobjects containing links, helices, or twists are very oftenseen as being attractive, as well as being loaded withsymbolism. Knots are particularly prominent. Interlockingand knotted rings were at the fore in the art of manyancient civilizations. This almost universal art reachedits peak in the magnificent, complex, interlaced designsand knots of Celtic Culture. More modern art has alsodevoted special attention to knotted threads. The Dutchartist Cornelius Escher is certainly one of the most popularartists among the community of chemists since many of hisworks contain symmetries, volumes, and interlaces closelyrelated to modern molecular sciences.

The beauty of the knots, for example, can be appreciatedin Figure 1, where the first 15 prime knots are drawn. Itwill be particularly interesting for the reader to reflect onthese structures in the light of the discussion to come.Particularly, perhaps, the 51 and 71 knots have seductive

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2 Self-processes

31

62

74

63

75

71

76

41 51 52

72

77

73

81

61

Figure 1 Representations of the first 15 prime knots.

symmetry, and the 74 knot appears to be a grid-like structurein the way it is drawn here, suggestive of possible chemicalstrategies toward it. Then, of course, the 31 knot is thesimplest yet perhaps most beautiful structure (one thatreceived the attention of Escher’s skills). In any of theknots, cutting the line just once in any place gives a simplelinear topology.

In mathematics, knots and links are the focus of keeninterest. They have been the objects of active thinkingfor more than a century, but the curious reader shouldhave a look at the relatively small, recent, and accessibletreatise entitled The Knot Book.4 The first 15 prime knotsare single-knotted loops, in contrast to “links” (or catenanes,see Self-Assembled Links: Catenanes, Volume 5), whichare sets of knotted or unknotted loops, all interlockedtogether. In 1994, Liang and Mislow presented fascinatingdiscussions on knots and links in relation to chirality.5 Thisbreakthrough work should help bridge the gap betweenthe communities of mathematical topologists and molecularchemists.

1.2 Biological knots and ravels

Naturally occurring DNA forms catenanes and knots, withextreme complexity at times. This discovery initiated thefield of research coined “biochemical topology.”6 KnottedDNA was found first by Liu and coworkers in single-stranded circular phage of DNA treated with Escherichiacoli w -protein7; double-stranded circular DNA also formsknots.8 The enzymes that effect the topological transfor-mations in natural systems are called topoisomerases, andtheir role in a large variety of biological functions is stud-ied intensively. The topoisomerases are able to solve thetopological problems arising during replication, site-specificrecombination, and transcription of circular DNA. Thetopoisomerases can be used for synthetic purposes to createexotic and beautiful chemical objects; besides the naturally

occurring DNA catenanes and knots, a fascinating familyof related molecules has been synthesized and described bySeeman and coworkers.9 The elegant approach of this grouputilizes synthetic single-stranded DNA fragments, whichare combined and knotted by topoisomerases.

The solid-state structures of many proteins contain cate-nanes and trefoil knots.10 This remarkable finding raisedthe general question of whether the topological propertiesof proteins have any biological significance. Work by Zhouseems to demonstrate that catenation of proteins increasesvery significantly the stability of their folded structures.10

Similar conclusions were drawn from an interesting studyon the properties of knots.11 It is particularly interesting toobserve that Nature has utilized topology as a functionaltool in order to control the properties of given proteins.

2 THE PIONEERS OF SYNTHETICCHEMICAL TOPOLOGY

From the chemical and synthetic viewpoint, the conceptof catenanes has fascinated chemists for many decades,and the application of graph theory to manmade moleculartargets led to the field of “chemical topology.” The rig-orous mathematical treatments applied to molecules cameinto existence only since Walba’s use of graph theory fordescribing molecular systems.12 But the first theoreticalwritten discussion to appear on chemical topology wasa publication by Frisch and Wasserman.13 This generalarticle seems to be the cornerstone of the field, since itcontains, expressed in a very chemical and accessible lan-guage, most of the notions that constitute the backgroundof chemical topology. The idea of topological isomers wasintroduced in this pioneering paper. It is best exemplifiedusing a single closed curve: normal (topologically trivial)or knotted cycle (the most simple nontrivial knot being thetrefoil knot). The three objects (a, b, and c in Figure 2)are topological stereoisomers. Although they may consistof exactly the same atoms and chemical bonds connect-ing these atoms, they cannot be interconverted by anytype of continuous deformation in three-dimensional space.

(a) (b) (c)

Figure 2 Topological stereoisomers: (a) the trivial ring and (band c) the Trefoil knots which are closed rings with three crossingpoints. b and c are topological enantiomers.


