Cooperative effect of a classical and a weak hydrogen bond for the metalInduced construction of a self-assembled β-turn mimic

FULL PAPER

DOI: 10.1002/chem.200900662

Cooperative Effect of a Classical and a Weak Hydrogen Bond for the Metal-

Induced Construction of a Self-Assembled b-Turn Mimic

Andy C. Laungani,^[a]Manfred Keller,^[a]John M. Slattery,^[b]Ingo Krossing,^[c]and

Bernhard Breit*^[a]

Abstract: A novel metal-induced tem-

plate for the self-assembly of two inde-

pendent phosphane ligands by means

of unprecedented multiple noncovalent

interactions (classical hydrogen bond,

weak hydrogen bond, metal coordina-

tion, p-stacking interaction) was devel-

oped and investigated. Our results ad-

dress the importance and capability of

weak hydrogen bonds (WHBs) as im-

portant attractive interactions in self-

assembling processes based on molecu-

lar recognition. Together with a classi-

cal hydrogen bond, WHBs may serve

as promoters for the specific self-as-

sembly of complementary monomeric

phosphane ligands into supramolecular

hybrid structures. The formation of an

NMR spectroscopy analysis. Further

evidence was demonstrated by DFT

calculations, which gave specific geo-

metric parameters for the proposed

conformations and allowed us to esti-

mate the energy involved in the hydro-

gen bonds that are responsible for the

molecular recognition process. The pre-

sented template can be regarded as a

new type of self-assembled b-turn

mimic or supramolecular pseudo amino

acid for the nucleation of b-sheet struc-

tures when attached to oligopeptides.

ꢀ

intermolecular C H···N hydrogen bond

and its persistence in the solid state

and in solution was studied by X-ray

crystal analysis, mass spectrometry and

Keywords: dimerization · hydrogen

bonds

·

molecular recognition

·

noncovalent interactions

assembly

·

self-

Introduction

tions, for example, ionic interactions, van der Waals forces

and hydrogen and coordinative bonding.

Molecular self-organisation and self-assembly,^[1]processes

that spontaneously create noncovalently joined structures

through a statistical exploration of many possibilities, have

emerged as a powerful tool for the construction of distinct,

novel supramolecular architectures^[1]and nanomaterials^[1,2]

There has been great interest in combining dynamic coor-

dination chemistry and hydrogen bonding to build complex

metal–organic coordination polymers, macrocycles, networks

and other supramolecular architectures or catalysts by self-

assembly from small, easily prepared building blocks.^[5–9]For

instance, we reported an alternative approach to generate

bidentate ligand libraries that relies on a self-assembly

system analogous to that of A·T base pairs, based on hydro-

gen bonding and ligand-to-metal-coordination interactions

of monodentate P-ligands (Scheme 1A and B).^[7]

with remarkable structural diversity and applications.^[1,3,4]

A

rational approach to such functional supramolecular struc-

tures requires mastering the multiple and competing interac-

[a] Dr. A. C. Laungani, Dr. M. Keller, Prof. Dr. B. Breit

Institut fꢀr Organische Chemie und Biochemie

Albert-Ludwigs-Universitꢁt Freiburg

In the past few years, the main interest in the investiga-

tion of hydrogen-bond-assisted self-assembly in the solid

ꢀ

and solution state was concentrated on heteroatom X H···Y

Albertstrasse 21, 79104 Freiburg (Germany)

Fax : (+49)761-203-8715

E-mail: bernhard.breit@organik.chemie.uni-freiburg.de

hydrogen-bonding-directed self-organisation with a strong

hydrogen donor.^[10–12]Besides these well known, comparably

[b] Dr. J. M. Slattery

ꢀ

strong hydrogen bonds, only a few examples of C H···X hy-

Department of Chemistry, University of York

Heslington, York, YO10 5DD (UK)

drogen bonds are described in the formation and stabilisa-

tion of self-assembled structures both in the solid state^[12–16]

and in solution.^[6f,g,15a,b]To the best of our knowledge, molec-

ular recognition through weaker hydrogen bonding has not

been employed for the directed construction of supramolec-

ular systems in solution, although this unusual interaction

[c] Prof. Dr. I. Krossing

Institut fꢀr Anorganische und Analytische Chemie

Albert-Ludwigs-Universitꢁt Freiburg, 79104 Freiburg (Germany)

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/chem.200900662.

Chem. Eur. J. 2009, 15, 10405 – 10422

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

10405

Results and Discussion

Synthesis of phosphane ligands and metal complexes: Sever-

al different ligands designed to initiate template self-assem-

bly were developed. The metal-binding templates provide

ꢀ

two reactive functional handles ( CO₂H and NH₂) and

therefore can be divided into two groups: C-linked and N-

linked phosphane ligands. The structures of these ligands

with different template backbones presented in this paper

are shown in Schemes 2 and 3.

Scheme 1. General concept of monomeric metal-templating modules ca-

pable of self-assembling upon metal complexation. Template backbones

are functionalised with metal-coordinating donor groups and possess ap-

pended hydrogen-bonding donor and acceptor sites for molecular recog-

nition. Addition of a metal (M) results in the direct formation of comple-

mentary noncovalent interactions, that is, metal complexation, classical

hydrogen bonding (A and B)^[7]or weak hydrogen bonding (C, this work).

Scheme 2. Synthesis of C-linked phosphane ligands.^[28]a) Na (4 equiv),

NH₃, PPh₃(2 equiv), THF, ꢀ788C!RT (63%); b) corresponding alcohol

or amine, DIC, DMAP, CH₂Cl₂, RT (57–78%); c) nBuLi, CH₂Cl₂,

Ph₂PCl, ꢀ788C!RT (66%); d) nBuLi, THF, CO₂, ꢀ1008C!RT (74%);

e) corresponding amine, DIC, DMAP, CH₂Cl₂, RT (56–74%).

has been the subject of much interest and it has been in-

voked to explain 1) enhanced stabilisation effects in A·T,

A·U^[15]and platinated G·C base-pair systems,^[6f,g]2) biologi-

cal processes^[16,17](i.e., protein–ligand interactions), 3) self-

assembly of 2D nanostructured surfaces^[12,14c–e]and 4) pro-

cesses in molecular crystal engineering.^[18]Moreover, C H

Phosphane ligands 3 and 8d–f were presented in a previ-

ous work.^[8]C-linked aryl phosphanes 3 were prepared in a

novel and efficient one-step synthesis from 2-chlorobenzoic

acid (1) and subsequent transformation of 3-diphenylphos-

phanylbenzoic acid (m-DPPBA, 2)^[29]into the corresponding

ester 3a or amides 3b,c. The peptide-based ligands were

easily synthesised by conventional solution-phase peptide

synthesis procedures.^[8]The novel C-linked pyridines 6 can

be easily prepared from 2,6-dibromopyridine (4) by means

of a bromine/lithium exchange with nBuLi in dichlorome-

thane at ꢀ788C to give exclusively the monolithiated prod-

uct. The efficiency of this method and the potential utility of

non-ethereal solutions of 2-bromo-6-lithiopyridine have al-

ready been shown elsewhere.^[30]

Next, the introduction of a carboxylic acid function (6-

DPPPCA, 5) through a second bromine/lithium exchange

and quenching with gaseous CO₂performed well. Ligand di-

versification to compounds 6a,b is then achieved in good

yield under Steglich conditions^[31](4-dimethylaminopyridine

(DMAP)/diisopropylcarbodiimide (DIC))^[28]with the corre-

sponding amines. The N-linked ligands 8 were synthesised

out of 6-diphenylphosphanyl-2-aminopyridine (6-DPPAP,

7)^[7b]and the corresponding acid chlorides to give the li-

gands 8a–f in good to excellent yields. Finally, the synthesis

of novel N-linked aryl phosphanes 11, outlined in Scheme 3,

involved a three-step reaction pathway that began with

1) TMS protection of the aniline NH₂protons,^[32]2) hal-

ꢀ

hydrogen bond donors have long been accepted by crystal-

lographers, but experimental solution-state evidence for the

[15,19]

ꢀ

presence of C H···X bonds is extremely rare.

In addi-

tion to that, weak hydrogen bonds (WHBs) are mostly just

co-stabilising interactions and there have been so far no

ꢀ

cases in which C H···O/N hydrogen bonds played a key role

in ligand design, nor were they used as an essential tool for

promoting a self-assembly process in the solution state.^[20]

We have previously reported the coordination-driven self-

assembly of novel peptide-based phosphane ligands into

well-defined b-sheet structures, which are part of a new

class of metal-containing supramolecular structures, chiral

bidentate ligands and protein mimics.^[8]Although several

pseudo amino acids and molecular templates for the direct

nucleation of defined b-sheet secondary structures have

been developed in the past,^[21–24]noncovalent templating ap-

proaches still remain scarce.^[8a,25,26]Herein we study the

scope and limitations of a novel, self-assembled b-turn mim-

icking template (Scheme 1C) and revise what factors are es-

sential for the stabilisation of the assemblages. Thus, com-

pared with other reported self-assembled systems (A and

B), we investigate the limits of this self-organising process

and ask ourselves if one classical hydrogen bond and at least

one additional but weak hydrogen bond may be the minimal

requirements for a molecular recognition process in these

interesting supramolecular systems.^[27]

10406

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 10405 – 10422

Self-Assembled b-Turn Mimic

FULL PAPER

actions (vide infra). In absence of the metal-ion, the ligands

did not self-associate and remained dispersed and unfolded.

Crystal structure of cis-[PtCl

crystals suitable for single-crystal X-ray diffraction analysis

were obtained from a solution of 3b, 8d and cis-[PtCl₂A(cod)]

₂ACHTUNGTNER(NUNG 3b·8d)]: Colourless plate-like

CHTUNGTRENNUNG

in toluene/CDCl₃(5:2 v/v) that was allowed to stand at

room temperature for two weeks. The crystal structure

(Figure 1) unambiguously showed the selective formation of

Scheme 3. Synthesis of N-linked phosphane ligands.^[28]a) NH₄OH, 1908C

(85%); b) Na, NH₃, PPh₃, toluene, ꢀ788C!RT (60%); c) corresponding

acid chloride, py or NEt₃, CH₂Cl₂, 08C!RT (60–96%); d) nBuLi, THF,

Me₃SiCl, 08C (48%); e) nBuLi, Et₂O, Ph₂PCl, 08C (88%); f) corre-

sponding acid chloride, py, CH₂Cl₂, 08C!RT (84–99%).

ogen–metal exchange with nBuLi in ether at 08C, addition

of diphenylphosphanyl chloride and deprotection of the

TMS groups under acidic conditions in a one-pot protocol^[33]

and 3) coupling with acid chlorides to afford ligands 11a,b

in excellent yields.

Thus, the starting P-modules (2, 5, 7 and 10) were quickly

accessible and diversification was achieved by changing C/

N-linked side chains and/or introducing a nitrogen atom

into the aromatic template subunits (3 vs. 6; 8 vs. 11). The

presence of a heteroatom in one or both complementary

metal-coordinating templates should convey interesting

properties to the whole system. Facile diversification of the

side chains also gives the possibility of studying the behav-

Figure 1. PLATON plot of cis-[PtCl₂ACTHNUTRGNEUGN(3b·8d)] in the solid state at 100 K.

ꢀ

Selected interatomic distances [ꢃ] and angles [8]: Pt P1 2.238, Pt P2

ꢀ

2.259, C2···N11 3.572, N12···O2 2.961; P1-Pt-P2 97.9, C H2···N11 139.7,

ꢀ

N12 H···O2 129.7. H atoms bound to C atoms (except H2) and disor-

dered toluene and CDCl₃solvent molecules in the lattice were omitted

for clarity.

a 1:1 complex between one C-linked (3b) and one N-linked

ligand (8d) linked by a pair of hydrogen-bonding interac-

tions well within the distances of definite hydrogen bonds.

ꢀ

iour of the atoms involved in this unusual weak C H···N in-

teraction. With this strategy, both the electronic structure of

the ligand and its steric environment can be varied to ex-

plore and modulate the topological and functional proper-

ties of the assembly process. Moreover, the dimensions of

the templates are chosen such that the pendant donor/ac-

ceptor groups and/or the attached peptide chains can theo-

retically be brought into hydrogen-bonding registry.

From the X-ray crystal structure of cis-[PtCl₂ACTHUNGTERNNU(G 3b·8d)], it ap-

peared that two different cis-coordinated phosphane ligands

form an unexpected hydrogen-bonding network, containing

a classical and a non-classical, weak hydrogen bond. The

classical and certainly stronger intermolecular hydrogen

bond is formed by the amide groups attached to the aromat-

ꢀ

ic rings. The N H···O=C length (2.225 ꢃ) and hydrogen

We reasoned that simple mixing of equimolar amounts of

C-peptide ligands L_C(3, 6) and N-peptide ligands L_N(8, 11)

bond angle (129.78) are in good agreement with typical hy-

drogen bonding.^[16,17a]

in the presence of, for example, cis-[PtCl

G

X-ray diffraction analysis also indicates a highly ordered

ꢀ

cyclooctadiene) should result in the exclusive formation of a

well-defined heterodimeric diphosphane metal complex cis-

structure stabilised by an additional weak intermolecular C

H···N hydrogen bond. Presumably, the enhanced comple-

mentarity of this supramolecular complex is a result of the

[PtCl

N

ꢀ

additional C H···N hydrogen bonding that involves the

basic aminopyridine ring nitrogen and the relatively acidic

(sp ) H2, flanked by a pre-coordinated phosphane group

and a carbonyl group, as suggested by the single-crystal X-

ray crystallographic analysis. Directionality, energetics, dis-

tance relative to van der Waals radii, and bond length are

useful criteria for classifying hydrogen bonds.^[16,35]The aryl

C H2 bond points to the nitrogen N11 of the pyridine ring.

To form the conventional, second hydrogen bond, the

2

ꢀ

C

U

and studied by ESI-MS, and H and ³¹P NMR spectroscopy.

Metal-ion coordination is achieved in solution and the com-

plexes show in some cases characteristic spectroscopic fea-

tures that match exactly those of self-assembled, hybrid

structures stabilised by various attractive, noncovalent inter-

ꢀ

Chem. Eur. J. 2009, 15, 10405 – 10422

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

10407

B. Breit et al.

system must twist somehow around the Pt P and P C

bonds and this separates the phenyl and pyridine group.

Nevertheless, the C2···N11 distance (D) of 3.572 ꢃ is within

the range of weak hydrogen bonds reported elsewhere

(3.00<D<4.00 ꢃ).^[16,35]Additionally, the cohesive angle of

this weak interaction (139.78), which has been used to distin-

guish hydrogen bonds from van der Waals interactions, sug-

gests a value comparable to those found in other systems

(100<q<1808), in which weak hydrogen-bonding interac-

tions are responsible for structural arrangements.^[16,35]More-

over, the bond lengths and angles are comparable to the

values obtained from the modelling in the present case, and

will be presented in the “Theoretical calculations” section

(vide infra).

It is also interesting to note that the current structure is

additionally stabilised by p–p stacking interactions between

one phenyl ring of the PPh₂group of 3b and the pyridine

ring of 8d. Thus, the overall complex geometry is dictated

by four different attractive, noncovalent interactions: metal

coordination, one classical hydrogen bond, one non-classical

weak hydrogen bond and p stacking. This unusual supra-

molecular structure is surprising because the self-association

of two complementary molecules in similar systems is

known to comprise at least two classical hydrogen bonds

that coexist^[7]and furthermore can be stabilised by one or

molecular ion corresponding to the heterodimer [M⁺Cl],

and this provided evidence for the formation of the self-as-

ꢀ

sembled heterodiphosphane Pt^IIcomplex cis-[PtCl

₂ACHTUNGTRENNUNG(3b·8d)]

in solution.

³¹P NMR spectroscopy: The complexation behaviour and

the self-organising process of the ligands were also investi-

gated by ³¹P NMR spectroscopy. Metal coordination is im-

mediately evident from characteristic changes in the

³¹P NMR spectra of the complexes. In this case, the diamag-

netic Pt^IIion is not just a template for ligand self-assembly,

but also a spectroscopic reporter group for the detection of

ligand binding. ³¹P NMR spectroscopy showed in some cases

the selective formation of a well-defined complex with a

heterodimeric ligand. The ³¹P NMR spectra suggest that sim-

ilar hybrid structures, as in the solid state, are only found

with m-DPPB-derived ligands 3 and 6-DPPAP-derived li-

gands 8 in non-polar solvents such as CDCl₃. As reported

previously with peptidyl ligands 3 and 8, the ³¹P NMR spec-

tra of cis-[PtCl₂ACHTUNRGTENNUG(3b·8d)] and cis-[PtCl₂ACHTUNGTNER(NUGN 3b·8c)] (Figure 3)

[6,15]

ꢀ

more C H···O/N interactions.

Interestingly, a molecular

ꢀ

recognition event formed out of a C H···N interaction and

only one classical hydrogen bond between two different

structural fragments is to date not reported. During the

preparation of this manuscript, a paper appeared reporting

on supramolecular ligands held together by a single hydro-

gen bond.^[9m]

Mass spectrometry: The supramolecular hybrid structure

was also confirmed by ESI mass spectrometry analysis.

Hence, the ESI-MS spectrum of a mixture of 3b, 8d and cis-

[PtCl₂ACHTUNGTRENNUNG(cod)] (Figure 2) showed exclusively the presence of a

Figure 3. ³¹P NMR spectrum (162 MHz) of a equimolar mixture of 3b, 8c

and cis-[PtCl₂A(cod)] in CDCl₃(37.5 mm) at 300 K. Two doublets stand for

CTHUNGTRENNUNG

the resonance of the heterodimeric complex (A, D). C-homodimer and

N-homodimer were assigned as B and C, respectively. All signals show

1

the associated ¹⁹⁵Pt satellites and J_Pt,P>3650 Hz, thus indicating cis-com-

plex formation.

2

also show an AB system with a typical J_{P, P}coupling of 13–

16 Hz, which confirms the presence of two non-equivalent

phosphane ligands coordinated to the same platinum

1

centre.^[34]Moreover, the J_Pt,Pcoupling constant greater than

3650 Hz is in the order expected for a cis-Pt^IIdiphosphane

complex.^[36]

A heterodimeric equilibrium constant K_Hetcan be defined

as [L_C·L_N]²/

N

ACHTUGNERTN[NUGN L_N·L_N]. If the equilibrium is statistical,

K

the homodimers are preferred, K_Het<4. When mixed with a

transition metal, combinations 3·11, 6·8 and 6·11 give typical

statistical mixtures, thereby indicating no dimerisation pref-

Figure 2. ESI-MS spectrum (5 kV) of an equimolar mixture of 3b, 8d and

cis-[PtCl₂ACHTUNGTRENNUNG(cod)] in CH₂Cl₂(37.5 mm).

10408

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 10405 – 10422

Self-Assembled b-Turn Mimic

FULL PAPER

erence (Table 1, entries 8–11). Only compounds 3 and 8

dimer. The phosphane resonances of cis-[PtCl

₂ACHTUNGTRENUN(NG 3b·8d)] and

equilibrate in the presence of the Pt^IIsalt to form a hetero-

cis-[PtCl₂A

CHTUNGTRENNUNG

trum, thus permitting the iden-

tification and quantification of

the dimers (e.g., Figure 3).

Quantification of these species

by integration of the phosphane

Table 1. ¹H NMR spectroscopic and thermodynamic data for the cis-[PtCl

₂ACTHNUTRGNEUNG(L_C·L_N)] complexes.

ꢀ

Entry cis-[PtCl

(L_C·L_N)]

NH N H···O ArH C H···N Hetero/Homo

K^[b]

DG^[c]

[ppm] [ppm]

ratio^[a]

[m^ꢀ1

]

[kJmol^ꢀ1

]

resonances reveals

a 98.3:1.7

mixture of heteroleptic and ho-

moleptic peptidyl phosphane

dimers at 300 K in the best case

and a 80.8:19.2 ratio in the best

case for the smaller, non-pepti-

dic ligands (Table 1, entries 5

and 3, respectively). These

ratios correspond to a heterodi-

1

8.05 7.97

9.41 9.09

9.85 8.88

9.31 8.91

10.75 9.59

10.78 9.61

8.82 8.61

8.75 8.05

71.5:28.5

6.3

13.1

18.1

17.4

ꢀ1.1

ꢀ3.0

ꢀ3.8

ꢀ3.7

ꢀ16.7

ꢀ12.8

0.8

2

3

4

5

6

7

8

78.4:21.6

80.8:19.2

80.7:19.3

98.3:1.7

96.3:3.7

63.0:37.0

ꢁ66:34

mer/homodimer

constant K_Hetof 3229 and 18.1,

and statistically corrected

equilibrium

a

free-energy difference of 16.7

and 3.8 kJmol^ꢀ1(DG=ꢀRTln

AHCTUNGTRENGN(UN K/4)), respectively. The equi-

librium is dependent upon sev-

eral factors (solvent, tempera-

ture, side-chain donor/acceptor

groups, electronic and steric ef-

fects) and the effects upon

ligand mutagenesis will be dis-

cussed in detail (see the “Muta-

genesis experiments” section).

Thus, these results suggest that

selective formation of a self-as-

sembled heteroligand complex

in solution is already achieved

to a great extent without com-

plementary peptide side-chains.

This is only explicable when the

3229

P-modules

self-organise

through reciprocal hydrogen

ꢀ

bonds (N H···O=C and

C

H···N) in the coordination

sphere of a late-transition-metal

centre.

685

¹H NMR spectroscopy: Paral-

lels can be drawn between mo-

lecular recognition events that

occur within model systems in

the liquid phase and those that

2.9

define

the

supramolecular

nature of a molecular network

in the solid state. Unlike IR

spectroscopy, NMR spectrosco-

py has not been widely used to

4

0

ꢀ

investigate C H···X hydrogen

bonding.^[16]The presence of sol-

vent molecules in solution usu-

Chem. Eur. J. 2009, 15, 10405 – 10422

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

10409

B. Breit et al.

(CDCl₃and C₆D₆). Table 1

Table 1. (Continued)

ꢀ

K^[b]

DG^[c]

shows the C H and the amino-

ꢀ

Entry cis-[PtCl

(L_C·L_N)]

NH N H···O ArH C H···N Hetero/Homo

[ppm] [ppm]

ratio^[a]

[m^ꢀ1

]

[kJmol^ꢀ1

]

ꢀ

pyridine N H proton shifts, and

the shift differences (Dd=0.3–

1.9 and 0.2–2.2 ppm) are largely

ꢀ

attributable to aryl C H···N

9

9.02 n.d.^[d]

ꢁ66:34

4

0

ꢀ

and

N H···O=C

hydrogen

bonds in CDCl₃, respectively.

As there is a large proton shift

difference of d=0.3–1.9 ppm

for the aryl C H resonance be-

tween the free C-linked ligands

ꢀ

10

11

n.d. n.d.

ꢁ66:34

4

3 and the metal-coordinated li-

gands in cis-[PtCl₂ACTHUNRGTNE(NUG 3·8)], the

ꢀ

aryl C H···N hydrogen bond in

these assembling systems ap-

pears to be retained in solution.

The involvement of an aromatic

proton in hydrogen bonding

with an N acceptor site is still

n.d. n.d.

ꢀ

quite rare, in contrast to C

H···O hydrogen bonds, the sig-

nificance of which in biological

systems is increasingly recog-

nised.^[16,17,38]However, these

significant downfield shifts with

[a] Determined by NMR spectroscopic integration. [b] K=[hetero]²/

4). [d] n.d.=not determined.

G

ACHTUNGERTN(NUNG K/

ally becomes a barrier to be overcome for the formation of

respect to the common values found for aryl protons were a

clear result of anisotropic deshielding. Thus, a ligand confor-

mation at the metal centre incorporating a WHB, as seen in

the solid-state structure, is likely.

The existence of the hydrogen-bonding motif given in

Scheme 1C is further substantiated by ROESY experiments,

ꢀ

weak C H···X intermolecular bonds. In addition to that, sol-

vents having hydrogen-acceptor capabilities may generate

ꢀ

competition toward the activated C H donor. Thus, a more

precise investigation of WHBs becomes obligatory when

dealing with molecules in solution.

ꢀ

Complexation of the phosphane-functionalised ligands to

Pt^IIaffords a supramolecular hybrid structure for ligands 3

and 8, a combination that does self-associate. Metal coordi-

nation is immediately evident from characteristic changes in

which indicate a spatial proximity between the aryl C H2

and the pyridinyl nitrogen. An evaluation of the ROESY

spectrum of, for example, cis-[PtCl₂ACTHNUGTRNE(NUG 3b·8d)] in CDCl₃re-

vealed intermolecular associations that resemble the solid-

state structure as well (Figure 4). Most notably, and as

the ¹H NMR spectra of the cis-[PtCl

₂ACTHNUTRGNE(NUG 3·8)] complexes in

ꢀ

CDCl₃(e.g., aminopyridinyl N H and aryl C H2 protons).

In all these cases, the spectra remain sharp and the resonan-

ces of individual residues are well separated upon complex-

ing with Pt^II, which rules out the formation of large, disor-

dered aggregates and suggests the formation of well-defined

supramolecular species with one predominant conformation.

¹H NMR spectroscopy also revealed that the heterodimeric

complexes are concentration-independent at concentrations

below 40 mm in CDCl₃, which suggests the formation of

monomeric assemblages. Unambiguous assignment of the

self-assembling complexes, especially for the peptide ligands,

was done by using a combination of 2D-TOCSY, DQF-

COSY, edHSQC-N and 2D-ROESY experiments.

It is known that the resonances of hydrogen-bonded pro-

tons are shifted downfield relative to protons that are not

involved in hydrogen bonds, thereby indicating that they are

deshielded due to their participation in the hydrogen bond-

ing.^[37]A study on proton NMR spectroscopic shifts of these

Figure 4. Expanded region of the ROESY spectrum (500 MHz, 300 ms)

ꢀ

complexes indicated that C H···N and amide hydrogen

of cis-[PtCl

₂ACHTUNGTREN(NUNG 3b·8d)] in CDCl₃(37.5 mm) at 300 K shows the diagnostic

bonds also occur in solution in non-coordinating solvents

ROE cross-peak of the heteromeric template backbone (see arrow).

10410

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 10405 – 10422

Self-Assembled b-Turn Mimic

FULL PAPER

shown in Figure 4, a key ROE contact is observed between

aryl proton H2 and aminopyridinyl proton NH. The proxim-

ity of these two protons is indicative of a compact, rather

than an extended structure and demonstrates that the dis-

tance between these two protons is relatively short and is

sufficiently strong to persist in solution. This is consistent

with a co-planar and a more closed than opened conforma-

tion of the aromatic hybrid subunits.

chains, which lead to a fixation of the template backbone

conformation and thus to a greater stability of the resulting

heterodimeric complex (dimerisation up to 98%). The total

hydrogen-bonding energy is presumably too high for the

molecule to open at room temperature and the NMR spec-

troscopic shift (dꢁ9.6 ppm) is very similar to the “closed”

hydrogen-bonded system. Any reduction in temperature

should reduce dynamic conformational motion that includes

ꢀ

conformations with longer C H···N distances. Thus, for the

three or more hydrogen-bonded systems one should only

Variable-temperature NMR spectroscopy: Another piece of

evidence for the close contact and conformational prefer-

ence of the two aromatic rings attached to Pt^IIcame from

variable-temperature (VT) experiments. Increasing the tem-

perature of the solvent should decrease the binding stability

ꢀ

see a slight downfield shift for the C H proton. The experi-

mental shift values for N H (d=10.92 ppm) and C H (d=

9.63 ppm) are very close to the calculated H NMR spectro-

scopic shifts for the model complex m3-iso3 (see the “Theo-

retical calculations” section), which predict “static” shifts of

d=11.7 and 9.6 ppm, respectively.

2) In contrast, the H NMR spectrum exhibited by com-

plex cis-[PtCl₂ACTHNUTRGNEUNG(3b·8d)], representing the two-hydrogen-

bonded system, contains amide and aromatic resonances

that undergo a significant chemical shift (Dd=0.98 and

0.46 ppm, respectively) when the sample is heated to 323 K

or cooled down to 263 K, a fact that supports the existence

of conformational flexibility (Figure 6). At the lower tem-

ꢀ

1

ꢀ

of the units and weaken the C H···N interaction. The tem-

perature dependence of two of the H NMR spectroscopic

1

resonances in CDCl₃provided clear evidence for an associa-

tive process. Specifically, the large upfield shift of the ami-

nopyridinyl NH and the aryl H2 proton with increasing tem-

perature is consistent with the proposed conformational

ꢀ

preference of close proximity and formation of a C H···N

hydrogen bond, which is weakened or broken by dynamic

motion at higher temperatures. This is most pronounced in

the two-hydrogen-bonded system cis-[PtCl₂ACHTNUTRGNEUNG(3b·8d)], where

there may be enough thermal energy at 323 K to overcome

the hydrogen-bond-derived association energy of these li-

gands. All the other ¹H NMR spectroscopic resonances

remain essentially unaffected. Examination of the chemical

shift dependence of the aminopyridinyl NH and aryl H2

proton on temperature reveals the following:

1) For complex cis-[PtCl₂ACTHNUTRGNEU(GN 3c·8 f)], representing a four-hy-

drogen-bonded system, both the amide and aryl proton reso-

nances are found at chemical shifts that are nearly insensi-

tive to temperature variations (263–323 K: Dd=0.25 and

0.07 ppm, respectively) (Figure 5). These data point to a so-

ꢀ

lution structure in a non-polar medium in which both N H

ꢀ

and C H are involved in relatively strong intermolecular

hydrogen bonding and a rigid conformation of the atoms

participating in these interactions. This is consistent with a

preference for a structure in which there are two or more

additional strong hydrogen bonds in the peptidyl side

Figure 6. Low-field sections of the ¹H NMR spectra of cis-[PtCl

in CDCl₃(37.5 mm) recorded at 323, 300 and 263 K.

₂ACHTUNGTRENNUNG(3b·8d)]

perature shift values of d=9.98 ppm for the amide proton

and d=9.23 ppm for the aromatic proton are observed. This

ꢀ

result suggests that the closer the C H···N distance, the

ꢀ

more downfield the aryl C H NMR spectroscopic shift, as

one would expect. At lower temperatures, it tends towards

the structure that is the thermodynamic minimum (i.e., the

one that we see in the calculations), thus indicating a closer

interaction and rigid conformation of the ligands. At room

temperature, however, it is likely that there is enough ther-

ꢀ

mal energy to break the N H···O=C hydrogen bond and

thus separate both the weak and the classical hydrogen

bond. Thus, the time-average structure that one can see on

the NMR spectroscopic timescale includes a contribution

from the separated ligands, which leads to upfield shifts for

both the NH and CH protons. The observable average value

for the resonance at room temperature and higher is conse-

Figure 5. Low-field sections of the ¹H NMR spectra of cis-[PtCl

in CDCl₃(37.5 mm) recorded at 323, 300 and 263 K.

₂ACHTUNGTRNE(NUNG 3c·8 f)]

Chem. Eur. J. 2009, 15, 10405 – 10422

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

10411

B. Breit et al.

ꢀ

quently due to conformational flexibility. The ROESY spec-

tra and VT NMR spectroscopic resonances observed for the

aminopyridinyl NH proton and the aryl CH in CDCl₃were

clearly supportive of the postulated conformation of the di-

meric hybrid modules in the solid state and fit well with the

NMR spectroscopic calculations discussed in the “Theoreti-

cal calculations” section.

this geometry are a shorter C H···N contact, a favourable

alignment of dipoles and greater distances between secon-

dary repulsive sites.

ꢀ

Pairing geometry and the role of the C H···N interaction

in the self-assembly subunits were also probed using a

double mutant cycle.^[15a,40]With this strategy, both the elec-

tronic and the steric properties of the template scaffold may

be varied to explore and modulate the topological and func-

tional requirements of the self-assembly event. We have at-

tempted to estimate the contribution of the WHB in the

self-associating process by performing an experimental

double-mutant cycle for each of the pairing combinations

and modified structures of 3·8. Therefore, the self-assem-

bling behaviours of ligand pairs 6·11, 3·11 and 6·8 were ex-

amined in solution under identical conditions. This cycle

compares the self-associating propensity of the original 3·8

ligand combination with those of three other structures in

Mutagenesis experiments: Further information about the

structural factors important for self-assembly of the 3·8 tem-

plate system came from ligand diversification and mutagen-

esis experiments. In Table 1 we are able to demonstrate how

minor variations in the molecular structure of derivatives

have a significant impact on the self-assembly properties of

these species. Substituents are known to play a crucial role

in dictating the mode of association of self-assembling sys-

tems, either through steric hindrance or through electronic

effects. Important features such as acidity/basicity of hydro-

gen-bond donors and acceptors are in direct connection to

the strength of hydrogen-bond interactions.^[39]

ꢀ

which the C H···N interaction is modified or eliminated:

1) a complex in which the pyridine nitrogen atom involved

in the interaction is replaced by C H (Table 1, entry 10),

ꢀ

One approach is to vary the amide N H acidity in the N-

2) a geometry in which the C H group in this interaction is

linked ligands 8 by introducing electron-withdrawing groups,

which hence leads to better hydrogen-donor ligands

(Table 1, entry 1 vs. entry 3). As expected, ligands with ter-

minal benzyl (8d) or CF₃(8c) groups gave better heterodi-

mer/homodimer ratios and K_Hetvalues (approx. 81% dimer-

isation). Of the numerous biotic, abiotic, small or oligomeric

duplexes that form interstrand hydrogen bonding,^[7,11]com-

removed and replaced by nitrogen (entry 11), and 3) a struc-

ture in which both of these changes are made (entries 8 and

ꢀ

9). In the latter case, the aryl C H group and the pyridine

nitrogen in this interaction are simply exchanged between

ꢀ

each other. It has been reported that the ability of a C H

group to act as a proton donor depends on the carbon

2

3

ꢀ

hybridisation C(sp) H>CACHTUNRGTENN(UG sp ) H>CCAHUTNGTREN(NNGU sp ) H, and in-

plex cis-[PtCl

G

N

creases with the number of adjacent electron-withdrawing

wherein a linear array of donor and acceptor groups pair

through formation of a strong and a single weak hydrogen

bond, both together strong enough to direct and stabilise a

self-assembled hybrid structure.

Another approach was chosen by changing the hydrogen-

acceptor properties of the carbonyl group within the C-

linked ligands (3). When introducing a weaker hydrogen ac-

ceptor, such as an ester group (3a), the self-assembly pro-

cess becomes unfavoured (Table 1, entry 7).

groups.^[19a,41]The combination 6·11 represents a type of

ꢀ

“electronic double mismatched case”. The aniline C H

proton in 11 is a worse hydrogen donor than the corre-

sponding C H proton in 3, which is flanked by an electron-

withdrawing carbonyl group. Moreover, in comparison to 3,

the electron-poor pyridinyl ring in 6 decreases the basicity

of the neighbouring carbonyl group and, thus, only a less

stable hydrogen bond with a relatively less acidic aniline

ꢀ

N H in 11 can be formed.

Increasing the number of intermolecular hydrogen bonds

should increase the binding stability of the self-assembled

templates. Complexes bearing peptide moieties assemble

into stable double-stranded complexes held together by sev-

eral hydrogen-bonding interactions (Table 1, entries 5 and

6).^[8]As the length of the donor/acceptor-functionalised li-

gands increases, the stability of the corresponding complexes

increases, thereby indicating significant cooperativity in the

intermolecular interactions along the chain. Selectivity in

recognition relies entirely on length in this system, since the

stability is preponderantly determined by the number of hy-

drogen-bonding interactions that can be made. Thus, the

For the second case, the combination of ligands 3 and 11

(Table 1, entry 10) results again in a statistical mixture of

heterodimeric and both homodimeric complexes. This sug-

gests the absence of any attractive interaction (e.g., WHB)

within the template scaffold. This is presumably due to

steric reasons because the formation of the stabilising amide

hydrogen bond goes hand-in-hand with an unfavoured con-

formation of the aromatic rings (i.e., repulsive contact of ad-

ꢀ

jacent C H groups). We suggest the hydrogen bonding

arrays are considerably forced out of plane due to steric

ꢀ

clash between both the C H groups, flanked by PPh₂and

CO/NH, at the template scaffold. Thus, this interaction

should lead to a steric, more favoured, twisted conformation

with repulsion minimisation having the aryl rings pointing

away from each other, and this inhibits cohesive heterodi-

mer formation.

fact that cis-[PtCl

more stable in solution than cis-[PtCl CHTUNGTRENNNUG

(3c·8 f)] (Table 1, entry 6) is remarkably

₂A(3b·8d)] (entry 4)

strongly suggests an important interplay between the WHB

and the additional classical hydrogen bonds in driving the

conformational fixation of the metal-binding aromatic units

and, hence, the formation of a rigid secondary structural

scaffold. Factors that might contribute to the preference for

The third and last pairing of 6 and 8 also suggested no

preference for the formation of a self-assembled complex

(Table 1, entry 11). This appears not to be due to sterical

10412

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 10405 – 10422

Self-Assembled b-Turn Mimic

FULL PAPER

reasons, but due to dipole–dipole repulsion effects of both

pyridine nitrogen sp²lone pairs, which would point toward

each other when an amide hydrogen bond was formed.

In conclusion, the stereoelectronic properties of the

donor/acceptor-functionalised aromatic rings (aryl versus

pyridinyl) have been shown to play a crucial role in the self-

organising process. Hence, these mutagenesis studies indi-

cate that 3·8 pairing geometry is preferred over the other as-

sembly combinations. A peculiar self-assembly of discrete

units develops, in which the aromatic rings of both P-mod-

ꢀ

ules are almost co-planar with the nitrogen lone pair and C

H groups facing inwards; they are thus capable of forming

an attractive interaction. All these results suggest that the

ꢀ

C H···N interaction is attractive in nature. It is also possible

Figure 7. The structure of m2-iso3, optimised at the BP86/TZVP level.

to define the minimal structural motif responsible for molec-

ular recognition in this system: it contains one classical hy-

drogen bond and at least one weak hydrogen bond.

ꢀ

Selected interatomic distances [ꢃ] and angles [8]: Pt P1 2.309, Pt P2

ꢀ

2.304, C2···N11 3.557, N12···O2 2.965; P1-Pt-P2 104.3, C H2···N11 2.577,

ꢀ

N12 H···O2 1.952. H atoms bound to C atoms (except H2) were omitted

for clarity.