Templated synthesis of knots and ravels 3

In addition, the compounds of Figure 2(b) and (c) aretopological enantiomers since the mirror image of any pre-sentation of Figure 2(b) is identical to a given presentationof Figure 2(c).

Two other historically important discussions are worthmentioning. A very imaginative paper was written byVan Gulick (Eugene, University of Oregon, USA) at thebeginning of the 1960s but, unfortunately, the manuscriptwas not accepted for publication at that time. It waspublished14 in a recommendable special issue of the NewJournal of Chemistry devoted to chemical topology, alongwith many other contributions spanning from mathematicaltopology to polymers and DNA. A review by Sokolov15

appeared in Russian literature and is particularly relevantto the present discussion since it mentions the possible useof a transition-metal center as template to prepare a trefoilknot.

3 APPROACHES TO MOLECULARKNOTS

The “Mobius strip”—an appealing object in itself—provides a route to a trefoil knot (Figure 3). This path,first suggested by Frisch and Wasserman in 1961,13 isattractive in the present context but extremely difficult toperform by covalent-bond-forming chemistry alone. Schilland colleagues tried valiantly and with no shortage of syn-thetic ingenuity to reach a knot through a Mobius strip-like

Rung removal

Macrocyclization

Figure 3 A depiction of the Mobius strip approach to a Trefoilknot.

M M

Figure 4 Sokolov’s strategy for constructing a trefoil knot onan octahedral tris-chelate complex.15

molecule,16 but the number of steps and unwanted topolo-gies generated in some of the steps meant that the goalremained unachieved. A noncovalent strategy has yet to bereported.

An inspired route toward a trefoil knot can be found inSokolov’s classic review.15 The principle of the synthesisimagined by this author and published in 1973 is given inFigure 4. Three bidentate chelates disposed in a suitablefashion around an octahedral transition-metal ion used asa template may, after connection of their ends, lead to amolecular knot. Obviously, the probability that the six endswill connect (two by two) in the required fashion is quitelow. Nevertheless, strict geometrical control of the involvedcoordinated fragments can give access to a knot using thisstrategy, as we shall see later in this chapter.

In general, it is clear that the preparation of knots and rav-els requires the controlled formation of crossing points, andthe molecular fragments must be orthogonal to one another.Therefore, simple square-planar complexes, for example,are intuitively of little use for templating interlocked sys-tems, because the four divergent ligands do not have aneasy way to cross each other (although they may help to ori-ent fragments for covalent linkage, which is an interestingpossibility in the Mobius strip approach to knots). Sev-eral examples of orthogonality in chemical structures exist(Figure 5): perhaps the tetrahedral copper(I) complexeschampioned in Strasbourg,17 or maybe the threaded sys-tems based on donor–acceptor systems, combining hydro-gen bonding,18 and why not the hydrogen-bonding systemthat leads to two strands whose planes are held at largeangles to one another.19–21

The covalent closure of the termini of helices22

(Figure 6)—closed in the right way of course thanks tothe correct positioning of reactive ends—leads to a seriesof knots and multiply interlocked catenanes. For example,doubly helical coordination complexes are ideal precursorsin this sense, where transition-metal ions are wrapped bycoordinating strands to give the double helix. Joining theirtermini in the correct fashion gives knots and multiply rav-eled2 catenanes.


4 Self-processes

(a)

N

N

O

O

N

N

O

O

++

+ +(b)

(c)

N

N

OH

OH

N

N

HO

HO

Cu

ON

NH

H

O

OH

O

N

+

Figure 5 Chemical fragments that display orthogonality: (a) thecomplex formed by phenanthroline derivatives with copper(I) ions, (b) the host–guest complexes formed between electron-rich and electron-poor macrocycles and threads (and vice versa)where the π -stacking leads to an angle between the axis ofthe macrocycle and the thread (b), and (c) the complex formedbetween diamide derivatives.

Figure 6 Oligocenter double-stranded helices and the molecularknots and catenanes derived from them by appropriately joiningof the termini in the helical strands. An integral number ofturns lead to knots and additional half turns give multiplycrossed2 catenanes.

4 MOLECULAR KNOTS CONSTRUCTEDON DICOPPER(I) HELICALCOMPLEXES

4.1 Strategy

The templated synthesis of trefoil knots is based oncopper(I) coordination by phenanthroline ligands deriveddirectly from the synthetic concept that had already affordedan easy access to catenanes.17 The strategy of catenanesynthesis relied on the well-known specific property oftransition metals, namely, their ability to gather and disposeligands in a given predictable geometry, thus inducingwhat is generally called a template effect (see TemplateStrategies in Self-Assembly, Volume 5).