Theoretical calculations: To better understand the interplay

between conventional and weak hydrogen bonding and pro-

vide additional structural insights into this system, DFT cal-

culations were performed on the model compounds m1–m3

(Scheme 4). Structure m1 was chosen as the simplest reason-

of cis-[PtCl₂ACHTUNTRGNEUNG(3b·8d)] shows a good agreement between

theory and experiment, given the differences expected be-

tween gas-phase and solid-state structures, and lends weight

to the calculations. The parameters that show the largest dif-

ference between the calculated and X-ray structure are

those involving the hydrogen atoms of the WHB and classi-

cal hydrogen bond. This is likely to be related to the rather

large uncertainty associated with hydrogen atom positions in

X-ray structures that contain heavy elements. Structure m3

is a slightly simplified analogue of compound cis-[PtCl₂-

AHCTUNGTRENNUNG

each corresponding to different conformational arrange-

ments of the ligands around the metal centre (see the Sup-

porting Information). A selection of bond lengths and

angles for all optimised structures (BP86/TZVP level) is

shown in Table 2 and compared to the X-ray structure of

cis-[PtCl₂ACTHNUTRGNEUG(N 3b·8d)]. An interesting feature of these calcula-

ꢀ

tions is the difference in C H···N distance in the different

ꢀ

isomers. In all cases the shortest C H···N distance is found

in iso3 (the same isomer found in the X-ray structure of cis-

[PtCl

₂ACHTUNGTRENUN(NG 3b·8d)]). For m1 and m2 this is also the lowest

Scheme 4. Schematic representations of the model complexes m1, m2

and m3.

energy isomer. However, at this level of theory, and consid-

Table 2. Selected structural parameters (distances in ꢃ and angles in 8) and energies (in kJmol^ꢀ1) for the X-

ray structure of cis-[PtCl₂A(3b·8d)] and model compounds m1–m3.

able model for the system and

its reduced size allowed a more

detailed investigation of the

system on a reasonable time-

scale (see the Supporting Infor-

mation). Structure m2 is a sim-

plified analogue of entries 1–4

in Table 1 and may be com-

pared to the X-ray crystal struc-

CTHUNGTRENNUNG

ꢀ

Structure

Relative

energy

N11

H2

N11

C2

N11-H2-

C2

O2

H11

O2

N12

O2-H11-

N12

p–p

cis-[PtCl₂-

–

2.873

3.572

135.8

2.198

2.966

148.8

3.631

AHCTUNGTRENN(GUN 3b·8d)]

m1-iso1

m1-iso2

m1-iso3

m2-iso1

m2-iso2

m2-iso3

m3-iso1

m3-iso2

m3-iso3

3

4

0

11

4

0

ꢀ12

ꢀ8

0

2.641

2.632

2.442

3.553

2.625

2.577

3.571

3.033

2.711

3.599

3.596

3.493

3.932

3.605

3.557

3.928

3.806

3.778

145.8

146.7

160.6

102.3

149.0

148.7

101.0

128.2

165.6

1.950

1.946

1.991

2.071

1.931

1.952

1.964

1.894

1.899

2.972

2.966

3.002

3.062

2.944

2.965

2.963

2.906

2.896

171.6

170.6

165.8

160.9

167.0

166.3

161.4

165.3

161.3

–

3.697

3.786

3.666

3.729

3.790

3.789

ture of cis-[PtCl₂ACHTUNGTRENNUNG(3b·8d)]. A

comparison of the calculated

structure of m2-iso3 (Figure 7)

with the X-ray crystal structure

Chem. Eur. J. 2009, 15, 10405 – 10422

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

10413

B. Breit et al.

ering the differences between the gas phase at 0 K and solu-

tion at 298 K, such small energy differences are not enough

to assign the isomer observed experimentally in solution.

namic motion of the ligands on the NMR spectroscopic

timescale. At room temperature and above, both the experi-

ꢀ

mental WHB C H and conventional hydrogen-bond proton

1

This was further investigated by calculation of the H NMR

shifts of cis-[PtCl

₂A

spectroscopic shifts for all isomers of m1 and m3 using the

(d=8.93 and 9.37 ppm at 303 K) from the calculated values.

However, when the sample is cooled to 263 K, the proton

signals shift downfield (d=9.23 and 9.98 for the WHB and

HB1, respectively) closer to the calculated values for m1-

iso3 (d=9.8 and 11.6 ppm). As previously discussed, this is

likely to be due to the rapid opening and closing of the hy-

drogen bonds on the NMR spectroscopic timescale. This is

supported by NMR spectroscopic shift calculations on the

model compound m1-iso4, which was generated by rotation

1

GIAO method.^[42]A summary of selected H NMR spectro-

scopic shifts is shown in Table 3 (see the Supporting Infor-

Table 3. Calculated ¹H NMR spectroscopic chemical shifts for model

compounds m1 and m3 compared to experimental data for cis-[PtCl₂-

A

₂ACHTUNGTRENNUNG

(3c·8 f)] at 303 K.^[a]

WHB

HB1

HB2

HB3

cis-[PtCl

m1-iso1

m1-iso2

m1-iso3

m1-iso4

m3-iso1

m3-iso2

m3-iso3

G

9.4

9.6

9.3

9.8

8.6

8.5

7.9

9.6

8.9

10.8

10.7

11.6

7.5

11.2

11.8

11.7

–

8.6

–

5.4

–

ꢀ

of one of the ligands by ꢁ1208 around the P C bond, fol-

lowed by geometry optimisation. This isomer has no hydro-

gen bonding and the calculated ¹H NMR spectroscopic

shifts of the WHB and HB1 (d=8.64 and 7.46 ppm, respec-

tively) are upfield of the experimental shifts. Thus, the ob-

served signals lie between the calculated shifts for the

“open” and “closed” isomers. In the case of m3 and the re-

–

9.7

9.8

9.6

7.3

7.5

[a] HB1, HB2 and HB3 correspond to the first, second and third classical

hydrogen bond, respectively, when reading along the peptide chains from

the metal.

lated experimental compound cis-[PtCl₂ACTHNGUTERNNU(G 3c·8 f)], the stabili-

sation gained from the two additional hydrogen bonds leads

to a much less dynamic system at around room temperature

and thus a closer agreement between theory and experi-

ment.

1

mation). As expected, the calculated H NMR spectroscopic

The total hydrogen-bonding energies, that is, the sum of

the energies of both the WHB and classical hydrogen bond,

for isomers of m1 were estimated by considering the energy

difference between each of the three “closed” isomers (i.e.,

those involving hydrogen bonding) and a fourth “open”

isomer, m1-iso4, which contained no hydrogen bonding be-

tween the ligands. The advantage of such a method is that

this should reduce the effects of the basis-set superposition

error (BSSE) on the hydrogen-bond energies. This was con-

firmed by calculations using the very large QZVPP basis

set, which gave very similar energies to calculations using

the TZVP basis set. The total hydrogen-bond energy for

m1-iso3 at the PBE0/TZVP level using this approach was

found to be 26 kJmol^ꢀ1. The hydrogen-bonding energies for

the other isomers are slightly smaller (23 kJmol^ꢀ1); this sug-

gests a reduced contribution from the WHB to the overall

ꢀ

shifts for the C H proton of the WHB are strongly depen-

ꢀ

dent on the C H···N distance, which can help with the as-

signment of solution structures.

ꢀ

For m3, the calculated C H chemical shift of iso3 (d=

ꢀ

9.6 ppm), which contains the shortest C H···N distance, is

very similar to that found in the experimental spectra of cis-

[PtCl₂ACHTUNGTRENNUNG(3c·8 f)] (d=9.63 ppm). The other isomers, which con-

ꢀ

tain longer C H···N distances, have calculated chemical

shifts considerably upfield from that observed experimental-

ly (d=8.5 and 7.9 ppm for iso1 and iso2, respectively), thus

suggesting that a structure similar to iso3 is found in solu-

tion for cis-[PtCl

the X-ray structure of cis-[PtCl CTHNUGTRENNUNG

(3c·8 f)]. This assignment is supported by

₂A(3b·8d)], which also shows

an iso3-like structure in the solid state. In contrast to the

WHB, the calculated classical hydrogen bond NMR spectro-

scopic shifts are relatively insensitive to the isomer. This is

consistent with the similar structures of the peptide parts of

the model complex that are found for all the isomers. The

absolute chemical shifts of the classical hydrogen-bond pro-

tons are all overestimated in the calculations by around d=

1 ppm for HB1 and HB2 and d=2 ppm for HB3. In the

case of HB1 and HB2, this may be due to a slight underesti-

mation of the H···O bond length at this level of theory, but

may also involve a contribution from dynamic motion of the

ꢀ

energy in these isomers, which have longer C H···N distan-

ces.

We were also interested in establishing the relative contri-

butions of the WHB and classical hydrogen bond to the

total hydrogen bond energy. However, this was not possible

using a structural approach, as breaking HB1 is not possible

without additionally breaking the WHB or disturbing the p

system of the ligands. Instead, an orbital-based approach

was used in which the WHB and HB1 energies were esti-

mated from natural bond orbital (NBO) calculations. In the

NBO approach, hydrogen bonding is modelled as a dona-

tion of electron density from lone-pair orbitals on the hydro-

1

ligands at 303 K. The observed H chemical shift for HB3 is

almost certainly affected by an opening and closing of the

hydrogen bond on the NMR spectroscopic timescale, which

explains the large difference between experimental and cal-

culated chemical shifts.

ꢀ

gen-bond acceptor to the X H s*-type orbital on the hydro-

gen-bond donor. Second-order perturbation theory analysis

of the Fock matrix in the NBO basis allows one to estimate

the energetic stabilisation of the structure due to each of

For model m1 a comparison of calculated and experimen-

1

tal H NMR spectroscopic shifts is also complicated by dy-

10414

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 10405 – 10422

Self-Assembled b-Turn Mimic

FULL PAPER

these donor/acceptor interactions and thus to estimate the

energies of each hydrogen bond. For m1-iso3, the stabilisa-

tion energies due to the WHB and HB1 were found to be 7

and 32 kJmol^ꢀ1, respectively. The combined stabilisation

energy of the WHB and classical hydrogen bond is thus esti-

mated by the NBO analysis to be 39 kJmol^ꢀ1. This is larger

than that found using the structural approach above, which

is likely to be due to inaccuracies associated with the

second-order perturbation analysis. However, the relative

energies of the WHB and HB1 are likely to be more relia-

ble, as they are both affected by the same errors. Thus, it is

possible to estimate from the NBO analysis that the WHB

constitutes around 18% of the total hydrogen-bonding

energy for this isomer. The relative contributions of the

WHBs in m1-iso1 and m1-iso2 to the total hydrogen-bond-

ing energies are slightly smaller (15%), which is consistent

in relation to the rules governing the self-assembly of a new

class of metal-directed hydrogen-bonding units. Although

ꢀ

the structural influence and functional relevance of C H···X

interactions are still hotly debated among scientists interest-

ed in materials science, biochemistry or fundamental struc-

ture/property issues,^[16]our results address the importance

and capability of non-classical, so-called weak hydrogen

bonds (WHBs) as important attractive interactions in self-

organising processes based on molecular recognition. Be-

cause WHBs are particularly attractive for biological appli-

cations and understanding^[16,17]but their persistence in solu-

tion is scarce,^[19]we examined the formation of a remarkably

ꢀ

stable C H···N hydrogen bond and its persistence in solid-

state and in solution by X-ray crystallography, mass spec-

trometry, NMR spectroscopy and mutagenesis experiments.

Further evidence was demonstrated by theoretical calcula-

tions, which gave specific geometric parameters for the pro-

posed conformations, and allowed us to estimate the energy

involved in the hydrogen bonds, which are responsible for

the molecular recognition process. Thus, the m-DPPB/6-

DPPAP system 3·8 not only provides a platform for generat-

ing self-assembled heterobidentate ligands, but can also be

regarded as a new type of self-assembled b-turn mimic or

supramolecular pseudo amino acid for the nucleation of b-

sheet structures^[21–24]when attached to oligopeptides.

ꢀ

with the longer C H···N distances in these isomers.

The calculations as well as the experimental results are in

ꢀ

agreement with the theory that the formation of the N

H···O=C hydrogen bond is essential for the dimerisation

process, but cannot be accomplished without an additional

attractive, intermolecular interaction like a second hydrogen

bond^[7]or, at least, a WHB. The driving force for the hetero-

molecular self-assembly process is clearly the stabilisation of

the heteroleptic complex by formation of a strong intermo-

lecular hydrogen bond. But nevertheless, only the interplay

of this attractive interaction, shape complementarity and an

additional non-classical, weak hydrogen bond at the scaffold

of the template provide sufficient stabilisation into hybrid

assemblages and finally lead to dimerisation and the forma-

tion of a defined self-assembled complex.

Experimental Section

General remarks: The following starting materials were purchased and

used without further purification: 2-chlorobenzoic acid (1, Merck), 2,6-di-

bromo-pyridine (4, Fluka), 3-bromo-aniline (9, Acros), Boc-l-valine,

Fmoc-l-valine and Fmoc-l-alanine (Boc=tert-butoxycarbonyl, Fmoc=9-

fluorenylmethoxycarbonyl; Fluka). Z-l-Val-l-Ala-OMe^[8](Z=benzyloxy-

carbonyl, Val=valine, Ala=alanine) and Z-l-Val-l-Val-OMe^[8]were pre-

pared according to literature procedures. All reactions, except those indi-

cated otherwise, were carried out in oven-dried glassware under an argon

atmosphere (argon 5.0 from Sauerstoffwerk Friedrichshafen GmbH)

using standard Schlenk techniques. Syringes were used to transfer air-

and moisture-sensitive liquids and solutions. All reagents were commer-

cially available unless otherwise noted. All solvents were dried and dis-

tilled by standard procedures. Organic solutions were concentrated under

reduced pressure by rotary evaporation. Chromatographic purification of

products was accomplished using flash chromatography on Merck silica

gel Si 60 (200–400 mesh). Nuclear magnetic resonance spectra were ac-

quired using a Varian Mercury 300 spectrometer (300, 121 and 75 MHz

for ¹H, ³¹P and ¹³C, respectively), a Bruker Avance 400 (400, 162 and

100 MHz for ¹H, ³¹P and ¹³C, respectively) and a Bruker Avance 500

(500, 202 and 125 MHz for ¹H, ³¹P and ¹³C, respectively) and are refer-

enced according to residual protio solvent signals (CDCl₃: d=7.26 (¹H),

77.10 ppm (¹³C)). Data for ¹H NMR spectroscopy are reported as follows:

chemical shift (d in ppm), multiplicity (s, singlet; brs, broad signal; d,

doublet; t, triplet; q, quartet; m, multiplet; m_c, symmetrical multiplet),

coupling constant (Hz), integration, assignment (if possible). See the Sup-

porting Information for signal nomenclature. Data for ¹³C and ³¹P NMR

spectroscopy are reported in terms of chemical shift (d in ppm), multi-

plicity (if not a singlet), coupling constant (Hz), assignment (if possible).

High-resolution mass spectra and ESI mass spectra were obtained using

a Finnigan MAT 95 instrument and a Finnigan LCQ Advantage, respec-

tively. Elementary analysis was performed using an Elementar Vario (Fa.

Elementar Analysensysteme GmbH). Optical rotations were measured

using a Perkin–Elmer 241 polarimeter.

In addition, enhancement of the individual hydrogen-

bond strengths by mutual polarisation is very likely.^[17a,43]

The energy of an array of n interlinked hydrogen bonds is

larger than the sum of n isolated hydrogen bonds. This non-

additive property arises because the ability of donor and ac-

ceptor groups to form hydrogen bonds is further increased

by an increase in polarity when the hydrogen bonds form

part of a collective ensemble. Given the importance of po-

larisation, there is every reason to believe that cooperativity

is of importance for WHBs.

Conclusion

In summary, a metal-induced supramolecular template for

the self-assembly of two independent phosphane ligands by

means of unprecedented multiple noncovalent interactions

ꢀ

(classical N H···O hydrogen bond, C H···N weak hydrogen

bond, metal coordination and p-stacking interaction) was

developed and investigated. Un-preorganised, monomeric

template subunits m-DPPB (3) and 6-DPPAP (8) were

shown to pair complementarily with unexpected stabilities

in both the crystalline form and in organic solvent when co-

ordinated to a metal. The resulting self-organised hybrid

structures [MX

₂ACHTUNGTRENNUNG(3·8)] adopt well-defined conformations in

solution and we have described the results of investigations

Chem. Eur. J. 2009, 15, 10405 – 10422

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

10415

B. Breit et al.

Synthesis of C-linked phosphane ligands

2ArC_ipso), 136.6 (d, J_C,P=15.0 Hz; C_4’), 138.1 (C₃), 138.5 (d, J_C,P=12.9 Hz;

C_3’), 167.1 ppm (C₁); ³¹P NMR (121 MHz, CDCl₃): d=ꢀ5.09 ppm (s);

HRMS (EIMS): m/z: calcd for C₂₆H₂₂NOP: 395.1439 [M⁺]; found:

395.1447; elemental analysis calcd (%) for C₂₆H₂₂NOP: C 78.97, H 5.61,

N 3.54; found: C 78.61, H 5.63, N 3.56.

3-(Diphenylphosphanyl)benzoic acid (m-DPPBA) (2):^[29]A heavy stream

of gaseous ammonia was filled into an oven-dried, 2 L three-necked

round-bottomed flask, cooled with a dry ice bath and equipped with a

mechanical stirrer and a dry ice condenser, which was cooled to ꢀ788C,

until 700 mL of liquid ammonia was condensed inside. Sodium metal

(10.4 g, 440 mmol, 4 equiv) in approximately 1 g pieces was then added

to the stirred ammonia, which resulted in a blue-coloured solution, and

was stirred at ꢀ788C for 1 h. Triphenylphosphine (58.4 g, 220 mmol,

2 equiv) was added in small portions over 10 min and the stirring and

cooling was continued for 12 h. 2-Chlorobenzoic acid (1) (17.4 g,

110 mmol) was added into the resulting deep red solution over a period

of 20–30 min and was allowed to stir for 3 h. Then dry THF (350 mL)

was added, the cooling device removed and the stirred reaction mixture

allowed to slowly warm to room temperature overnight. Then water was

added (1 L) and the resulting solution was washed with Et₂O (3ꢄ

100 mL), then acidified to pHꢁ2 with concentrated HCl (ca. 40 mL) and

finally extracted with CH₂Cl₂(3ꢄ100 mL). The combined CH₂Cl₂layers

were washed with water (3ꢄ100 mL), dried (Na₂SO₄) and concentrated

by evaporation in vacuo. The resulting yellow oil was dissolved in MeOH

and crystallisation occurred during cooling at 58C. The crystalline prod-

uct was collected from the cold solution and washed with some MeOH to

give the title compound 2 as a white to pale yellow solid (21.0 g, 63%).

M.p. 1458C (MeOH); ¹H NMR (400 MHz, CDCl₃): d=7.28–7.40 (m,

10H; ArH), 7.40–7.56 (m, J=7.7 Hz, 2H; ArH), 8.05–8.13 ppm (m, J=

(+)-(3-Diphenylphosphanyl)-benzoyl-l-valyl-l-alanine methyl ester (3c):

Pd-C (10%, 37 mg, Fluka) was added to a solution of Z-l-Val-l-Ala-

OMe (3e) (0.700 g, 2.08 mmol) in dry MeOH (9.5 mL) and CH₂Cl₂

(3 mL), and the suspension was stirred under H₂(1 atm) at room temper-

ature for 17 h. The reaction mixture was filtered through Celite and the

solvent was removed in vacuo to yield the free amine H-l-Val-l-Ala-

OMe as a viscous oil (quant.). The amine was dissolved in dry CH₂Cl₂

(10 mL), and m-DPPBA (2) (0.624 g, 2.04 mmol, 1.0 equiv), DMAP

(0.249 g, 2.04 mmol, 1.0 equiv) and DIC (0.257 g, 2.04 mmol, 1.0 equiv)

were added at room temperature. The reaction mixture was stirred at

room temperature for further 24 h. After concentration in vacuo, the resi-

due was subjected to chromatography on silica gel (PE/EE, 1:1) to afford

the peptidyl ligand 3c as a glass foam (0.640 g, 64%, R_f=0.31). M.p.