In the presence of copper(I), 2,9-dianisyl-1,10-phenan-throline or related compounds form a very stable pseudo-tetrahedral complex in which the two ligands are inter-twined around the metallic center. The success encounteredin the synthesis of various catenanes following the strat-egy, depicted in Figure 7, led to a molecular trefoil knotsynthesis by extending the former synthetic concept fromone to two copper(I) ions. As shown in Figure 8, twobis-chelating molecular threads can be interlaced on two-transition metal centers, leading to a double helix (A). Aftercyclization to (B) and demetalation, a knotted system (C)should be obtained. An important prerequisite for the suc-cess of this approach is the formation of a helical dinuclearcomplex (A).

Although the preparation of double helices from varioustransition metals and bis-chelate ligands is very likely tohave occurred long ago, it is only relatively recently that

2

Figure 7 The synthesis principle of a [2]catenane based oncation coordination by chelating ligands.



2

22

A

BC

Figure 8 Strategy leading to a trefoil knot (C) which involvestwo metal centres and two coordinating organic threads givingcomplex A, followed by ring closure to give B and then removalof the templating ions.

the first such system was recognized and characterized.23

Moreover, apart from their beauty, their scientific relevancewas not at all obvious. One of the earliest dinuclear heli-cal complexes was identified by Fuhrhop and coworkers in1976 (Figure 9).23 Since then, several double helical com-plexes have been formed, and their interest in the contextof interlocking molecular structures has been pointed out.24

In particular, if synthesis is to be done, the helices must beformed efficiently and must be stable to the conditions ofthe covalent-bond-forming reactions. As we shall see, theadvances in softer reactions for covalent bond formation areproviding a fillip for the preparation of complex molecularforms.

4.2 The first synthetic molecular trefoil knot

After many attempts with various linkers, it was found that1,10-phenanthroline nuclei connected via their 2-positionsby a –(CH2)4 – linking unit will indeed form a double helixwhen it forms a complex with two copper(I) ions. In addi-tion, by introducing appropriate functions at the 9-positions,the strategy of Figure 8 could be followed to achieve thesynthesis of a molecular knot of the (C) type. The dipheno-lic bis-chelating molecular thread 1 (prepared in a few stepsstarting from 1,10-phenanthroline and Li–(CH2)4 –Li wasreacted in 2 : 2 stoichiometry with Cu(CH3CN)4 . BF4 toafford the dinuclear precursor double helix 22+ (Scheme 1)together with a significant proportion of other copper(I)complexes. The complex mixture containing the double

N

N

N

N

OHCO

N

N

N

N

OOHC

Zn2+

Zn2+

Figure 9 A ravelled complex formed by coordination by chelat-ing ligands when bound to zinc(II) ions.

Figure 10 The structure of 32+ as it exists in its crystals.

helix was reacted under high dilution with two equivalentsof the di-iodo derivative of hexaethyleneglycol in the pres-ence of caesium carbonate. After a long and difficult purifi-cation process, the bis-copper(I) complex 32+ could be iso-lated in 3% yield.25 Its knotted topology, first evidenced bymass and nuclear magnetic resonance (NMR) spectroscopy,was later fully confirmed by an X-ray structure determina-tion26 (Figure 10).

Treatment of 32+ with a large excess of potassiumcyanide led quantitatively to the free knot 4 (Scheme 2)whose topological chirality was demonstrated by NMRspectroscopy.


6 Self-processes

N N

OH

OH

OH

2 Cu(CH3CN)4+

Cs2CO3, DMF, 60° C

N N

HO

2

HO

HO

N N N

N N

NNN

NO

O

O

O O O

O

O

O

O

OOO

O

N

N

N

N N N N

OH

OH

NN

N NNN

N NHO

HO

I-CH2(CH2OCH2)5CH2-I

1 22+

22+ 32+

Scheme 1

N N

NN

N N

N N O

O

O

O

O

O

O

OO

O

O

O

O

OO

O

O

OOO

O

O

OOO

O

O

O

NNNN

NNNN

CN−

32+ 4

Scheme 2

4.3 Generalization and improvements

The modest yield (only 3%) obtained for the originaldicopper knotted 86-membered ring could be significantlyimproved by modifying the length of the linker connecting

the two chelates and the long functionalized chain usedin the cyclization step.27 The best yields obtained werein the range of 8% but, using polymethylene linkersbetween the phenanthroline nuclei, it turned out to bethe upper limit. A very great improvement was achieved



by using a 1,3-phenylene spacer between the coordinatingunits.28

Preparation of the double-stranded helical precursorwith copper(I) using the 1,3-phenylene linker turned outto be quantitative. Reaction of this tetraphenolic doublehelix with two equivalents of the di-iodo derivative ofhexaethyleneglycol, in the presence of caesium carbonate,afforded a single isolable copper(I) complex; the dicopper(I)knot was isolated in 29% yield after chromatography. 1H-NMR spectroscopy data indicated that the knot contained acompact helical core. This was fully confirmed by its subse-quent X-ray structure determination.28, 29 The spectacularlyimproved yield can be increased even further by optimizingthe covalent-bond-forming reactions, whose conditions canharm the helical precursors.