758C (PE/EE); [a]²_D⁰=+5.18 (c=1.270 in CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=0.97 (d, J=6.9 Hz, 3H; 7-H₃or 8-H₃), 1.00 (d, J=6.7 Hz,

3H; 7-H₃or 8-H₃), 1.38 (d, J=7.2 Hz, 3H; 3-H₃), 2.16 (m_c, J=6.7 Hz,

1H; 6-H), 3.75 (s, 3H; OCH₃), 4.47 (dd, J=8.5, 6.6 Hz, 1H; 5-H), 4.70

(dq, J=7.3, 7.2 Hz, 1H; 2-H), 6.52 (d, J=7.3 Hz, 1H; 2-NH), 6.68 (d, J=

8.5 Hz, 1H; 5-NH), 7.26–7.43 (m, 12H; ArH), 7.70–7.80 ppm (m, 2H;

ArH); ¹³C NMR (100 MHz, CDCl₃): d=18.1, 18.2, 19.2 (C₃, C₇, C₈), 31.7

(C₆), 48.2 (C₂), 52.5 (OCH₃), 58.7 (C₅), 127.6 (C_6’), 128.7 (d, J_C,P=6.9 Hz;

8.2 Hz, 2H; ArH); ¹³C NMR (100 MHz, CDCl₃): d=128.7 (d, J_C,P

5.8 Hz; C₅), 128.8 (d, J_C,P=7.2 Hz; 4ArC_meta), 129.1 (2ArC_para), 129.7 (d,

=

4ArC_meta), 128.9 (d, J_C,P=5.8 Hz; C_5’), 129.1 (2ArC_para), 132.3 (d, J_C,P

=

23.9 Hz; C_2’), 133.8 (d, J_C,P=19.9 Hz; 2ArC_ortho), 133.9 (d, J_C,P=19.9 Hz;

2ArC_ortho), 134.5 (d, J_C,P=7.2 Hz; C_1’), 136.5 (2d, J_C,P=10.7 Hz; 2ArC_ipso),

136.8 (d, J_C,P=15.8 Hz; C_4’), 138.7 (d, J_C,P=13.5 Hz; C_3’), 167.3, 170.7,

173.1 ppm (C₁, C₄, C₉); ³¹P NMR (162 MHz, CDCl₃): d=ꢀ5.26 ppm (s);

elemental analysis calcd (%) for C₂₈H₃₁N₂O₄P: C 68.56, H 6.37, N 5.71;

found: C 68.43, H 6.62, N 5.97.

J

_C,P=6.9 Hz; C₁), 130.5 (C₆), 133.8 (d, J_C,P=19.9 Hz; 4ArC_ortho), 135.6 (d,

_C,P=22.2 Hz; C₂), 136.5 (d, J_C,P=10.7 Hz; 2ArC_ipso), 138.7 (d, J_C,P

=

13.8 Hz; C₃), 138.8 (d, J_C,P=17.6 Hz; C₄), 171.7 ppm (C=O); ³¹P NMR

(162 MHz, CDCl₃): d=ꢀ5.23 ppm (s); HRMS (EIMS): m/z: calcd for

C₁₉H₁₅O₂P: 306.0809 [M⁺]; found: 306.0803; elemental analysis calcd

(%) for C₁₉H₁₅O₂P: C 74.50, H 4.94; found: C 74.35, H 5.05.

6-(Diphenylphosphanyl)pyridine-2-carboxylic acid (5): nBuLi (20.5 mL,

23.3 mmol, 1.1 equiv, 1.14m in hexanes) was added dropwise to a solution

of 2,6-dibromopyridine (4) (5.040 g, 21.27 mmol) in dry CH₂Cl₂(350 mL)

at ꢀ788C and stirred 0.5 h at this temperature. Then chlorodiphenylphos-

phine (5.125 g, 23.22 mmol, 1.1 equiv) was added dropwise, and the reac-

tion mixture was stirred 1 h at ꢀ788C and 4 h at room temperature.

Water (100 mL) was then added to the resulting orange-brown solution,

and the separated aqueous layer was extracted with CH₂Cl₂(3ꢄ50 mL).

The combined organic layers were dried (Na₂SO₄) and partially concen-

trated (60 mL) by evaporation in vacuo. Short filtration on silica gel

(CH₂Cl₂) and concentration in vacuo gave a yellow oil, which crystallised

after some time at room temperature. Trituration with PE/Et₂O (3:1) af-

forded 6-diphenylphosphanyl-2-bromopyridine as a white solid (4.80 g,

66%). M.p. 818C (CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃): d=6.98 (dd,

J=6.8, 1.4 Hz, 1H; ArH), 7.30–7.45 ppm (m, 12H; ArH); ¹³C NMR

(100 MHz, CDCl₃): d=126.7 (d, J_C,P=5.5 Hz; C₃), 126.8 (d, J_C,P=9.2 Hz;

3-(Diphenylphosphanyl)benzoic acid methyl ester (3a): Dicyclohexylcar-

bodiimide (DCC) (0.135 g, 0.653 mmol, 1.0 equiv) was added to a solu-

tion of m-DPPBA (2) (0.200 g, 0.653 mmol) and DMAP (8.8 mg,

0.07 mmol, 0.1 equiv) in dry MeOH (2 mL) at room temperature. The re-

sulting white, chalky solution was stirred at room temperature for further

3 h. The mixture was filtered through a 2 cm pad of Celite (wetted with

CH₂Cl₂), and the filter cake was washed with some CH₂Cl₂. After con-

centration in vacuo, the residue was subjected to chromatography on

silica gel (PE/EE, 5:1; PE= petroleum ether, EE=ethyl acetate) and re-

crystallised from PE/Et₂O (2:1) to give the methylester 3a as a white

solid (0.120 g, 57%, R_f=0.71 with 1:1). M.p. 688C (PE/Et₂O); ¹H NMR

(400 MHz, CDCl₃): d=3.87 (s, 3H; OCH₃), 7.26–7.49 (m, 12H; ArH),

7.98–8.08 ppm (m, 2H; ArH); ¹³C NMR (100 MHz, CDCl₃): d=52.2

(OCH₃), 128.7 (d, J_C,P=6.9 Hz; 4ArC_meta), 129.1 (2ArC_para), 129.1 (over-

lapped d, C₅), 129.9 (C₆), 130.5 (d, J_C,P=7.5 Hz; C₁), 133.8 (d, J_C,P

19.9 Hz; 4ArC_ortho), 134.9 (d, J_C,P=23.3 Hz; C₂), 136.6 (d, J_C,P=10.7 Hz;

2ArC_ipso), 137.9 (d, _C,P=16.4 Hz; C₄), 138.4 (d, _C,P=13.5 Hz; C₃),

=

C₅), 128.8 (d, J_C,P=7.2 Hz; 4ArC_meta), 129.4 (2ArC_para), 134.3 (d, J_C,P

19.9 Hz; 4ArC_ortho), 135.6 (d, J_C,P=10.9 Hz; 2ArC_ipso), 137.9 (d, J_C,P

=

J

=

166.9 ppm (C=O); ³¹P NMR (162 MHz, CDCl₃): d=ꢀ5.18 ppm (s);

HRMS (EIMS): m/z: calcd for C₂₀H₁₇O₂P: 320.0966 [M⁺]; found:

320.0965; elemental analysis calcd (%) for C₂₀H₁₇O₂P: C 74.99, H 5.35;

found: C 74.70, H 5.59.

1.7 Hz; C₄), 142.8 (d,

J

_C,P=12.4 Hz; C₆), 166.3 ppm (C₂); ³¹P NMR

(121 MHz, CDCl₃): d=ꢀ2.88 ppm (s); elemental analysis calcd (%) for

C₁₇H₁₃BrNP: C 59.67, H, 3.83, N 4.09; found: C 59.47, H 3.90, N 4.26.

nBuLi (2.60 mL, 3.47 mmol, 1.1 equiv, 1.35m in hexanes) was added drop-

wise to a solution of 6-diphenylphosphanyl-2-bromopyridine (1.081 g,

3.159 mmol) in dry THF (40 mL) at ꢀ110 to ꢀ1008C and stirred at that

temperature for further 0.5 h. Then CO₂gas was bubbled through the re-

action mixture for 0.5 h and the colour changed from orange-red to

yellow. The cooling bath was removed and the stirred solution was al-

lowed to slowly warm to room temperature. The mixture was washed

with aqueous HCl (2n, 3ꢄ30 mL), dried (MgSO₄) and concentrated by

evaporation in vacuo. Short filtration of the yellow oil on silica gel (EE)

and concentration in vacuo gave a pale yellow oil, which crystallised

after some time at room temperature. Trituration with PE/Et₂O (3:1)

gave the acid 5 as a white solid (0.715 g, 74%). M.p. 1228C (PE/Et₂O);

¹H NMR (400 MHz, CDCl₃): d=7.32–7.45 (m, 10H; ArH), 7.46 (over-

lapped d, J=7.6 Hz, 1H; 5-H), 7.82 (ddd, J=7.8, 7.8, 1.8 Hz, 1H; 4-H),

8.09 (d, J=7.6 Hz, 1H; 3-H), 10.47 ppm (brs, 1H; COOH); ¹³C NMR

N-Benzyl-3-(diphenylphosphanyl)benzamide (3b): Benzylamine (0.218 g,

2.03 mmol, 1.25 equiv) and DIC (0.208 g, 1.65 mmol, 1.0 equiv) were

added to a solution of m-DPPBA (2) (0.500 g, 1.63 mmol) and DMAP

(0.212 g, 1.73 mmol, 1.06 equiv) in dry CH₂Cl₂(2 mL) at room tempera-

ture. The mixture was stirred at room temperature for further 24 h and

filtered through a short plug of silica gel (CH₂Cl₂/EE, 3:1). Concentration

in vacuo and trituration with Et₂O gave the benzylamide 3b as a white

solid (0.500 g, 78%, R_f=0.95 with 3:1). M.p. 1298C (Et₂O); ¹H NMR

(500 MHz, CDCl₃): d=4.59 (d, J=5.7 Hz, 2H; 2-H₂), 6.32 (s, 1H; NH),

7.27–7.42 (m, 17H; ArH), 7.73 (d, J=8.2 Hz, 1H; ArH), 7.79 ppm (m,

1H; ArH); ¹³C NMR (125 MHz, CDCl₃): d=44.2 (C₂), 127.7 (C_6’, C₆),

127.9 (2C₅), 128.7 (d, J_C,P=7.5 Hz; 4ArC_meta), 128.9 (2C₄), 129.0 (d, J_C,P

5.4 Hz; C_5’), 129.1 (2ArC_para), 132.0 (d, J_C,P=24.7 Hz; C_2’), 133.8 (d, J_C,P

=

20.4 Hz; 4ArC_ortho), 134.7 (d, J_C,P=7.5 Hz; C_1’), 136.5 (d, J_C,P=10.1 Hz;

10416

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 10405 – 10422

Self-Assembled b-Turn Mimic

FULL PAPER

(100 MHz, CDCl₃): d=122.0 (C₃), 129.0 (d, J_C,P=7.5 Hz; 4ArC_meta), 129.8

(2ArC_para), 132.1 (d, J_C,P=20.2 Hz; C₅), 134.3 (d, J_C,P=20.4 Hz; 4ArC_ortho),

134.8 (d, J_C,P=9.5 Hz; 2ArC_ipso), 138.0 (d, J_C,P=3.2 Hz; C₄), 146.3 (d,

concentrated in vacuo to give the acetyl-substituted ligand 8b as a pale

yellow solid (0.307 g, 89%). M.p. 1518C (PE/Et₂O); ¹H NMR (300 MHz,

CDCl₃): d=2.14 (s, 3H; CH₃), 6.78 (dd, J=7.5, 0.4 Hz, 1H; 5-H), 7.32–

7.40 (m, 10H; PPh₂), 7.57 (ddd, J=7.9, 7.9, 1.6 Hz, 1H; 4-H), 8.05 (brs,

1H; NH), 8.07 ppm (overlapped d, Jꢁ8.2 Hz, 1H; 3-H); ¹³C NMR

(75 MHz, CDCl₃): d=24.7 (CH₃), 112.7 (C₃), 124.0 (d, J_C,P=13.0 Hz; C₅),

128.7 (d, J_C,P=7.2 Hz; 4ArC_meta), 129.2 (2ArC_para), 134.2 (d, J_C,P=19.9 Hz;

4ArC_ortho), 135.8 (d, J_C,P=10.4 Hz; 2ArC_ipso), 138.1 (d, J_C,P=1.7 Hz; C₄),

151.4 (d, J_C,P=14.1 Hz; C₆), 161.9 (d, J_C,P=4.6 Hz; C₂), 168.8 ppm (C=O);

³¹P NMR (121 MHz, CDCl₃): d=ꢀ3.87 ppm (s); HRMS (EIMS): m/z:

calcd for C₁₉H₁₇N₂OP: 320.1078 [M⁺]; found: 320.1073; elemental analy-

sis calcd (%) for C₁₉H₁₇N₂OP: C 71.24, H 5.35, N 8.75; found: C 70.95, H

5.45, N 8.77.

J

_C,P=7.2 Hz; C₆), 163.7 (d, J_C,P=6.6 Hz; C₂), 163.9 ppm (C=O); ³¹P NMR

(121 MHz, CDCl₃): d=ꢀ2.31 ppm (s); elemental analysis calcd (%) for

C₁₈H₁₄NO₂P: C 70.36, H 4.59, N 4.56; found: C 70.20, H 4.79, N 4.70.

6-(Diphenylphosphanyl)pyridine-2-carboxylic acid benzylamide (6a):

Benzylamine (96 mg, 0.89 mmol, 1.1 equiv) and DIC (0.113 g, 0.89 mmol,

1.1 equiv) were added to a solution of acid 5 (0.250 g, 0.814 mmol) and

DMAP (0.100 g, 0.814 mmol, 1.0 equiv) in dry CH₂Cl₂(8 mL). The reac-

tion mixture was stirred at room temperature for further 24 h, then fil-

tered through a 2 cm pad of Celite (wetted with CH₂Cl₂), and the filter

cake was washed with CH₂Cl₂. After concentration in vacuo, the residue

was subjected to chromatography on silica gel (PE/EE, 3:1) to give the

benzylamide 6a as a white to pale yellow solid (0.180 g, 56%, R_f=0.30

with 2:1). M.p. 888C (PE/EE); ¹H NMR (400 MHz, CDCl₃): d=4.55 (d,

J=6.0 Hz, 2H; 2-H₂), 7.21–7.40 (m, 16H; 5’-H, ArH), 7.74 (ddd, J=7.8,

7.8, 2.2 Hz, 1H; 4’-H), 8.08 (overlapped brs, 1H; NH), 8.09 ppm (d, J=

7.8 Hz, 1H; 3’-H); ¹³C NMR (100 MHz, CDCl₃): d=43.5 (C₂), 120.9 (C_3’),

127.5 (C₆), 127.9 (2C₅), 128.7 (d, J_C,P=7.8 Hz; 4ArC_meta, 2C₄), 129.4

(2ArC_para), 130.6 (d, J_C,P=21.9 Hz; C_5’), 134.3 (d, J_C,P=19.9 Hz; 4Ar-

C_ortho), 135.7 (d, J_C,P=9.8 Hz; 2ArC_ipso), 137.0 (d, J_C,P=4.0 Hz; C_4’), 138.2

(C₃), 150.0 (d, J_C,P=8.4 Hz; C_6’), 162.4 (C_2’), 164.1 ppm (C₁); ³¹P NMR

(121 MHz, CDCl₃): d=ꢀ2.46 ppm (s); elemental analysis calcd (%) for

C₂₅H₂₁N₂OP: C 75.74, H 5.34, N 7.07; found: C 75.52, H 5.48, N 7.03.

6-(Diphenylphosphanyl)-N-trifluoroacetyl-2-aminopyridine

(8c):

Tri-

fluoroacetic anhydride (0.910 g, 4.30 mmol, 1.2 equiv) was added to a so-

lution of 6-DPPAP (7) (1.00 g, 3.60 mmol) and NEt₃(0.550 g, 5.40 mmol,

1.5 equiv) in dry CH₂Cl₂(15 mL) at 08C. The cooling bath was removed

and the reaction mixture was stirred 0.5 h at room temperature. The solu-

tion was filtered through a short plug of silica gel (CH₂Cl₂) and concen-

trated by evaporation in vacuo. The residue was dissolved in CH₂Cl₂and

a second filtration on silica gel (PE/CH₂Cl₂, 1:1) and concentration in

vacuo afforded the trifluoroacetyl (TFAc)-substituted ligand 8c as a

white solid (1.30 g, 96%, R_f=0.69 with CH₂Cl₂). ¹H NMR (400 MHz,

CDCl₃): d=6.93 (d, J=7.5 Hz, 1H; 5-H), 7.31–7.47 (m, 10H; PPh₂), 7.68

(ddd, J=7.6, 7.6, 1.5 Hz, 1H; 4-H), 8.08 (d, J=8.4 Hz, 1H; 3-H),

8.55 ppm (brs, 1H; NH); ¹³C NMR (100 MHz, CDCl₃): d=113.3 (C₃),

(+)-6-(Diphenylphosphanyl)pyridine-2-carbonyl-l-valyl-l-valine methyl

ester (6b): Pd-C (10%, 15 mg, Fluka) was added to a solution of Z-l-Val-

l-Val-OMe (0.250 g, 0.686 mmol) in dry MeOH (4 mL) and the suspen-

sion was stirred under H₂(1 atm) at room temperature for 18 h. The re-

action mixture was filtered through Celite and the solvent removed in

115.6 (q, J_C,F=289.2 Hz; CF₃), 125.8 (d, J_C,P=12.4 Hz; C₅), 128.9 (d, J_C,P

=

7.5 Hz; 4ArC_meta), 129.5 (2ArC_para), 134.3 (d, J_C,P=20.2 Hz; 4ArC_ortho),

135.3 (d, J_C,P=10.1 Hz; 2ArC_ipso), 138.6 (d, J_C,P=1.4 Hz; C₄), 149.3 (d,

J

_C,P=13.8 Hz; C₆), 155.2 (d, J_C,F=36.9 Hz; C=O), 163.4 ppm (C₂);

³¹P NMR (121 MHz, CDCl₃): d=ꢀ3.65 ppm (s); HRMS (EIMS): m/z:

calcd for C₁₉H₁₄F₃N₂OP: 374.0795 [M⁺]; found 374.0791; elemental anal-

ysis calcd (%) for C₁₉H₁₄F₃N₂OP: C 60.97, H 3.77, N 7.48; found: C

61.02, H 3.51, N 7.47.

vacuo to yield the free amine H-l-Val-l-Val-OMe as

(0.160 g, 0.686 mmol, quant.). The amine was dissolved in dry CH₂Cl₂

(2 mL), and acid (0.211 g, 0.686 mmol, 1.0 equiv), DMAP (84 mg,

a viscous oil

5

0.69 mmol, 1.0 equiv) and DIC (88 mg, 0.69 mmol, 1.0 equiv) were added

at room temperature. The resulting white, chalky solution was stirred at

room temperature for a further 16 h. The mixture was filtered through a

2 cm pad of Celite (wetted with CH₂Cl₂), and the filter cake was washed

with some CH₂Cl₂. After concentration in vacuo, the residue was subject-

ed to chromatography on silica gel (PE/EE, 3:1) to afford the dipeptide

ligand 6b as a glass foam (0.262 g, 74%, R_f=0.40 with 1:1). M.p. 588C

(PE/EE); [a]²_D⁰=+23.08 (c=1.010 in CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=0.78 (d, J=6.7 Hz, 3H; CH₃), 0.86 (d, J=6.7 Hz, 3H; CH₃),

0.88 (d, J=5.7 Hz, 3H; CH₃), 0.92 (d, J=6.7 Hz, 3H; CH₃), 2.14 (m_c, J=

6.7 Hz, 1H; 3-H), 2.16 (m_c, J=6.7 Hz, 1H; 8-H), 3.72 (s, 3H; OCH₃),

4.30 (dd, J=8.8, 6.7 Hz, 1H; 7-H), 4.51 (dd, J=8.6, 4.8 Hz, 1H; 2-H),

6.49 (d, J=8.6 Hz, 1H; 2-NH), 7.33–7.50 (m, 11H; 5’-H, ArH), 7.73

(ddd, J=7.8, 7.8, 2.2 Hz, 1H; 4’-H), 8.05 (d, J=7.8 Hz, 1H; 3’-H),

8.13 ppm (d, J=8.8 Hz, 1H; 7-NH); ¹³C NMR (100 MHz, CDCl₃): d=

17.9, 18.0, 19.0, 19.6 (C₄, C₅, C₉, C₁₀), 30.0, 31.2 (C₃, C₈), 52.2 (OCH₃),

57.2, 59.1 (C₂, C₇), 120.9 (C_3’), 128.7 (d, J_C,P=7.8 Hz; 2ArC_meta), 128.8 (d,

6-(Diphenylphosphanyl)-N-phenylacetyl-2-aminopyridine

(8d):

NEt₃

(0.600 g, 5.93 mmol, 5.5 equiv) and phenylacetyl chloride (0.200 g,

1.29 mmol, 1.2 equiv; added dropwise) were added to a solution of 6-

DPPAP (7) (0.300 g, 1.08 mmol) in dry CH₂Cl₂(5 mL) at 08C and stirred

at room temperature for a further 24 h. The resulting white, chalky solu-

tion was washed with half-saturated aqueous KHSO₄(7 mL) and saturat-

ed aqueous NaHCO₃(7 mL) and dried (Na₂SO₄). The organic layer was

concentrated in vacuo, and the waxy residue crystallised after 1 h. Tritu-

ration with Et₂O/CH₂Cl₂(9:1) afforded the title compound 8d as a

yellow solid (0.320 g, 75%, R_f=0.60 with PE/EE 2:1). M.p. 1678C (Et₂O/

1

CH₂Cl₂); H NMR (300 MHz, CDCl₃): d=3.70 (s, 2H; 2-H₂), 6.77 (d, J=

7.5 Hz, 1H; 5’-H), 7.25–7.40 (m, 15H; ArH), 7.55 (ddd, J=8.4, 7.5,

1.8 Hz, 1H; 4’-H), 7.92 (brs, 1H; NH), 8.10 ppm (d, J=8.4 Hz, 1H; 3’-

H); ¹³C NMR (100 MHz, CDCl₃): d=45.0 (C₂), 112.8 (C_3’), 124.3 (d,

J

_C,P=12.7 Hz; C_5’), 128.7 (d, J_C,P=7.2 Hz; 4ArC_meta), 129.1 (2C₅), 129.2

(2ArC_para), 129.5 (2C₄), 134.0 (C₃), 134.2 (2d, J_C,P=19.6 Hz; 4ArC_ortho),

135.9 (2d, J_C,P=10.4 Hz; 2ArC_ipso), 138.1 (d, J_C,P=1.7 Hz; C_4’), 151.4 (d,

J

_C,P=7.8 Hz; 2ArC_meta), 129.4 (ArC_para), 129.5 (ArC_para), 131.0 (d, J_C,P=

25.3 Hz; C_5’), 134.3 (d, J_C,P=20.4 Hz; 2ArC_ortho), 134.5 (d, J_C,P=20.4 Hz;

2ArC_ortho), 135.6 (d, J_C,P=9.5 Hz; ArC_ipso), 135.8 (d, J_C,P=9.5 Hz; ArC_ipso),

J

_C,P=14.4 Hz; C_6’), 161.9 (d, J_C,P=4.6 Hz; C_2’), 169.6 ppm (C₁); ³¹P NMR

(121 MHz, CDCl₃): d=ꢀ4.10 ppm (s); HRMS (EIMS): m/z: calcd for

137.0 (d, J_C,P=4.6 Hz; C_4’), 149.4 (d, J_C,P=7.2 Hz; C_6’), 162.9 (d, J_C,P

=

C₂₅H₂₁N₂OP: 396.1391 [M⁺]; found: 396.1399.

4.0 Hz; C_2’), 164.6, 170.8, 172.2 ppm (C₁, C₆, C₁₁); ³¹P NMR (121 MHz,

CDCl₃): d=ꢀ1.83 ppm (s); elemental analysis calcd (%) for

C₂₉H₃₄N₃O₄P: C 67.04, H 6.60, N 8.09; found: C 66.88, H 6.73, N 8.02.

(ꢀ)-6-(Diphenylphosphanyl)-2-aminopyridinyl-l-alanyl-Fmoc (8e): SOCl₂

(1.40 mL, 2.24 g, 18.9 mmol, 10 equiv) was added to a suspension of

Fmoc-l-alanine (0.587 g, 1.89 mmol) in dry CH₂Cl₂(11 mL) and stirred

for 0.5 h at 608C. The clear reaction mixture was concentrated in vacuo

and the residue was re-dissolved in dry CH₂Cl₂(5 mL). The solvent was

removed in vacuo and this procedure was repeated two more times to

give Fmoc-l-Ala-Cl as a waxy oil (0.622 g, 1.89 mmol, quant.). The amino

acid chloride was dissolved in dry CH₂Cl₂(5 mL) and was added drop-

wise at 08C to a solution of 6-DPPAP (7) (0.500 g, 1.80 mmol, 0.95 equiv)

and pyridine (0.165 g, 2.08 mmol, 1.1 equiv) in dry CH₂Cl₂(3 mL). The

yellow solution was stirred at room temperature for further 24 h, then

washed with half-saturated aqueous KHSO₄(6 mL) and saturated aque-

ous NaHCO₃(6 mL) and dried (MgSO₄). The organic layer was concen-

trated in vacuo, and the crude product was purified by column chroma-

Synthesis of N-linked phosphane ligands

6-(Diphenylphosphanyl)-2-aminopyridine (6-DPPAP) (7) and 6-(Diphe-

nylphosphanyl)-N-pivaloyl-2-aminopyridine (8a) were prepared accord-

ing to procedures in the literature.^[7b]

6-(Diphenylphosphanyl)-N-acetyl-2-aminopyridine (8b): Acetyl chloride

(0.099 g, 1.3 mmol, 1.2 equiv) was added to a solution of 6-DPPAP (7)

(0.300 g, 1.08 mmol) and pyridine (0.128 g, 1.62 mmol, 1.5 equiv) in dry

CH₂Cl₂(3 mL) at 08C. The cooling bath was removed and the reaction

mixture was stirred for 24 h at room temperature. The solution was then

washed with half-saturated aqueous KHSO₄(3 mL) and saturated aque-

ous NaHCO₃(3 mL) and then dried (Na₂SO₄). The organic layer was

Chem. Eur. J. 2009, 15, 10405 – 10422

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

10417

B. Breit et al.

tography on silica gel (CH₂Cl₂/EE, 20:1) to afford the monopeptidyl

phosphane 8e as a glass foam (0.913 g, 89%, R_f=0.62). M.p. 938C

(CH₂Cl₂/EE); [a]²_D⁰=ꢀ14.18 (c=0.655 in CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=1.45 (d, J=5.4 Hz, 3H; 3-H₃), 4.19 (t, J=6.6 Hz, 1H; 6-H),

4.42 (m, J=6.7 Hz, 3H; 2-H, 5-H₂), 5.39 (brs, 1H; 2-NH), 6.80 (d, J=

7.5 Hz, 1H; 5’-H), 7.25–7.43 (m, 14H; ArH), 7.52–7.64 (m, J=8.1 Hz,

3H; 4’-H, fluorenyl H), 7.75 (d, J=7.5 Hz, 2H; fluorenyl H), 8.10 (d, J=

8.4 Hz, 1H; 3’-H), 8.44 ppm (brs, 1H; 2’-NH); ¹³C NMR (100 MHz,

CDCl₃): d=18.8 (C₃), 47.2 (C₆), 51.6 (C₂), 67.3 (C₅), 113.0 (C_3’), 120.1

(2 fluorenyl C), 124.5 (d, J_C,P=12.1 Hz; C_5’), 125.1 (2 fluorenyl C), 127.2

(2 fluorenyl C), 127.8 (2 fluorenyl C), 128.7 (d, J_C,P=7.2 Hz; 4ArC_meta),

2008C/0.5 mbar; ¹H NMR (400 MHz, CDCl₃): d=0.00 (s, 18H; SiMe₃),

6.77 (ddd, J=7.8, 1.7, 1.7 Hz, 1H; 6-H), 6.88 (d, J=7.8 Hz, 1H; 2-H),

7.04 (dd, J=7.8, 7.8 Hz, 1H; 4-H), 7.20 (ddd, J=7.8, 7.8, 2.0 Hz, 1H; 5-

H), 7.28–7.40 ppm (m, 10H; PPh₂); ³¹P NMR (121 MHz, CDCl₃): d=

ꢀ5.70 ppm (s). The TMS-protected aniline (10.24 g, 24.29 mmol) was hy-

drolyzed with aqueous HCl (2n, 50 mL) in MeOH (150 mL) and stirred

for 2 h at room temperature. The reaction mixture was then neutralised

with aqueous NaOH (2n, 50 mL) and extracted with Et₂O (3ꢄ150 mL).

The combined organic layers were dried (MgSO₄) and concentrated in

vacuo. The residue was recrystallised from CH₂Cl₂to afford the phos-

phane-substituted aniline 10 as a white to pale yellow solid (6.75 g,

quant.). M.p. 878C (PE/EE); ¹H NMR (400 MHz, CDCl₃): d=3.60 (brs,

2H; NH₂), 6.59–6.77 (m, J=7.8 Hz, 3H; 2-H, 4-H, 6-H), 7.14 (ddd, J=

7.8, 7.8, 1.8 Hz, 1H; 5-H), 7.28–7.42 ppm (m, 10H; ArH); ¹³C NMR

(100 MHz, CDCl₃): d=115.6 (C₆), 120.1 (d, J_C,P=20.2 Hz; C₂), 124.1 (d,

129.3 (2ArC_para), 134.2 (d, J_C,P=19.9 Hz; 4ArC_ortho), 135.8 (2d, J_C,P

=

10.5 Hz; 2ArC_ipso), 138.2 (d, J_C,P=1.4 Hz; C_4’), 141.4 (2 fluorenyl C), 143.8

(fluorenyl C), 143.9 (fluorenyl C), 151.1 (d, J_C,P=14.1 Hz; C_6’), 156.0 (C₄),

162.3 (d, J_C,P=3.7 Hz; C_2’), 171.1 ppm (C₁); ³¹P NMR (121 MHz, CDCl₃):

d=ꢀ4.04 ppm (s); elemental analysis calcd (%) for C₃₅H₃₀N₃O₃P: C

73.54, H 5.29, N 7.35; found: C 73.35, H 5.39, N 7.30.

J

_C,P=19.9 Hz; C₄), 128.5 (d, J_C,P=6.9 Hz; 4ArC_meta), 128.7 (2ArC_para),

129.4 (d, J_C,P=8.1 Hz; C₅), 133.8 (d, J_C,P=19.6 Hz; 4ArC_ortho), 137.4 (d,

J

_C,P=10.9 Hz; 2ArC_ipso), 138.2 (d, J_C,P=10.1 Hz; C₃), 146.5 ppm (d, J_C,P=

(ꢀ)-(6-Diphenylphosphanyl)-2-aminopyridinyl-l-alanyl-l-valine-Boc (8 f):

Et₂NH (0.70 mL, 6.7 mmol, 19 equiv) was added to a solution of the

Fmoc-protected peptidyl ligand 8e (0.200 g, 0.350 mmol) in dry THF

(2 mL) and stirred at room temperature for 3.5 h (TLC control: PE/EE,

2:1). Evaporation in vacuo gave a waxy oil (quant.). The free amine was

dissolved in dry CH₂Cl₂(3 mL) and treated successively with Boc-l-

valine (76 mg, 0.35 mmol, 1.0 equiv), HOBt (47 mg, 0.35 mmol, 1.0 equiv)

and DIC (44 mg, 0.35 mmol, 1.0 equiv) at room temperature. The result-

ing solution was stirred at room temperature for a further 20 h and con-

centrated in vacuo. The residue was subjected to chromatography on

silica gel (CH₂Cl₂/EE, 10:1) to afford the dipeptidyl ligand 8 f as a glass

8.1 Hz; C₁); ³¹P NMR (121 MHz, CDCl₃): d=ꢀ4.53 ppm (s); HRMS

(EIMS): m/z: calcd for C₁₈H₁₆NP: 277.1020 [M⁺]; found: 277.1017; ele-

mental analysis calcd (%) for C₁₈H₁₆NP: C 77.96, H 5.82, N 5.05; found:

C 77.87, H 5.94, N 4.80.

N-(3-Diphenylphosphanyl-phenyl)-2-phenylacetamide (11a): Phenylacetyl

chloride (0.239 g, 1.54 mmol, 1.07 equiv) was added to a solution of 3-

DPPA (10) (0.400 g, 1.44 mmol) and pyridine (0.186 g, 2.35 mmol,

1.6 equiv) in dry CH₂Cl₂(6 mL) at 08C. The cooling bath was removed

and the reaction mixture was stirred 18 h at room temperature. The re-

sulting clear solution was washed with half-saturated aqueous KHSO₄

(4 mL) and saturated aqueous NaHCO₃(4 mL) and dried (Na₂SO₄).

Evaporation in vacuo afforded the amide 11a as a pale yellow foam

foam (0.115 g, 60%, R_f=0.47 with 5:1). M.p. 958C (CH₂Cl₂/EE); [a]_D²⁰

=

1

ꢀ31.08 (c=1.200 in CHCl₃); H NMR (400 MHz, CDCl₃): d=0.87 (d, J=

6.7 Hz, 3H; 7-H₃or 8-H₃), 0.90 (d, J=7.0 Hz, 3H; 7-H₃or 8-H₃), 1.42 (s,

9H; tBu), 1.43 (overlapped d, J=7.2 Hz, 3H; 3-H₃), 2.08 (m_c, J=6.5 Hz,

1H; 6-H), 3.94 (dd, J=7.2, 7.0 Hz, 1H; 5-H), 4.66 (dq, J=7.2, 7.0 Hz,

1H; 2-H), 5.13 (brs, 1H; 5-NH), 6.67 (d, J=7.0 Hz, 1H; 2-NH), 6.78 (d,

J=7.5 Hz, 1H; 5’-H), 7.29–7.38 (m, 10H; PPh₂), 7.56 (dd, J=8.1, 7.8 Hz,

1H; 4’-H), 8.06 (d, J=8.4 Hz, 1H; 3’-H), 8.57 ppm (brs, 1H; 2’-NH);

¹³C NMR (100 MHz, CDCl₃): d=17.9, 19.4 (C₇, C₈), 18.4 (C₃), 28.4

(3C₁₁), 31.0 (C₆), 49.8 (C₂), 60.0 (C₅), 80.0 (C₁₀), 112.9 (C_3’), 124.4 (d,

1

(0.566 g, 99%, R_f=0.50 with PE/EE, 2:1). M.p. 408C (CH₂Cl₂); H NMR

(400 MHz, CDCl₃): d=3.68 (s, 2H; 2-H₂), 6.98 (dd, J=7.3, 7.0 Hz, 1H;

5’-H), 7.10 (s, 1H; NH), 7.15 (d, J=8.5 Hz, 1H; ArH), 7.20–7.43 (m,

16H; ArH), 7.67 ppm (d, J=7.9 Hz, 1H; ArH); ¹³C NMR (100 MHz,

CDCl₃): d=44.8 (C₂), 120.8 (C_6’), 125.2 (d, J_C,P=24.8 Hz; C_2’), 127.7 (C₆),

128.6 (d, J_C,P=6.4 Hz; 4ArC_meta), 128.9 (2ArC_para), 129.29 (overlapped d,

J

_C,P=6.4 Hz; C_5’), 129.30 (2C₅), 129.6 (2C₄), 129.6 (d, J_C,P=14.7 Hz; C_4’),

133.8 (d, J_C,P=19.3 Hz; 4ArC_ortho), 134.4 (C₃), 136.8 (d, J_C,P=11.0 Hz;

J

_C,P=13.3 Hz; C_5’), 128.7 (d, J_C,P=7.2 Hz; 4ArC_meta), 129.2 (2ArC_para),

2ArC_ipso), 137.9 (d, J_C,P=9.2 Hz; C_1’), 138.3 (d, J_C,P=12.0 Hz; C_3’),

134.2 (2d, J_C,P=19.8 Hz; 4ArC_ortho), 135.9 (2d, J_C,P=10.4 Hz; 2ArC_ipso),

138.1 (C_4’), 151.1 (d, J_C,P=13.8 Hz; C_6’), 156.0 (C₉), 162.2 (d, J_C,P=3.6 Hz;

C_2’), 170.9, 171.8 ppm (C₁, C₄); ³¹P NMR (121 MHz, CDCl₃): d=

ꢀ4.09 ppm (s); HRMS (EIMS): m/z: calcd for C₃₀H₃₇N₄O₄P: 548.2552

[M⁺]; found: 548.2562.

169.1 ppm (C₁); ³¹P NMR (121 MHz, CDCl₃): d=ꢀ4.85 ppm (s); HRMS

(EIMS): m/z: calcd for C₂₆H₂₂NOP: 395.1439 [M⁺]; found: 395.1439; ele-

mental analysis calcd (%) for C₂₆H₂₂NOP: C 78.97, H 5.61, N 3.54;

found: C 78.68, H 5.68, N 3.28.