The metallo-carbene catalysts for ring-closing metathesis(RCM) reactions are ideal for this purpose.30 As a resultof the mild reaction conditions and lack of competitionwith the coordination chemistry of the intermediate helicalcomplex, the RCM strategy is particularly well adapted tothe synthesis of copper(I)-complexed catenanes.31 A naturalextension of this work was the preparation of a trefoil knotfollowing the strategy depicted in Figure 11.

Mixing the strand-like molecule 5 and Cu(I) resultedin the quantitative formation of the helical knot precursor62+ (Scheme 3). The double RCM reaction of the ter-minal olefins catalyzed by RuCl2(PCy3)2(=CHPh) (Ph =phenyl, Cy = cyclohexyl) afforded the trefoil knot 72+ in74% yield32 (Figure 15). The only other products wereoligomers arising from intermolecular metathesis reactions.

Therefore, combining the quantitative formation and highstability of the helical precursor composed of Cu(I) bis-phenanthroline units linked by 1,3-phenylene units and thehighly efficient RCM methodology developed by Grubbsand coworkers, the dicopper(I) trefoil knot 72+ could beobtained in seven steps from commercially available 1,10-phenanthroline, with an overall yield of 35%.32 The cisor trans nature of the two cyclic olefins formed in themetathesis reaction meant that the dicopper(I) trefoil knot72+ was first obtained as a mixture of isomers (cis –cis,cis – trans, and trans – trans products). This issue is easilyaddressed because the olefins can be quantitatively reducedat room temperature by catalytic hydrogenation.

The great improvements in yield made it possible to studythe specific properties of the knots related to their topology,to resolve the enantiomers, and also to study their coordina-tion chemistry. It also became possible to prepare the firstchemical knot composite33 and to prove its complex andunusual topology. The various complexes of knotted ligandsdisplay extraordinary kinetic inertness toward demetalationand, because of the proximity between the two copper ionsin the helical core of the knot, novel electronic proper-ties could be evidenced.34 In particular, the Cu(II)–Cu(II)oxidation state is strongly destabilized, as shown by theextremely high redox potential of the system [∼0.9 V vsSCE (standard calomel electrode) in acetonitrile], whichmakes it almost unique in copper chemistry.

5 TO MOLECULAR KNOTS BYHYDROGEN BONDING

In general terms, the construction of knots using purelyorganic molecular fragments is a far greater challenge thanthe approaches using coordination bonds. The generallyweaker nature of the interactions between organic moieties,the reversibility of association, and the less well-definedorthogonal interaction between units are the reasons for thisdifficulty.

The construction of a trefoil knot through the use ofπ-stacking interactions between dioxynapthalene units andbipyridinium residues as well as hydrogen bonds led to thepreparation of the knot 8, albeit in very low yield.35

N

N

N

N

++

+ +

O

N

N

+

+

O

O

O

O

O

O

O

O

O

O

O

OO

O

8.6PF6

6PF6−

H2[Ru]22

Figure 11 A general strategy to knot synthesis based on the combination of metal templating and the ring-closing metathesis reaction.


8 Self-processes

NN N

N

O

OOO

O OOO

O

O

N N

N N

NN

N N

N N

N N

N

N N

O

O

O

OO

O

O

OOO

O

O

O

OO

OOO

N

O

O

Grubb'scatalyst[Ru]

Cu(I) 2+

5

62+

72+

2+

Scheme 3

A remarkably efficient molecular trefoil knot synthesisbased on organic templates was reported by Vogtle andcoworkers, who serendipitously made and astutely iden-tified the “knotane.”36 In the course of the synthesis of[n]catenanes, reaction of the simple precursors 9 and 10 inthe presence of triethylamine under high dilution conditions(10−3 mM in dichloromethane) produced three colorlessproducts: macrocycle 11 (15% yield, 1 : 1 ratio of reagents

N

OCl

OCl

ONH

O

HN

H2N

H2N

N

O

O

ONH

O

HN

NH

HN

NO

O

ONHO

NH HN

NH

N

O

O

O NH

OHN

NHHN

N

O

O

O

NHO

NH

NH

NH

N

O

O

ONH

O

HN

NH

HN

N

O

O

O

HN

O

NH

HN

NH

910

11

12

13

CH2Cl2 NEt3

Scheme 4

in the product); the 2 + 2 macrocycle 12 (23% yield); andthe knot, which incorporates three of each reactant, in 20%yield (Scheme 4).