(ꢀ)-Fmoc-l-valyl-(3-diphenylphosphanyl)anilide (11b): SOCl₂(2.0 mL,

27 mmol, 9 equiv) was added to a suspension of Fmoc-l-valine (1.00 g,

2.94 mmol) in dry CH₂Cl₂(5 mL) and stirred 1 h at 50–558C. The clear

reaction mixture was concentrated in vacuo and the residue was re-dis-

solved in dry CH₂Cl₂(3 mL). The solvent was removed in vacuo and this

procedure was repeated two more times to give Fmoc-l-Val-Cl as a mois-

ture-sensitive white solid (1.06 g, 2.94 mmol, quant.). The amino acid

chloride was dissolved in dry CH₂Cl₂(4 mL) and was added dropwise at

08C to a solution of 3-DPPA (10) (0.753 g, 2.71 mmol, 0.92 equiv) and

pyridine (0.25 mL, 3.04 mmol, 1.03 equiv) in dry CH₂Cl₂(8 mL). The

yellow solution was stirred at room temperature for a further 5 h, then

washed with half-saturated aqueous KHSO₄(10 mL) and saturated aque-

ous NaHCO₃(10 mL), and dried (MgSO₄). The organic layer was con-

centrated in vacuo and the crude product was purified twice by column

chromatography on silica gel (PE/EE, 4:1) to afford the monopeptidyl

phosphane 11b as a glass foam (1.389 g, 84%, R_f=0.45 with 2:1). M.p.

878C (CH₂Cl₂); [a]²_D⁰=ꢀ21.08 (c=0.795 in CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=0.97 (brs, 6H; 4-H₃, 5-H₃), 2.17 (m_c, 1H; 3-H), 4.09 (m_c, 1H;

2-H), 4.17 (t, J=6.7 Hz, 8-H), 4.28–4.48 (m, J=7.2 Hz, 2H; 7-H₂), 5.54

(brs, 1H; 2-NH), 7.01 (dd, J=7.2, 7.2 Hz, 1H; ArH), 7.18–7.42 (m, J=

7.5 Hz, 16H; ArH), 7.43 (d, J=7.5 Hz, 2H; ArH), 7.70 (d, J=8.2 Hz,

1H; ArH), 7.75 (d, J=7.5 Hz, 2H; ArH), 8.07 ppm (brs, 1H; 1’-NH);

¹³C NMR (100 MHz, CDCl₃): d=18.1, 19.4 (C₄, C₅), 31.1 (C₃), 47.2 (C₈),

61.4 (C₂), 67.3 (C₇), 120.1 (2 fluorenyl C), 120.8 (C_6’), 125.1 (2 fluorenyl

C), 125.2 (overlapped d, J_C,P=22.5 Hz; C_2’), 127.2 (2 fluorenyl C), 127.8

(2 fluorenyl C), 128.6 (d, J_C,P=6.9 Hz; 4ArC_meta), 128.9 (2ArC_para), 129.3

3-Diphenylphosphanylaniline (3-DPPA) (10): nBuLi (164 mL, 216 mmol,

2.3 equiv, 1.32m in hexanes) was added dropwise to a solution of 3-bro-

moaniline (9) (10.1 mL, 16.0 g, 93.0 mmol) in dry THF (100 mL) at 08C

and stirred for a further 3 h at room temperature. After dropwise addi-

tion of chlorotrimethylsilane (27.5 mL, 23.4 g, 215.2 mmol, 2.15 equiv) at

08C, the resulting turbid brown reaction mixture was stirred at room

temperature for a further 17 h. The precipitated LiCl was rapidly re-

moved by filtration through a short pad of Celite and washed with dry

Et₂O (100 mL). The solution was concentrated in vacuo and the black

residue was distilled using a Vigreux column to give 3-bromo-N,N-bis(tri-

methylsilyl)aniline as a yellow liquid (14.22 g, 48%). B.p. 888C/0.5 mbar;

¹H NMR (300 MHz, CDCl₃): d=0.07 (s, 18H; SiMe₃), 6.81 (m_c, J=

7.9 Hz, 1H; 6-H), 7.04–7.10 (m, J=7.9, 7.9 Hz, 2H; ArH), 7.12 ppm (m_c,

J=7.9 Hz, 1H; ArH); ¹³C NMR (75 MHz, CDCl₃): d=2.1 (SiMe₃), 121.9

(C₃), 126.8, 128.9, 129.7, 133.1 (C₂, C₄, C₅, C₆), 150.0 ppm (C₁). nBuLi

(21.8 mL, 34.8 mmol, 1.1 equiv, 1.60m in hexanes) was added dropwise to

a solution of 3-bromo-N,N-bis(trimethylsilyl)aniline (10.30 g, 32.55 mmol)

in dry Et₂O (30 mL) at 08C. After stirring for 3 h at 08C, freshly distilled

chlorodiphenylphosphine (7.68 g, 34.8 mmol, 1.1 equiv) was added drop-

wise at 08C and the turbid beige reaction mixture was stirred at room

temperature for a further 18 h. The precipitated LiBr was removed by fil-

tration through a short pad of Celite and washed with Et₂O. The solution

was concentrated in vacuo, and Kugelrohr distillation of the red-brown

residue afforded 3-[N,N-bis(trimethylsilyl)aminophenyl]diphenylphos-

phine as a pale yellow oil (12.02 g, 88%, R_f=0.45 with PE/EE, 2:1). B.p.

10418

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 10405 – 10422

Self-Assembled b-Turn Mimic

FULL PAPER

(d, J_C,P=6.1 Hz; C_5’), 129.8 (d, J_C,P=16.1 Hz; C_4’), 133.7 (d, J_C,P=19.6 Hz;

2ArC_ortho), 133.8 (d, J_C,P=19.9 Hz; 2ArC_ortho), 136.9 (d, J_C,P=10.9 Hz;

2ArC_ipso), 137.6 (d, J_C,P=8.6 Hz; C_1’), 138.5 (d, J_C,P=12.1 Hz; C_3’), 141.4

(2 fluorenyl C), 143.7 (fluorenyl C), 143.8 (fluorenyl C), 156.8 (C₆),

169.9 ppm (C₁); ³¹P NMR (121 MHz, CDCl₃): d=ꢀ4.75 ppm (s); elemen-

tal analysis calcd (%) for C₃₈H₃₅N₂O₃P: C 76.24, H 5.89, N 4.68; found: C

76.05, H 6.00, N 4.56.

(100) [M⁺ꢀCl]; elemental analysis calcd (%) for C₆₃H₆₁Cl₂N₅O₇P₂Pt: C

56.97, H 4.63, N 5.27; found: C 57.03, H 4.72, N 5.13; heterodimer/C-

homodimer ratio=98.3:1.7.

cis-[PtCl

was obtained from cis-[PtCl CTHGNUTRENNUNG

(3c·8 f)]: Following the general procedure, the title compound

₂A(cod)] (11.3 mg, 30.0 mmol, 1.0 equiv), C-di-

peptidyl ligand 3c (14.8 mg, 30.0 mmol, 1.0 equiv) and N-dipeptidyl ligand

8 f (16.6 mg, 30.0 mmol, 1.0 equiv). M.p. 1558C (CH₂Cl₂); [a]²_D⁰=ꢀ14.08

1

General procedure for the generation of heterodimeric platinum(II) com-

(c=1.000 in CHCl₃); H NMR (500 MHz, CDCl₃): d=1.00 (d, J=6.9 Hz,

plexes: Ligand

(30.0 mmol, 1.0 equiv) and cis-[PtCl CHTUNGTRENNNUG

1

(30.0 mmol, 1.0 equiv),

a complementary ligand 2

3H; 27-H₃or 28-H₃), 1.03 (d, J=6.6 Hz, 3H; 27-H₃or 28-H₃), 1.14 (d,

J=6.9 Hz, 3H; 7-H₃or 8-H₃), 1.17 (d, J=6.9 Hz, 3H; 7-H₃or 8-H₃), 1.46

(d, J=6.0 Hz, 3H; 3-H₃), 1.47 (s, 9H; tBu), 1.74 (d, J=6.9 Hz, 3H; 23-

H₃), 2.22 (m_c, 1H; 26-H), 2.26 (m, J=6.9 Hz, 1H; 6-H), 3.79 (s, 3H;

OCH₃), 4.05 (dd, J=6.9, 6.6 Hz, 1H; 25-H), 4.63 (dq, J=7.3, 6.9 Hz, 1H;

2-H), 5.18 (dd, J=9.1, 6.9 Hz, 1H; 5-H), 5.38 (d, J=8.5 Hz, 1H; NH_E),

5.47 (dd, J=7.3, 6.9 Hz, 1H; 22-H), 6.75 (dd, J=7.6, 4.1 Hz, 1H; 17-H),

6.80 (m_c, 2H; ArH), 7.03–7.10 (m, 2H; ArH, 13-H), 7.12–7.22 (m, 10H;

ArH, 14-H, NH_D, NH_B), 7.23–7.47 (m, 7H; ArH, 18-H), 7.62 (m_c, 2H;

ArH), 7.74 (dd, J=7.7, 1.1 Hz, 1H; 15-H), 7.95 (m_c, 2H; ArH), 8.19 (dd,

J=8.3, 2.3 Hz, 1H; 19-H), 8.60 (d, J=6.9 Hz, 1H; NH_A), 9.61 (d, J=

14.8 Hz, 1H; 11-H), 10.78 ppm (s, 1H; NH_C); ¹³C NMR (125 MHz,

CDCl₃): d=17.9 (C₃, C_27/28), 18.7, 19.0 (C₇, C₈), 19.5 (C_27/28), 20.3 (C₂₃),

28.4 (3C₃₁), 31.1 (C₂₆), 33.0 (C₆), 48.3 (C₂), 49.7 (C₂₂), 52.3 (OCH₃), 58.2

(C₅), 60.4 (C₂₅), 80.1 (C₃₀), 114.6 (C₁₉), 124.2 (d, J_C,P=16.1 Hz; C₁₇), 127.5

(d, J_C,P=11.8 Hz; 2ArC_meta), 127.6 (d, J_C,P=10.8 Hz; 2ArC_meta), 127.9 (d,

₂A(cod)] (11.2 mg, 30.0 mmol, 1.0 equiv)

were dissolved in CDCl₃(0.8 mL, 37.5m) at room temperature and ana-

lyzed by NMR (¹H; ³¹P) spectroscopy and ESI-MS. For other characteri-

sation experiments, an appropriate amount of the complex was dissolved

in CH₂Cl₂and stirred for 10 min at room temperature. The solvent was

removed in vacuo and the residue was washed with n-pentane. The re-

maining white solid was dried in vacuo. In most of the cases, the N-

homodimer signals in the ³¹P NMR spectra were broad or not detectable

due to line broadening. Thus, heterodimer/C-homodimer ratios were de-

termined by integration of corresponding signals in the ³¹P NMR and/or

¹³C NMR spectra.

cis-[PtCl

was obtained from cis-[PtCl CTHGNUTRENNUNG

(3b·8a)]: Following the general procedure, the title compound

₂A(cod)] (11.2 mg, 30.0 mmol, 1.0 equiv), benzyl-

amide ligand 3b (11.9 mg, 30 mmol, 1.0 equiv) and pivaloyl ligand 8a

(10.9 mg, 30.0 mmol, 1.0 equiv). ³¹P NMR (121 MHz, CDCl₃): d=11.03 (d

1

2

1

J

_C,P=10.7 Hz; 2ArC_meta), 128.1 (d,

_C,P=8.6 Hz; C₁₄), 128.5 (ArC), 128.5 (ArC), 129.4 (d, J_C,P=61.3 Hz;

J_C,P=11.8 Hz; 2ArC_meta), 128.3 (d,

and brs, J_{P, Pt}ꢁ3730.6 Hz, J_P,Pnot detectable; 8a), 14.50 ppm (dd, J_{P, Pt}

=

3686.6 Hz, ²J_P,P=15.6 Hz; 3b); MS (ESI, 5 kV): m/z (%): calcd for

C₄₈H₄₅Cl₂N₃O₂P₂Pt: 988.1 (39) [M⁺ꢀCl], 955.1 (100) [M⁺ꢀCl] (8a homo-

dimer), 918.3 (94) [M⁺ꢀClꢀHCl] (8a homodimer); heterodimer/C-

homodimer ratio=71.5:28.5.

ArC), 130.4 (ArC), 130.6 (ArC), 131.3 (ArC), 131.4 (ArC), 134.4 (d,

_C,P=9.7 Hz; 2ArC), 134.7 (d, _C,P=14.0 Hz; ArC), 135.1 (d, J_C,P=

J

10.8 Hz; 2ArC), 135.2 (d, J_C,P=10.7 Hz; 2ArC), 137.2 (d, J_C,P=7.5 Hz;

C₁₈, 2ArC), 138.1 (d, J_C,P=21.5 Hz; C₁₁), 151.6 (d, J_C,P=20.4 Hz; C₂₀),

cis-[PtCl

was obtained from cis-[PtCl CTHGNUTRENNUNG

(3b·8b)]: Following the general procedure, the title compound

₂A(cod)] (11.2 mg, 30.0 mmol, 1.0 equiv), benzyl-

153.9 (d,

J_C,P=96.7 Hz; C₁₆), 156.0 (C₂₉), 166.9, 171.2, 171.7, 172.1,

173.2 ppm (C₁, C₄, C₉, C₂₁, C₂₄); ³¹P NMR (202 MHz, CDCl₃): d=4.37

(dd, ¹J_P,Pt=3622.7 Hz, ²J_{P, P}=14.8 Hz; N-peptide 8 f), 15.92 ppm (dd,

amide ligand 3b (11.9 mg, 30 mmol, 1.0 equiv) and acetyl ligand 8b

(9.6 mg, 30.0 mmol, 1.0 equiv). ³¹P NMR (121 MHz, CDCl₃): d=9.53 (d

2

1

2

1

¹J_{P, Pt}=3790.1 Hz, J_{P, P}=14.8 Hz; C-peptide 3c); MS (ESI) 5 kV: m/z (%):

and brs, J_{P, Pt}ꢁ3821.9 Hz, J_{P, P}not detectable, 8b), 15.07 ppm (dd, J_{P, Pt}

=

calcd for C₅₈H₆₈Cl₂N₆O₈P₂Pt: 1269.2 (100) [M⁺ꢀCl]; elemental analysis

calcd (%) for C₅₈H₆₈Cl₂N₆O₈P₂Pt: C 53.38, H 5.25, N 6.44; found: C

53.24, H 5.37, N 6.38; heterodimer/C-homodimer ratio=96.3:3.7. Reso-

nance assignments were based on DQF-COSY, edHSQC, TOCSY and

ROESY analysis.

3740.0 Hz, ²J_P,P=16.2 Hz; 3b); MS (ESI, 5 kV): m/z (%): calcd for

C₄₅H₃₉Cl₂N₃O₂P₂Pt: 946.1 (60) [M⁺ꢀCl], 909.2 (9) [M⁺ꢀClꢀHCl], 871.1

(100) [M⁺ꢀCl] (8b homodimer), 834.3 (45) [M⁺ꢀClꢀHCl] (8b homodi-

mer); heterodimer/C-homodimer ratio=78.4:21.6.

cis-[PtCl

was obtained from cis-[PtCl CTHGNUTRENNUNG

(3b·8c)]: Following the general procedure, the title compound

₂A(cod)] (11.2 mg, 30.0 mmol, 1.0 equiv), benzyl-

cis-[PtCl

was obtained from cis-[PtCl CTHGNUTRENNUNG

(3a·8c)]: Following the general procedure, the title compound

₂A(cod)] (11.2 mg, 30.0 mmol, 1.0 equiv), ester

amide ligand 3b (11.9 mg, 30 mmol, 1.0 equiv) and trifluoroacetylamide

ligand 8c (11.2 mg, 30.0 mmol, 1.0 equiv). ³¹P NMR (162 MHz, CDCl₃):

ligand 3a (9.6 mg, 30 mmol, 1.0 equiv) and trifluoroacetylamide ligand 8c

(11.2 mg, 30.0 mmol, 1.0 equiv). ³¹P NMR (121 MHz, CDCl₃): d=10.12

d=9.33 (dd, ¹J_{P, Pt}=3678.0 Hz, ²J_{P, P}=15.9 Hz; 8c), 15.14 ppm (dd, J_{P, Pt}

=

1

(dd, ¹J_{P, Pt}=3669.9 Hz, ²J_P,P=15.6 Hz; amide 8c), 15.53 ppm (dd, J_{P, Pt}

=

3701.8 Hz, ²J_P,P=13.9 Hz; 3b); MS (ESI, 5 kV): m/z (%): calcd for

C₄₅H₃₆Cl₂F₃N₃O₂P₂Pt: 100.1 (52) [M⁺ꢀCl], 979.0 (54) [M⁺ꢀCl] (8c

homodimer), 963.1 (46) [M⁺ꢀClꢀHCl], 942.2 (100) [M⁺ꢀClꢀHCl] (8c

homodimer); heterodimer/C-homodimer ratio=80.8:19.2.

3728.3 Hz, ²J_{P, P}=15.6 Hz; ester 3a); MS (ESI, 5 kV): m/z (%): calcd for

C₃₉H₃₁Cl₂F₃N₂O₃P₂Pt: 979.0 (56) [M⁺ꢀCl] (8c homodimer), 942.1 (66)

[M⁺ꢀClꢀHCl] (8c homodimer), 925.0 (63) [M⁺ꢀCl], 888.2 (100) [M⁺

ꢀClꢀHCl]; heterodimer/C-homodimer ratio=63.0:37.0.

cis-[PtCl

was obtained from cis-[PtCl CTHGNUTRENNUNG

(3b·8d)]: Following the general procedure, the title compound

₂A(cod)] (11.2 mg, 30.0 mmol, 1.0 equiv), benzyl-

cis-[PtCl

₂ACHTUGNRTEN(UNGN 6a·11a)], cis-[PtCl₂ACHTUNRTGEGNUN(N 6b·11b)], cis-[PtCl₂ACHTUNGTREN(NUGN 3c·11b)] and cis-

[PtCl₂A

CTHUNGTRENNUNG

amide ligand 3b (12.0 mg, 30 mmol, 1.0 equiv) and benzylamide ligand 8d

(12.0 mg, 30.0 mmol, 1.0 equiv). ³¹P NMR (202 MHz, CDCl₃): d=9.32 (d

exclusively in the formation of a statistical mixture of heterodimer and

both homodimers (typical ratio of 2:1:1).

and brs, ¹J_P,Pt=3788.4 Hz, J_P,Pnot detectable; 8d), 14.49 ppm (dd over-

2

lapped with C-homodimer, ¹J_{P, Pt}=3674.4 Hz, ²J_{P, P}<19 Hz; 3b); MS (ESI,

5 kV): m/z (%): calcd for C₅₁H₄₃Cl₂N₃O₂P₂Pt: 1022.1 (100) [M⁺ꢀCl],

985.2 (16) [M⁺ꢀClꢀHCl]; elemental analysis calcd (%) for

C₅₁H₄₃Cl₂N₃O₂P₂Pt: C 57.91, H 4.10, N 3.97; found: C 57.62, H 4.31, N

3.72; heterodimer/C-homodimer ratio=80.7:19.3. Colourless plate-like

crystals suitable for single-crystal X-ray diffraction analysis were ob-

tained from a solution of the complex in toluene/CDCl₃(5:2, v/v), which

was allowed to stand at room temperature for two weeks.