While the first analysis (1H NMR and mass spectrometry)did not give enough information to determine the structureof 13 (knotted or catenated) although the molecular weightcorresponded to a 3 : 3 macrocyclization, the surprisingdefinitive proof came from single-crystal X-ray diffraction.



Figure 12 The structure of purely organic knot 13 in its crystals.

The knotted structure was patent in the crystal structure(Figure 12), which showed a pattern of hydrogen bondsbetween amide groups. A similar pattern is also found in thestructure of [2]catenanes and rotaxanes synthesized usingthe same basic template.20

The knot can also be prepared using a stepwise synthesis,which helps to determine the route by which it is formedin the one-step reaction.37 The string-like molecule 14(Figure 13) was prepared in order to ascertain whetherindeed it is an intermediate on the pathway to knot 13.Indeed, reaction of this “open knot” with di-acid chloride 9generates the knot 13 in 11% yield.37 Clearly, the possibilityof using the “open knot” as a reagent with different di-acidchlorides is possible, and leads to a variety of substitutedknot molecules.37

The proposed mechanisms and routes for formation ofthe knot are shown in Figure 14. These routes may passthrough various complexes, but the knot must be formedultimately from raveled molecules such as 14. In contrast tothe Cu(I)-based template synthesis, no external templatingagent is necessary.

Further studies of the two precursors 9 and 10 provedthe reliability of this templated synthesis leading to alarge number of molecular knot analogs of 1338, 39 andmore exotic structures.40 The possibility of forming com-pounds that contain various knots was made possibleby the functionalization of the 5-position of the pyri-dine rings with different synthetically useful groups,39

which makes possible selective reaction at each exter-nal loop and can be appreciated in the X-ray structureof the native compound. For example, the functional-ization of the knots’ allyloxy units presents the oppor-tunity for forming linear and branched oligomers ofknots.40

The conformational dynamics of the knots has been stud-ied by NMR spectroscopy,39 which shows that in dimethyl-sulfoxide (DMSO) the compound has an essentially fixedconformation on the NMR time scale with a structure sim-ilar to that seen in the solid state, while in chloroform theknot shows dynamics at the time scale of the spectroscopicexperiment.

This purely organic knot synthesis is appealing becausein its simplest form it is a one-pot procedure that affordsreasonable yields and unique possibilities for the prepa-ration of derivatives in the context of the knots preparedto date. This advantage is at the same time the principaldefect of the molecules, as they have yet to show anyrecognition behavior, and the knot is essentially a closedsystem. However, the functionalization of the knots makesit possible to use them as scaffolds for pendant groupswhich have some function, for example, as fluorescentswitches.41 The many other possibilities for these knotshave yet to be explored, although the synthetic foundationis laid.

6 MOLECULAR KNOTS CONSTRUCTEDON OCTAHEDRAL COMPLEXES

After Sokolov’s idea of the formation of a knot bythe use of an octahedral transition-metal ion as a tem-plate for three bidentate chelates disposed in a suitablefashion, Hunter and colleagues reached the goal veryrecently.42 An “open” knot was prepared by the samegroup43 and was used as the basis for the eventuallysuccessful approach. The strand 15 (Scheme 5) was usedto make the ravelled structure 16 by complexation with


10 Self-processes

NO

O

ONH

O

NH HN

NH

N

O

O

O NH

OHN

NHHN

O

NHO

NH

NH2

H2N

O

HN

O

HN

H2N

HN

NO

O

O

HN

O

HN

HN

HN

14

HN

H2N

NO

O

O

HN

O

HN

Figure 13 The open and raveled conformation of strand 14.



Cl

Cl

+

NH2

NH2

NH2

NH2NH2

NH2

NH2

NH2

NH2

NH2

H2N

H2N

NH2

Possiblecomplex

RavellingDirectsynthesis

14

910

13

O

O

N

O

O

Figure 14 Routes to the molecular knot 13.

N N

OOO O

N

N

RO

N

N

ORN N

OO

OO

N

N

OR

N

N

RO

Zn

Zn(II)

15

16

Scheme 5

Zn(II). The three chelates in the strand—2,2′-bipyridinemoieties linked through the 3,3′-positions to ensure enoughspace around the coordinating groups—probably coor-dinate to the transition-metal ion through a kind of“arm crossing” mechanism, by which one bipyridineunit in an intermediate structure is temporarily releasedbecause of the labile nature of the zinc–nitrogen inter-action, which does not give a kinetically stable loopstructure.

This route has now led to the formation of a trefoilknot using either esterification or RCM of appendagesto the alcohol functions. The ester functions are ratherunstable, but the compound formed by RCM allows theremoval of the templating zinc ion, giving the “free”knot. This ligand forms much more stable complexeswith zinc(II) than the precursor linear complex, whichis a characteristic trait of topologically nontrivial ligandsystems.


12 Self-processes

7 TOPOLOGICAL ENANTIOMERS ANDDIASTEREOMERS

Topological chirality is a level of chirality beyond thatof Euclidean geometry—where the relative disposition ofgroups in a chemical object (in the case of stereochemistry)defines its chirality—involving molecular objects withnonplanar molecular graphs (they cannot be drawn on aplane of paper without crossing points) that cannot beconverted into their enantiomers even upon total distortion.The trefoil knot, which is a single-knotted, closed ringthat has three crossing points in its representation in two-dimensional space, can be considered as the prototypicalexample of an unconditionally topologically chiral object(no need to either orient or color the edges for the speciesto be chiral).

The syntheses of knots using the copper(I)-templatedstrategy lead to the target molecules such as cationic dicop-per(I) complexes. Therefore, the possibility of forming apair of diastereomeric salts by combining them with anoptically active anion is interesting. Binaphthyl phosphate(BNP−) is persistently chiral on account of the twisteddisposition of the naphthyl rings, and the high barrierto interconversion of the enantiomers makes the ion agood resolving agent. This helical structure bears struc-tural resemblance to the dicopper(I) knots. Besides, bothcompounds are aromatic and thus one can expect somepotentially helpful stacking interactions. To introduce thechiral auxiliary, a labile anion, unlike the classical BF4

− orPF6

− which are hard to exchange, is required. Preliminarystudies showed triflate to be appropriate. It was introducedduring the formation step of the double helix of the bis-chelating diphenolic strand with the 1,3-phenylene spacer(Figure 15). One equivalent of copper(I) triflate was addedto the strand in a reductive medium. 1H-NMR showed thatthe dinuclear copper(I) double helix was formed quantita-tively, with CF3 –SO3

− as the counterion. The bicycliza-tion reaction afforded the racemic copper(I) knot triflate in23% yield.

The racemic mixture of the knot was converted intodiastereomers using a liquid–liquid extractor taking advan-tage of the solubility of potassium triflate in water comparedto the insolubility of BNP salts. The 1H-NMR spectrumof the diastereomeric mixture indicated a strong differenceof association between the chiral auxiliary and each enan-tiomer of the knot. This difference was large enough to givethe two diastereomers different solubilities. Indeed the (+)isomers of knot and anion crystallize together,44 while thelaevorotatory knot remains in the mother liquor.

The pure topological enantiomers were liberated fromthe diastereomeric salts by counterion exchange with hex-afluorophosphate. The optical rotatory power of the cop-per(I) knots is very high: At the sodium D line (589 nm),

the optical rotatory power was ±7000 ◦ mol−1 l dm−1.The circular dichroism (CD) spectra of the enantiomers(Figure 15) show mirror image forms with maxima cor-responding to the chromophores in the molecule.

The enantiomerically pure free ligands were preparedin order to investigate the properties of a molecule forwhich chirality was exclusively originating from its topol-ogy (i.e., it had nothing to do with that of transition-metalcomplexes). The double helix of the metalated species haspure classical Euclidian chirality present. Each enantiomerwas demetalated using cyanide as copper(I) quencher.The optical rotatory power of the free knot was then± 2000◦ mol−1 l dm−1. These topological enantiomers can-not be interconverted by continuous deformation, so racem-ization is impossible as long as no bond in their organicbackbone is broken. In addition, the combination of thislatter topological property with the high thermodynamic sta-bility of copper(I) 2,9-diphenyl-1,10-phenanthroline com-plexes provides such complexes with promising catalyticproperties for enantioselective processes.