X-ray crystal-structure analysis: A single crystal of cis-[PtCl₂ACTHNUGRTENUNG(3b·8d)] was

submitted for X-ray data collection using a Rigaku R-AXIS SPIDER

image-plate diffractometer using graphite monochromated Mo_Karadia-

tion at 100 K. Structure solution was carried out by SHELXS-97,^[44]re-

finement against F²with SHELXL-97.^[45]Crystallographic data of cis-

[PtCl₂ACTHNUGRTENUNG(3b·8d)] have been deposited with the Cambridge Crystallographic

Data Centre. CCDC-650318 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_

request/cif.

cis-[PtCl

was obtained from cis-[PtCl

peptidyl ligand 3c (14.7 mg, 30 mmol, 1.0 equiv) and N-monopeptidyl

(3c·8e)]: Following the general procedure, the title compound

CTHUNGTRENNUNG

Theoretical calculations: Initial optimisations of m1–m3 were performed

at the BP86/SV(P) level and were followed by frequency calculations to

confirm that the stationary points were minima on the potential-energy

surface (except in the case of m3, due to hardware limitations). All geo-

metries were then further optimised using the larger TZVP basis set. For

models m2 and m3 single-point calculations on the BP86/TZVP-opti-

ligand 8e (17.1 mg, 30.0 mmol, 1.0 equiv). M.p. 1508C (CH₂Cl₂); [a]_D²¹

=

ꢀ40.08 (c=0.700 in CHCl₃); ³¹P NMR (202 MHz, CDCl₃): d=4.56 (dd,

1

¹J_{P, Pt}=3660.9 Hz, ²J_{P, P}=16.2 Hz; N-peptide 8e), 16.17 ppm (dd, J_{P, Pt}

=

2

3797.9 Hz, J_{P, P}=16.2 Hz; C-peptide 3c); MS (ESI, 5 kV): m/z (%): calcd

for C₆₃H₆₁Cl₂N₅O₇P₂Pt: 1373.1 (34) [M⁺ꢀCl] (8e homodimer), 1292.1

Chem. Eur. J. 2009, 15, 10405 – 10422

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

10419

B. Breit et al.

mised geometries were performed using the hybrid PBE0 functional and

the TZVP basis set to obtain more accurate energies. For structure m1,

single-point calculations on the BP86/TZVP geometries were performed

using the very large QZVPP basis set to test the effects of further basis-

set extension. Additionally for m1, optimisations were performed at the

PBE0/SV(P) and PBE0/TZVP levels to investigate the effects of differ-

ent functionals on the structures and energies of the different isomers.

For m1 and m2, all reported energies are those from single-point calcula-

tions at the PBE0/TZVP level and include zero-point energies; for m3,

the PBE0/TZVP SCF energies are reported. In all calculations a 60-elec-

tron effective core potential (ECP) replaced the core electrons of Pt. All

of the above calculations were performed using the TURBOMOLE

package using the resolution of identity (RI) approximation.^[46–48]NMR

spectroscopic shift and natural bond orbital (NBO) calculations were per-

formed using Gaussian 03.^[49,50]Shielding parameters (s) were calculated

using the GIAO formalism^[42]from the geometries previously optimised

at the BP86/TZVP level. For all NMR spectroscopic calculations the

hybrid B3LYP functional was used with the IGLOIII basis set for H and

C,^[51]TZVP basis set for N, P and O and the LanL2DZ basis set including

10- and 60-electron ECPs for Cl and Pt, respectively. Chemical shifts (d)

were calculated from s using d=(31.58ꢀs) ppm, in which 31.58 is the cal-

Angew. Chem. Int. Ed. 2001 , 40 , 202 2 –2 043; c) A. M. Beatty, Coord.

Chem. Rev. 2003 , 246 , 13 1 –1 43; d) H. W. Roesky, M. Andruh,

Coord. Chem. Rev. 2003 , 236 , 9 1 –1 19; e) D. Braga, F. Grepioni,

Acc. Chem. Res. 2000 , 33 , 60 1 –6 08; f) D. Braga, F. Grepioni, G. R.

Desiraju, Chem. Rev. 1998 , 98 , 137 5 –1 406; g) A. D. Burrows, C.-W.

Chan, M. M. Chowdhry, J. E. McGrady, D. M. P. Mingos, Chem. Soc.

Rev. 1995 , 24 , 32 9 –3 39; h) Y. Sunatsuki, Y. Motoda, N. Matsumoto,

Coord. Chem. Rev. 2002 , 226 , 19 9 –2 09; i) V. Balamurugan, W.

Jacob, J. Mukherjee, R. Mukherjee, CrystEngComm 2004 , 6 , 39 6 –

400; j) K. Biradha, CrystEngComm 2003 , 5 , 37 4 –3 84; k) S. Kitaga-

wa, S. Kawata, Coord. Chem. Rev. 2002 , 224 , 1 1 –3 4; l) M. Tadokoro,

K. Nakasuji, Coord. Chem. Rev. 2000 , 198 , 20 5 –2 18; m) D. Natale,

J. C. Mareque-Rivas, Chem. Commun. 2008 , 42 5 –4 37; n) B. Coner-

ney, P. Jensen, P. E. Kruger, B. Moubaraki, K. S. Murray, CrystEng-

Comm 2003 , 5 , 45 4 –4 58; o) C. J. Kuehl, F. M. Tabellion, A. M. Arif,

P. J. Stang, Organometallics 2001 , 20 , 195 6 –1 959, and reference [6]

therein; p) T. J. Burchell, R. J. Puddephatt, Inorg. Chem. 2005 , 44 ,

371 8 –3 730, and reference [2–4] therein; q) S. L. James, D. M. P.

Mingos, X. Xu, A. J. P. White, D. J. Williams, J. Chem. Soc. Dalton

Trans. 1998 , 133 5 –1 340, and reference [2] therein.

[6] DNA–metal base pairs: a) G. H. Clever, C. Kaul, T. Carell, Angew.

Chem. 2007 , 119 , 634 0 –6 350; Angew. Chem. Int. Ed. 2007 , 46 , 622 6 –

6236; b) S. D. Wettig, D. O. Wood, J. S. Lee, J. Inorg. Biochem. 2003 ,

94 , 9 4 –9 9; c) J. S. Lee, L. J. P. Latimer, R. S. Reid, Biochem. Cell

Biol. 1993, 71, 162–168; d) P. Aich, S. L. Labiuk, L. W. Tari, L. J. T.

Delbaere, W. J. Roesler, K. J. Falk, R. P. Steer, J. S. Lee, J. Mol. Biol.

1999 , 294 , 47 7 –4 85; e) E. Fusch, B. Lippert, J. Am. Chem. Soc.

1994 , 116 , 720 4 –7 209; f) R. K. O. Sigel, E. Freisinger, S. Metzger, B.

Lippert, J. Am. Chem. Soc. 1998 , 120 , 1200 0 –1 2007; g) S. Metzger,

B. Lippert, J. Am. Chem. Soc. 1996 , 118 , 1246 7 –1 2468; h) O. Kriza-

novic, M. Sabat, R. B. Pfnꢀr, B. Lippert, J. Am. Chem. Soc. 1993 ,

115 , 553 8 –5 548; i) I. Dieter-Wurm, M. Sabat, B. Lippert, J. Am.

Chem. Soc. 1992 , 114 , 35 7 –3 59; j) C. Price, B. R. Horrocks, A.

Mayeux, M. R. J. Elsegood, W. Clegg, A. Houlton, Angew. Chem.

2002 , 114 , 108 9 –1 091; Angew. Chem. Int. Ed. 2002 , 41 , 104 7 –1 049.

[7] Our group has extensively studied self-assembling, hydrogen-bond

donor/acceptor-functionalised ligands for catalysis: a) B. Breit, W.

Seiche, J. Am. Chem. Soc. 2003 , 125 , 660 8 –6 609; b) B. Breit, W.

Seiche, Angew. Chem. 2005 , 117 , 166 6 –1 669; Angew. Chem. Int. Ed.

2005 , 44 , 164 0 –1 643; c) W. Seiche, A. Schuschkowski, B. Breit, Adv.

Synth. Catal. 2005 , 347 , 148 8 –1 494; d) B. Breit, W. Seiche, Pure

Appl. Chem. 2006 , 78 , 24 9 –2 56; e) F. Chevallier, B. Breit, Angew.

Chem. 2006 , 118 , 162 9 –1 632; Angew. Chem. Int. Ed. 2006 , 45 , 159 9 –

1602; f) M. Weis, C. Waloch, W. Seiche, B. Breit, J. Am. Chem. Soc.

2006 , 128 , 418 8 –4 189; g) C. Waloch, J. Wieland, M. Keller, B. Breit,

Angew. Chem. 2007 , 119 , 309 7 –3 099; Angew. Chem. Int. Ed. 2007 ,

46 , 303 7 –3 039; h) M.-N. Birkholz, N. V. Dubrovina, H. Jiao, D. Mi-

chalik, J. Holz, R. Paciello, B. Breit, A. Bçrner, Chem. Eur. J. 2007 ,

13 , 589 6 –5 907; i) M.-N. Birkholz, N. V. Dubrovina, I. A. Shuklov, J.

Holz, R. Paciello, C. Waloch, B. Breit, A. Bçrner, Tetrahedro n :

Asymmetry 2007 , 18 , 205 5 –2 060; j) I. Usui, S. Schmidt, M. Keller, B.

Breit, Org. Lett. 2008 , 10 , 120 7 –1 210; k) M. de Greef, B. Breit,

Angew. Chem. 2009, 121, 559–562; Angew. Chem. Int. Ed. 2009, 48,

551–554.

1

culated isotropic shielding parameter of the H NMR spectroscopic refer-

ence compound SiMe₄(d=0 ppm) at the same level of theory. NBO cal-

culations were performed using the B3LYP functional and the Lan2DZ

basis set (including 60-electron ECP) for Pt and the TZVP basis set for

all other atoms. The Supporting Information contains all XYZ coordi-

nates, energies, vibrational frequencies and NMR spectroscopic shielding

parameters.

Acknowledgements

This work was supported by the Fonds der Chemischen Industrie, DFG

(Int. Research Training Group GRK 1038), the Alfried Krupp Award for

Young University Teachers from the Krupp Foundation (to B.B.), and

BASF. J.M.S. is grateful to the Alexander von Humboldt Foundation for

a fellowship. We also thank J. “Leo” Leonhardt and B. Ruf for great lab-

oratory assistance, and Dr. M. Keller for ROE spectroscopy experiments.

[1] a) F. Vçgtle, Supramolecular Chemistry: Introduction, Teubner,

Stuttgart, 1989; b) J.-M. Lehn, Supramolecular Chemistry: Concepts

and Perspectives, Wiley-VCH, Weinheim, 1995; c) Supramolecular

Chemistry: A Concise Introduction (Eds.: J. W. Steed, J. L. Atwood),

Wiley, New York, 2000; d) Principles and Methods in Supramolec-

ular Chemistry (Eds.: H.-J. Schneider, A. K. Yatsimirsky), Wiley,

New York, 2000; e) Comprehensive Supramolecular Chemistry,

Vol. 1–11 (Eds.: J.-M. Lehn, J. L. Atwood, J. E. D. Davies, D. D.

MacNicol, F. Vçgtle), Pergamon, Oxford, 1996; f) Templating, Self-

Assembly and Self-Organization, Vol. 9 (Eds.: J.-P. Sauvage, M. W.

Hosseini), Pergamon, New York, 1996.

[2] Nanomaterials: a) C. Niemeyer, Angew. Chem. 2001 , 113 , 425 4 –

4287; Angew. Chem. Int. Ed. 2001 , 40 , 412 8 –4 158; b) N. C. Seeman,

Angew. Chem. 1998 , 110 , 340 8 –3 428; Angew. Chem. Int. Ed. 1998 ,

37 , 322 0 –3 238; c) F. Fujimura, S. Kimura, Org. Lett. 2007 , 9 , 79 3 –

796, and references therein.

[3] Biomacromolecules and functions: R. H. Horton, L. A. Moran, R. S.

Ochs, D. J. Rawn, G. K. Scrimgeour, Principles of Biochemistrv,

Prentice Hall International Inc., London, 1992.

[4] Molecular machines: a) Molecular Devices and Machines (Eds.: V.

Balzani, M. Venturi, A. Credi), Wiley-VCH, Weinheim, 2003; b) V.

Balzani, A. Credi, F. M. Raymo, J. F. Stoddart, Angew. Chem. 2000 ,

112 , 348 4 –3 530; Angew. Chem. Int. Ed. 2000 , 39 , 334 8 –3 391;

c) C. A. Schalley, A. Lutzen, M. Albrecht, Chem. Eur. J. 2004 , 10 ,

107 2 –1 080.

[8] a) A. C. Laungani, J. M. Slattery, I. Krossing, B. Breit, Chem. Eur. J.

2008 , 14 , 448 8 –4 502; b) A. C. Laungani, B. Breit, Chem. Commun.

2008 , 84 4 –8 46; c) A. C. Laungani, PhD thesis, University of Frei-

burg i. Br. (Germany), 2008.

[9] For other self-assembled catalysts based on hydrogen bonding, see:

a) M. E. Wilson, G. M. Whitesides, J. Am. Chem. Soc. 1978 , 100 ,

30 6 –3 07; b) M. Skander, N. Humbert, J. Collot, J. Gradinaru, G.

Klein, A. Loosli, J. Sauser, A. Zocchi, F. Gillardoni, T. R. Ward, J.

Am. Chem. Soc. 2004 , 126 , 1441 1 –1 4418; c) M. L. Clarke, J. A.

Fuentes, Angew. Chem. 2007 , 119 , 94 8 –9 51; Angew. Chem. Int. Ed.

2007 , 46 , 93 0 –9 33; d) X.-X. Lu, H.-S. Tang, C.-C. Ko, J. K.-Y. Wong,

N. Zhu, V. W.-W. Yam, Chem. Commun. 2005 , 157 2 –1 574; e) P. A.

Duckmanton, A. J. Blake, J. B. Love, Inorg. Chem. 2005 , 44 , 770 8 –

7710; f) L. K. Knight, Z. Freixa, P. W. N. M. van Leeuwen, J. N. H.

Reek, Organometallics 2006 , 25 , 95 4 –9 60; g) A. J. Sandee, A. M.

[5] Self-assembly using both coordination chemistry and hydrogen

bonding: a) M. Albrecht, Chem. Rev. 2001 , 101 , 345 7 –3 497; b) B. J.

Holliday, C. A. Mirkin, Angew. Chem. 2001 , 113 , 207 6 –2 097;

10420

www.chemeurj.org

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 10405 – 10422

Self-Assembled b-Turn Mimic

FULL PAPER

van der Burg, J. N. H. Reek, Chem. Commun. 2007 , 86 4 –8 66; h) R.

Chen, R. P. J. Bronger, P. C. J. Kamer, P. W. N. M. van Leeuwen,

J. N. H. Reek, J. Am. Chem. Soc. 2004 , 126 , 1455 7 –1 4566; i) L. Shi,

X. Wang, C. A. Sandoval, M. Li, Q. Qi, Z. Li, K. Ding, Angew.

Chem. 2006 , 118 , 421 4 –4 218; Angew. Chem. Int. Ed. 2006 , 45 , 410 8 –

4112; j) B. Schꢁffner, J. Holz, S. P. Verevkin, A. Bçrner, Tetrahedron

Lett. 2008 , 49 , 76 8 –7 71; k) Y. Liu, C. A. Sandoval, Y. Yamaguchi, X.

Zhang, Z. Wang, K. Kato, K. Ding, J. Am. Chem. Soc. 2006 , 128 ,

1421 2 –1 4213; l) F. W. Patureau, M. Kuil, A. J. Sandee, J. N. H.

Reek, Angew. Chem. 2008 , 120 , 322 4 –3 227; Angew. Chem. Int. Ed.

2008 , 47 , 318 0 –3 183; m) P.-A. R. Breuil, F. W. Patureau, J. N. H.

Reek, Angew. Chem. 2009 , 121 , 219 6 –2 199; Angew. Chem. Int. Ed.

2009 , 48 , 216 2 –2 165.

2007 , 129 , 93 4 –9 41; b) R. K. Castellano, V. Gramlich, F. Diederich,

Chem. Eur. J. 2002 , 8 , 11 8 –1 29; c) C. Fonseca Guerra, F. M. Bickel-

haupt, Angew. Chem. 2002 , 114 , 219 4 –2 197; Angew. Chem. Int. Ed.

2002 , 41 , 209 2 –2 095; d) A. N. Patwa, S. Gupta, R. G. Gonnade,

V. A. Kumar, M. M. Bhadbhade, K. N. Ganesh, J. Org. Chem. 2008 ,

73 , 150 8 –1 515.

[16] In general, crystal structures can be regarded as “supermolecules”,

ꢀ

thus leading to many other examples of C H···X interactions in the

solid state, in which these interactions are rather common: G. R.

Desiraju, T. Steiner, The Weak Hydrogen Bond in Structural

Chemistry and Biology, Oxford University Press, Oxford, 1999.

[17] a) G. A. Jeffrey, W. A. Saenger, Hydrogen Bonding in Biological

Structures, Springer, Berlin, 1994; b) R. K. Castellano, Curr. Org.

Chem. 2004 , 8 , 84 5 –8 65; c) A. C. Pierce, E. ter Haar, H. M. Binch,

D. P. Kay, S. R. Patel, P. Li, J. Med. Chem. 2005 , 48 , 127 8 –1 281;

d) S. K. Panigrahi, G. R. Desiraju, J. Biosci. 2007 , 32 , 67 7 –6 91;

e) A. C. Pierce, K. L. Sandretto, G. W. Bemis, Protein J. 2002, 49,

567–576; f) S. Sarkhel, G. R. Desiraju, Proteins 2004 , 54 , 24 7 –2 59;

g) L. Jiang, L. H. Lai, J. Biol. Chem. 2002 , 277 , 3773 2 –3 7740; h) A.

Senes, I. Ubarretxena-Belandia, D. M. Engelman, Proc. Natl. Acad.

Sci. USA 2001 , 98 , 905 6 –9 061; i) B. Loll, G. Raszewski, W. Saenger,

J. Biesiadka, J. Mol. Biol. 2003 , 328 , 73 7 –7 47; j) M. Mottamal, T.

Lazaridis, Biochemistry 2005 , 44 , 160 7 –1 613; k) S. Aravinda, N. Sha-

mala, A. Bandyopadhyay, P. Balaram, J. Am. Chem. Soc. 2003 , 125 ,

1506 5 –1 5075; l) S. Scheiner, J. Phys. Chem. B 2006 , 110 , 1867 0 –

18679; m) G. F. Fabiola, S. Krishnaswamy, V. Nagarajan, V. Pattabhi,

Acta Crystallogr. Sect. A 1997, 53, 316–320; n) P. Chakrabarti, S,

Chakrabarti, J. Mol. Biol. 1998 , 284 , 86 7 –8 73; o) F. Cordier, M. Bar-

field, S. Grzesiek, J. Am. Chem. Soc. 2003 , 125 , 1575 0 –1 5751.

[18] a) G. R. Desiraju, Crystal Engineering. The Design of Organic

Solids, Elsevier, Amsterdam, 1989; b) D. Braga, F. Grepioni, G. R.

Desiraju, Chem. Rev. 1998 , 98 , 137 5 –1 406; c) G. R. Desiraju,

Angew. Chem. 1995 , 107 , 254 1 –2 558; Angew. Chem. Int. Ed. Engl.

1995 , 34 , 231 1 –2 327; d) J. D. Dunitz, A. Gavezzotti, Acc. Chem.

Res. 1999 , 32 , 67 7 –6 84; e) D. Braga, F. Grepioni, Acc. Chem. Res.

2000 , 33 , 60 1 –6 08.

[10] Hydrogen-bonded networks: a) M. M. Conn, J. Rebek, Jr., Chem.

Rev. 1997 , 97 , 164 7 –1 668; b) M. C. T. Fyfe, J. F. Stoddart, Acc.

Chem. Res. 1997 , 30 , 39 3 –4 01; c) J. C. Mac Donald, G. M. White-

sides, Chem. Rev. 1994, 94, 2383–2420; d) C. B. Aakerçy, K. R.

Seddon, Chem. Soc. Rev. 1993 , 22 , 39 7 –4 08; e) Stimulating Concepts

in Chemistry (Eds.: F. Vçgtle, J. F. Stoddart, M. Shibasaki), Wiley-

VCH, Weinheim, 2000; f) L. Brunsveld, B. J. B. Folmer, E. W.

Meijer, R. P. Sijbesma, Chem. Rev. 2001 , 101 , 407 1 –4 097; g) D. S.

Lawrence, T. Jiang, M. Levett, Chem. Rev. 1995 , 95 , 222 9 –2 260;

h) R. G. Chapman, J. C. Sherman, Tetrahedron 1997 , 53 , 1591 1 –

15945; i) J. Rebek, Jr., Chem. Soc. Rev. 1996 , 25 , 25 5 –2 64; j) D.

Philp, J. F. Stoddart, Angew. Chem. 1996 , 108 , 124 2 –1 286; Angew.

Chem. Int. Ed. Engl. 1996 , 35 , 115 4 –1 196; k) G. M. Whitesides,

E. E. Simanek, J. P. Mathias, C. T. Seto, D. N. Chin, M. Mammen,

D. M. Gordon, Acc. Chem. Res. 1995 , 28 , 3 7 –4 4; l) S. Shenhar, V. M.

Rotello, Acc. Chem. Res. 2003 , 36 , 54 9 –5 61; m) C. J. Kuehl, F. M.

Tabellion, A. M. Arif, P. J. Stang, Organometallics 2001 , 20 , 195 6 –

1959, and reference [4] therein; n) C. B. Aakerçy, A. M. Beatty,

D. S. Leinen, Angew. Chem. 1999 , 111 , 193 2 –1 936; Angew. Chem.

Int. Ed. 1999 , 38 , 181 5 –1 819; o) C. B. Aakerçy, A. M. Beatty, D. S.

Leinen, K. R. Lorimer, Chem. Commun. 2000 , 93 5 –9 36; p) C. B.

Aakerçy, A. M. Beatty, Chem. Commun. 1998 , 106 7 –1 068, and ref-

erence [2] therein.

[11] Hydrogen-bond donor/acceptor arrays: a) R. P. Sijbesma, E. W.

Meijer, Chem. Commun. 2003 , 5 –1 6; b) S. C. Zimmerman, P. S.

Corbin, Struct. Bonding (Berlin) 2000, 96, 63–94; c) C. Schmuck, W.

Wienand, Angew. Chem. 2001 , 113 , 449 3 –4 499; Angew. Chem. Int.

Ed. 2001 , 40 , 436 3 –4 369; d) B. Gong, Synlett 2001, 582–589; e) P. K.

Baruah, R. Gonnade, U. D. Phalgune, G. J. Sanjayan, J. Org. Chem.

2005 , 70 , 646 1 –6 467, and references 5–7 cited therein; f) J. Zhu, J.-

B. Lin, Y.-X. Xu, X.-B. Shao, X.-K. Jiang, Z.-T. Li, J. Am. Chem.

Soc. 2006 , 128 , 1230 7 –1 2313, and reference [4,5,10] therein;

g) Supramolecular Assembly via Hydrogen Bonds (Ed.: D. M. P.

Mingos), Springer, Berlin, 2004.

[12] Nanopatterns through hydrogen-bond-assisted self-assembly at the

solid/liquid interface: C. Meier, U. Ziener, K. Landfester, P. Weih-

rich, J. Phys. Chem. B 2005 , 109 , 2101 5 –2 1027, and refs. [3–25]

therein.

[13] Self-assembly just by weak hydrogen bonding in the solid state:

a) D. S. Reddy, B. S. Goud, K. Panneerselvam, G. R. Desiraju, J.

Chem. Soc. Chem. Commun. 1993 , 66 3 –6 64; b) G. Mehta, R. Vidya,

J. Org. Chem. 2000 , 65 , 349 7 –3 502; c) P. W. Baures, J. R. Rush, S. D.

Schroeder, A. M. Beatty, Cryst. Growth Des. 2002 , 2 , 10 7 –1 10; d) C.

Meier, U. Ziener, K. Landfester, P. Weihrich, J. Phys. Chem. B 2005 ,

109 , 2101 5 –2 1027, and refs. [3–25] therein.

[14] Weak hydrogen-bond-directed nanostructures: a) C. L. D. Gibb,

E. D. Stevens, B. C. Gibb, J. Am. Chem. Soc. 2001 , 123 , 584 9 –5 850;

b) U. Ziener, J.-M. Lehn, A. Mourran, M. Mçller, Chem. Eur. J.

2002 , 8 , 95 1 –9 57; c) J. V. Barth, J. Weckesser, C. Cai, P. Gꢀnter, L.

Bꢀrgi, O. Jeandupeux, K. Kern, Angew. Chem. 2000 , 112 , 128 5 –

1288; Angew. Chem. Int. Ed. 2000 , 39 , 123 0 –1 234; d) F. Vidal, E.

Delvigne, S. Stepanow, N. Lin, J. V. Barth, K. Kern, J. Am. Chem.

Soc. 2005 , 127 , 1010 1 –1 0106; e) P. Zell, F. Mçgele, U. Ziener, B.

Rieger, Chem. Commun. 2005 , 129 4 –1 296.

ꢀ

[19] C H···X interactions in the solution state: a) L. Huggins, J. Org.

Chem. 1936 , 1 , 40 7 –4 56; b) M. P. Sammes, R. L. Harlow, S. H. Si-

monsen, J. Chem. Soc. Perkin Trans. 2 1976 , 112 6 –1 130; c) P. Jed-

lovszky, L. Turi, J. Phys. Chem. B 1997 , 101 , 542 9 –5 436; d) K.

Mizuno, T. Ochi, Y. Shindo, J. Chem. Phys. 1998 , 109 , 950 2 –9 507;

e) A. Donati, S. Ristori, C. Bonechi, L. Panza, G. Martini, C. Rossi,

J. Am. Chem. Soc. 2002 , 124 , 877 8 –8 779; f) E. S. Alekseyeva, A. S.

Batsanov, L. A. Boyd, M. A. Fox, T. G. Hibbert, J. A. K. Howard,

J. A. Hugh MacBride, A. Mackinnon, K. Wade, Dalton Trans. 2003 ,

47 5 –4 82; g) A. Cappelli, G. Giorgi, M. Anzini, S. Vomero, S. Ris-

tori, C. Rossi, A. Donati, Chem. Eur. J. 2004 , 10 , 317 7 –3 183; h) J. R.

Quinn, S. C. Zimmerman, Org. Lett. 2004 , 6 , 164 9 –1 652; i) I. El

Drubi Vega, P. A. Gale, M. E. Light, S. J. Loeb, Chem. Commun.

2005 , 491 3 –4 915; j) Z. Li, J. Ding, G. Robertson, M. Day, Y. Tao,

Tetrahedron Lett. 2005 , 46 , 649 9 –6 502; k) J. L. Russ, J. Gu, K.-H.

Tsai, T. Glass, J. C. Duchamp, H. C. Dorn, J. Am. Chem. Soc. 2007 ,

129 , 701 8 –7 027.

[20] Weak hydrogen bonds as structural motifs for a self-assembly pro-

cess have been noted previously in solid state (see refs. [12,13,17b]),

but not in solution or in the context of ligand design (see ref. [17c]).

[21] Design of artificial b-sheets through introduction of structure-direct-

ing templates and molecular scaffolds (reviews): a) J. P. Schneider,

J. W. Kelly, Chem. Rev. 1995 , 95 , 216 9 –2 187; b) J. S. Nowick, E. M.

Smith, M. Pairish, Chem. Soc. Rev. 1996 , 25 , 40 1 –4 15; c) J. Venka-

traman, S. C. Shankaramma, P. Balaram, Chem. Rev. 2001 , 101 ,

313 1 –3 152.

[22] a) M. Feigel, J. Am. Chem. Soc. 1986 , 108 , 18 1 –1 82; b) G. Wagner,

M. Feigel, Tetrahedron 1993 , 49 , 1083 1 –1 0842; c) H. Dꢅaz, J. W.

Kelly, Tetrahedron Lett. 1991, 32, 5725–5728; d) H. Dꢅaz, J. R.

Espina, J. W. Kelly, J. Am. Chem. Soc. 1992, 114, 8316–8318; e) H.

Dꢅaz, K. Y. Tsang, D. Choo, J. W. Kelly, Tetrahedron 1993, 49, 3533–

3545; f) K. Y. Tsang, H. Dꢅaz, N. Graciani, J. W. Kelly, J. Am. Chem.

ꢀ

[15] C H···O hydrogen bonds in A·T and G·C base pairs: a) J. R. Quinn,

S. C. Zimmerman, J. E. Del Bene, I. Shavitt, J. Am. Chem. Soc.

Chem. Eur. J. 2009, 15, 10405 – 10422

ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

10421

B. Breit et al.

Soc. 1994 , 116 , 398 8 –4 005; g) C. L. Nesloney, J. W. Kelly, J. Am.

Chem. Soc. 1996 , 118 , 583 6 –5 845.

c) H. G. Alt, R. Baumgꢁrtner, H. A. Brune, Chem. Ber. 1986 , 119 ,

169 4 –1 703.

[37] K. S. Satheeshkumar, G. Vasu, V. Vishalakshil, M. S. Moni, R. Jaya-

kumar, J. Mol. Recognit. 2004 , 17 , 6 7 –7 5.

[38] R. A. Musah, G. M. Jensen, R. J. Rosenfeld, D. E. McRee, D. B.

Goodin, J. Am. Chem. Soc. 1997 , 119 , 908 3 –9 084, and reference [1–

5] therein.

[39] R. Taylor, O. Kennard, W. Versichel, Acta Crystallogr. Sect. B 1984 ,

40 , 28 0 –2 88.

[40] H. Adams, F. J. Carver, C. A. Hunter, J. C. Morales, E. M. Seward,

Angew. Chem. 1996 , 108 , 162 8 –1 631; Angew. Chem. Int. Ed. Engl.

1996 , 35 , 154 2 –1 544.

[41] A. Allerhand, P. von Raguꢇ, Schleyer, J. Am. Chem. Soc. 1963 , 85 ,

171 5 –1 723; Schleyer, J. Am. Chem. Soc. 1963, 85, 1715–1723.

[42] a) J. Gauss, J. Chem. Phys. 1993 , 99 , 362 9 –3 643; b) J. Gauss, J. F.

Stanton, J. Chem. Phys. 1995 , 102 , 25 1 –2 53; c) K. Wolinski, J. F.

Hinton, P. Pulay, J. Am. Chem. Soc. 1990 , 112 , 825 1 –8 260.

[43] a) T. Steiner, Angew. Chem. 2002 , 114 , 5 0 –8 0; Angew. Chem. Int.

Ed. 2002 , 41 , 4 8 –7 6; b) J. Rossmeisl, J. K. Nørskov, K. W. Jacobsen,

J. Am. Chem. Soc. 2004 , 126 , 1314 0 –1 3143.

[44] a) SHELXS97, Program for the solution of crystal structures, G. M.

Sheldrick, University of Gçttingen, Gçttingen, 1997; b) SHELXS97,

Program for the refinement of crystal structures, G. M. Sheldrick,

University of Gçttingen, Gçttingen, 1997.

[45] SHELXTL, The complete software package for single crystal struc-

ture determination, release 5.10, G. M. Sheldrick, Bruker AXS, Inc.,

Madison, 1997.

[46] R. Ahlrichs, M. Baer, M. Hꢁser, H. Horn, C. Koelmel, Chem. Phys.

Lett. 1989 , 162 , 16 5 –1 69.

[47] M. von Arnim, R. Ahlrichs, J. Chem. Phys. 1999 , 111 , 918 3 –9 190.

[48] F. Weigend, M. Hꢁser, Theo. Chem. Acc. 1997, 97, 331–340.

[49] Gaussian 03, Revision B.04, M. J. Frisch, G. W. Trucks, H. B. Schle-

gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgom-

ery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.

Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,

N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.

Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,

O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,

J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,

O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y.

Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg,

V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O.

Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Fores-

man, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski,

B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.

Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Na-

nayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,

M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Pittsburgh

PA, USA, 2003.

[50] a) J. E. Carpenter, F. Weinhold, J. Mol. Struct. 1988, 172, 41–62;

b) J. E. Carpenter, PhD thesis, University of Wisconsin (USA),

1987; c) J. P. Foster, F. Weinhold, J. Am. Chem. Soc. 1980 , 102 ,

721 1 –7 218; d) A. E. Reed, F. Weinhold, J. Chem. Phys. 1983 , 78 ,

406 6 –4 073; e) A. E. Reed, F. Weinhold, J. Chem. Phys. 1983, 78,

1736–1740; f) A. E. Reed, R. B. Weinstock, F. Weinhold, J. Chem.

Phys. 1985 , 83 , 73 5 –7 46; g) A. E. Reed, L. A. Curtiss, F. Weinhold,

Chem. Rev. 1988 , 88 , 89 9 –9 26; h) F. Weinhold, J. E. Carpenter in

The Structure of Small Molecules and Ions (Eds.: R. Naaman, Z.

Vager), Plenum, New York, 1988, pp. 227–236.

[23] a) J. S. Nowick, N. A. Powell, E. J. Martꢅnez, E. M. Smith, G. Noro-

nha, J. Org. Chem. 1992 , 57 , 376 3 –3 765; b) J. S. Nowick, E. M.

Smith, G. Noronha, J. Org. Chem. 1995 , 60 , 738 6 –7 387; c) J. S.

Nowick, S. Mahrus, E. M. Smith, J. W. Ziller, J. Am. Chem. Soc.

1996 , 118 , 106 6 –1 072; d) J. S. Nowick, S. Insaf, J. Am. Chem. Soc.

1997 , 119 , 1090 3 –1 0908.

[24] a) D. Ranganathan, V. Haridas, S. Kurur, R. Nagaraj, E. Bikshapa-

thy, A. C. Kunwar, A. V. S. Sarma, M. Vairamani, J. Org. Chem.

2000 , 65 , 36 5 –3 74; b) C. P. R. Hackenberger, I. Schiffers, J. Runsink,

C. Bolm, J. Org. Chem. 2004 , 69 , 73 9 –7 43; c) F. Sansone, L. Baldini,

A. Casnati, E. Chierici, G. Faimani, F. Ugozzoli, R. Ungaro, J. Am.

Chem. Soc. 2004 , 126 , 620 4 –6 205; d) A. Aemissegger, V. Krꢁutler,

W. F. van Gunsteren, D. Hilvert, J. Am. Chem. Soc. 2005 , 127 , 292 9 –

2936; e) A. S. M. RessurreiÅ¼o, A. Bordessa, M. Civera, L. Belvisi,

C. Gennari, U. Piarulli, J. Org. Chem. 2007, 72, 652–660.

[25] a) H. Zeng, X. Yang, R. A. Flowers II, B. Gong, J. Am. Chem. Soc.

2002 , 124 , 290 3 –2 910; b) K. S. Satheeshkumar, G. Vasu, V. Vishalak-

shi, M. S. Moni, R. Jayakumar, J. Mol. Recognit. 2004 , 17 , 6 7 –7 5.

[26] Metal-directed b-sheet self-assembly: a) J. P. Schneider, J. W. Kelly,

J. Am. Chem. Soc. 1995 , 117 , 253 3 –2 546; b) M. Kruppa, C. Bonauer,

V. Michlovꢆ, B. Kçnig, J. Org. Chem. 2005 , 70 , 530 5 –5 308; c) N.

Barooah, R. J. Sarma, J. B. Baruah, Eur. J. Inorg. Chem. 2006 , 294 2 –

2946.

[27] The dimerisation of polarised DNA double strands by strong diva-

lent metal coordination and only one intermolecular hydrogen-

bonding interaction has been proposed by Lee and Lippert (see, for

example, ref. [6a]). The exact structures of these DNA–metal com-

plexes are, however, still the subject of controversy.

[28] Abbreviations used within this paper: A: acceptor; Ac: acetate;

Ala: alanine; Bn: benzyl; cod: 1,5-cyclooctadiene; D: donor; DCC:

dicyclohexylcarbodiimide; DIC: diisopropylcarbodiimide; DMAP:

dimethylamino-pyridine; Fmoc: 9-fluorenylmethoxycarbonyl; EE:

ethyl acetate; PE: petroleum ether (b.p. 40–658C); Piv: pivaloyl;

TFAc: trifluoroacetyl; Val: valine; WHB: weak hydrogen bond; Z:

benzyloxycarbonyl.

[29] An alternative m-DPPBA synthesis has been reported previously:

a) O. Herd, A. Heßler, M. Hingst, M. Tepper, O. Stelzer, J. Organo-

met. Chem. 1996 , 522 , 6 9 –7 6; b) M. Hingst, M. Tepper, O. Stelzer,

Eur. J. Inorg. Chem. 1998 , 7 3 –8 2.

[30] M. A. Peterson, J. R. Mitchell, J. Org. Chem. 1997 , 62 , 823 7 –8 239.

[31] G. Hçfle, W. Steglich, H. Vorbrꢀggen, Angew. Chem. 1978 , 90 , 60 2 –

615; Angew. Chem. Int. Ed. Engl. 1978 , 17 , 56 9 –5 83.

[32] J. R. Pratt, W. D. Massey, F. H. Pinkerton, S. F. Thames, J. Org.

Chem. 1975 , 40 , 109 0 –1 094.

[33] Synthesis of m-DPPA has already been reported: A. Hessler, O.

Stelzer, J. Org. Chem. 1997 , 62 , 236 2 –2 369.

[34] a) P. S. Pregosin, ³¹P NMR Spectroscopy in Stereochemical Analysis,

Organic Compounds and Metal Complexes (Eds.: J. G. Verkade,

L. D. Louis), VCH, Weinheim, 1987; b) ³¹P and ¹³C NMR of Transi-

tion Metal Phosphine Complexes: P. S. Pregosin, R. W. Kunz in

NMR Basic Principles and Progress, Vol. 16 (Eds.: P. Diehl, E.

Fluck, R. Kosfeld), Springer, Heidelberg, 1979, and references there-

in.

[35] In the last 20 years, database mining of the Cambridge Structural

Database (CSD) and the Brookhaven Protein Data Bank (PDB)

have increasingly been applied to identify and characterise weak in-

termolecular interactions in chemical and biological systems:

a) G. R. Desiraju, Acc. Chem. Res. 1996 , 29 , 44 1 –4 49; b) T. Steiner,

Chem. Commun. 1997 , 72 7 –7 34; c) T. Steiner, G. R. Desiraju,

Chem. Commun. 1998 , 89 1 –8 92; d) M. Mascal, Chem. Commun.

1998 , 30 3 –3 04; e) T. Steiner, Cryst. Res. Technol. 2003, 9, 177–228;

f) R. Taylor, O. Kennard, J. Am. Chem. Soc. 1982 , 104 , 506 3 –5 070.

Article Doi

Cooperative effect of a classical and a weak hydrogen bond for the metalInduced construction of a self-assembled β-turn mimic

DOI: 10.1002/chem.200900662

Source and publish data:

Authors:

Article abstract of DOI:10.1002/chem.200900662

Full text of DOI:10.1002/chem.200900662

Products guided by the article

R&D Labs maybe for 1041871-71-9

Relevant to this article

Hot Product