The knots based on neutral, purely organic moleculesare obviously not prone to classical diastereomer resolu-tion, and, while chromatographic methods were not suitablefor the separation of the two enantiomers of the metal-templated trefoil knot, they have been proved successfulin the amide-containing knots. As far as these knottedmolecules are concerned, it must be noted that they incorpo-rate “classical” stereogenic centers (carbon atoms), whichmakes them very different from the copper-based systems interms of chirality. In the first instance, the separation of thetwo enantiomers of six different knots was achieved witha column that was not commercially available (chiral-ADtype).38 Trichloromethane was needed to obtain an optimalseparation. The silica gel and the chiral stationary phasewere covalently bound so that the material did not bleed outwhen the lipophilic eluent was used. Moreover, comparisonof the experimental CD of the pure enantiomers of a knotwith a theoretically calculated CD (based on X-ray structureand a fully optimized AM1 geometry) permitted assign-ment of the absolute configuration of this knot. The latterpreparation of soluble knots based on substitution of the5-position of the pyridine moieties in 13 afforded moleculesthat were soluble in solvents which could be used in com-mercially available chiral columns.45 On the other hand,the substitution of a racemic mixture of knots with chi-ral auxiliaries allows the separation of the diastereomericproduct.46

The stereoselective formation of knots is also possible:that is, to use Euclidian chirality and transfer it to topo-logical chirality. This feat was surprisingly achieved inthe cyclization of a steroid–amino acid sequence.47 Theactivated ester 17 was cyclized in a mixture of solvents giv-ing the cyclic trimer (not shown) and the cyclic hexamer



O

ONN

N NN NO

OO O O

O

O

O

O O OO

O

O

OOOO

O

O

O

O

N N

N N N

N N

N

O O OO

NN

650

0

−650280 490 700

∆e

x 14

2+

2+

Right-handed knot (−)

Left-handed knot (+)

nm

Figure 15 CD spectra of the left- and right-handed knots indicated as their hexafluorophosphate salts.

(in 21% yield) which is a knot (Figure 16). Only one ofthe diastereomeric products is observed, denoted 3ppp

1 , witha p-type crossing. The molecule is bowl-shaped, and hasan apolar exterior and polar core, with propanol and watermolecules included. The possible driver of the cyclic assem-bly is a hydrogen bond between the amide carbonyl groupand a hydroxyl group of the steroid moiety. The fact thatthe molecule has polar and apolar regions made the authors

suggest the possibility of the use of this type of structurefor catalysis.

8 BORROMEAN RINGS

This chapter is centered around knots, and up to now purelysynthetic knots (not incorporating DNA nor composite


14 Self-processes

OH

NaHCO3, H2O, CHCl3, CH2Cl2

17

18

H2NNH

O

O

O

F

F

F

F

F

O3FN1F N8C

N8FO10C

O10F

O25C

O25F

O10D

O25D

O25A

O10E

O25EO25B

O3E

N1E

N8E

N8B

O3B

N1B

O10B

O10A

N1D

O3DN8D

O3A

N1A

N8A

O3CN1C

Figure 16 Synthesis of a knot from a steroid–amide conjugate,showing the crystal structure of the product.

knots) have only been made with three crossing points.Linked structures, such as doubly interlocked catenanes,48

have been prepared, and offer clues as to how higher knotsmay be approached. A special example of this kind ofmultiply interlocked structures, which shows how design ofthe positioning of groups can lead to complexity in raveling,follows. The Borromean rings (Figure 17) comprise threeinterlocked rings, none of which are interlocked directlywith each other: Breaking one ring results in the liberationof two rings and a thread. They are a link, not a knot,but contain complex raveling of the components. For manyyears, the Borromean rings were an enticing but elusiveobject for the chemist. Many were the eager students andseniors in different research groups attacking catenanesand knots who would plan their strategies to such achallenge.49

The rings were prepared in an all-in-one strategy, com-bining noncovalent and dynamic covalent chemistry withthe geometrical precision given by coordination chemistry.Cooperativity between π –π stacking interactions and coor-dination geometries was optimized. Molecular modelingindicated that the reaction (Scheme 6) of aldehyde 19 withamine 20 would afford macrocycle 21 which, in the pres-ence of zinc(II), would optimize its structure so that the

The Borromean ringsVennrepresentation Orthogonal

representation

BA

C D

Figure 17 The Borromean rings and the strategies for theirformation.

N

OH

OH

19 20

N N

OOH2N NH2

N

O

O

21

N N

OON N

N

O

O

NN

O ONN

Scheme 6

metal ion was 5-coordinate with one exo- (the bipyridine)and one endo- (the pyridine bis-imine) ligands to give theBorromean rings. This indeed proved to be the case.

In the Borromean rings made in this way, three macro-cycles are present diagonally in pairs, and six exo-bidentatebipyridyl and six endo-diiminopyridyl ligands coordinate tothe six zinc(II) ions. The rings were made from 18 compo-nents by virtue of template-directed formation of 12 imineand 30 coordinative bonds. Each ring is tetranucleatingand decadentate overall. Its formation is near-quantitative,and has been taken to the gram scale.50 This kind of exo-coordination combined with endo-complexation gives clear



messages as to how to go about the preparation of higherknots.

9 INSPIRATION FROM DNA KNOTS

Single-stranded DNA has been used for the construction oftopologically complex unnatural interlocked structures in amost impressive manner.51 The Watson–Crick base pairingallows mutually compatible sequences of DNA—designedso as to form interlocked structures—to control preciselythe raveling necessary to form knots. The design andpreparation of a synthetic knot comprising a single-strandedDNA molecule was described in 1991.52 Two full turns ofa DNA double helix was the starting point for a trefoilknot, which is made by the appropriate connection of thetermini of the double helix. A 41 knot has been made ina similar fashion.53 This figure-of-eight knot contains twopositive and two negative nodes, defined by the directionin which the strands cross one another. The direction ofDNA can be defined as the 5′ to 3′ vector, and the right-handed helix formed B-DNA having exclusively negativenodes, while the left-handed Z-DNA double helix results inexclusively positive nodes. Control of the type of DNA ateach crossing permits the stereoselective formation of theknots. This approach is inspirational for the purely syntheticapproach to knots of increased complexity.

10 CONCLUSION

The use of noncovalent bonds (coordination chemistry,hydrogen bonds, ion–dipole interactions, hydrogen bond-ing, and so on) to help create the suitable arrangementof molecular fragments leads to the efficient raveling ofstrands and—with the right chemistry—to knots in rela-tively high yields, and certainly were unthinkable at thetime of their earliest mention in the chemical literature(1960). Transition metals have proved extremely useful intheir ability to gather and intertwine string-like molecu-lar fragments, before the appropriate ring-forming reactionsare carried out. The second efficient approach is basedon hydrogen bonding. This impressive synthetic achieve-ment was probably not totally predicted by the authorsthemselves, but the result is that another novel and reallypreparative method is now available. Because the first seriesof molecular knots stem from coordination chemistry, mostof their interesting properties are related to transition-metalchemistry. On the other hand, the Bonn series made byVogtle and coworkers is purely organic and structurallymuch closer to biological molecules. New properties couldthus be expected in relation to modeling biological pro-cesses such as the knotting or the catenation of proteins.

Both series of molecular knots are thus complementary andit is expected that, in the future, other families of knottedmolecules with distinct properties will also be made andstudied.54 In this context, the properties of a pure poly-methylene knotted ring should be fascinating, although thesynthesis of such a compound seems to be presently out ofreach.

Where will the chemistry of knots lead us? Today, it is ofcourse difficult to know whether practical applications willbe found, although one could easily imagine that polymerscontaining knotted fragments could be interesting organicmaterials or that knotted compounds able to interact ina specific way with DNA could display new biologicalproperties. It remains that the field is still fascinating froma purely fundamental viewpoint. The challenge of makingnontrivial prime knots beyond the trefoil knot is certainlyworth considering, although when looking at the beautifulbut very complex knots of Figure 2, one can foresee greatchemical difficulties.

Obviously, chirality is an essential property in molecularchemistry, and knots are exciting systems in this context.The stereoselective synthesis of knots is an attractive andchallenging goal as yet assailed on only one occasion.With a touch of fantasy, it can be conceived that someof the chemical processes for which chirality is essential(enantioselection of substrates, asymmetric induction andcatalysis, cholesteric phases and ferroelectric liquid crystals,molecular materials for nonlinear optics, etc.) can one dayuse enantiomerically pure knots. The future of molecularknots will, to a large extent, be determined by their accessi-bility and, even though the transition-metal-templated strat-egy and the hydrogen-bond approach represent interestingsynthetic achievements, there is still a long way to go beforemolecular knots can be made at a preparative scale com-patible with industrial applications.

The use of molecules to template knots is a greatchallenge, and one that would afford topologically complexsystems capable of recognizing substrates. It is likely thatthis kind of structure would yield unprecedented selectivityin stereoselective binding.

Nature has used raveled and knotted structures to over-come many problems often related to enzyme stability, andwe therefore believe that it is only a matter of time before aknotty chemical solution will make a breakthrough in somearea of the synthetic molecular sciences.

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Templated Synthesis of Knots and Ravels · 9 Inspiration from DNA Knots 15 10 Conclusion 15...

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