Synthesis and characterization of PY2- and TPA-appended diphenylglycoluril receptors and their bis-CuI complexes

FULL PAPER

DOI: 10.1002/ejoc.200500865

Synthesis and Characterization of PY2- and TPA-Appended Diphenylglycoluril

Receptors and Their Bis-Cu^IComplexes

Vera S. I. Sprakel,^[a]Johannes A. A. W. Elemans,^[a]Martin C. Feiters,*^[a]Baldo Lucchese,^[b]

Kenneth D. Karlin,^[b]and Roeland J. M. Nolte^[a]

Keywords: Host–guest systems / Bioinorganic chemistry / Copper / N ligands / NMR spectroscopy / High-pressure chemistry

A number of metallohosts mimicking dinuclear copper oxy-

genases have been designed and synthesized. These metallo-

hosts combine a substrate binding site, i.e. the diphenyl-

glycoluril basket receptor, with two types of metal-binding

ligands, viz. tri-coordinating bis(2-ethylpyridine)amine (PY2)

and tetra-coordinating tris(2-methylpyridine)amine (TPA).

The preparation of the bis-Cu^Icomplexes of the ligand-

appended receptors and their characterization by NMR are

reported. NMR spectroscopic data provide evidence for a dy-

namic inclusion behavior of some of the pyridine moieties

in the receptor of both the metal-free ligands and the Cu^I

complexes.

Germany, 2006)

Introduction

Copper proteins that transport or activate dioxygen are

abundant in nature.^[1–4]Hemocyanin transports O₂in mol-

luscs and arthropods,^[2,5,6]tyrosinase causes pigment forma-

tion in plants and animals,^[7]while dopamine-β-hydroxylase

and peptidylglycine α-amidating mono-oxygenase assist in

neurotransmitter biosynthesis/hormone regulation in ver-

tebrate brains.^[8,9]These proteins have different functions,

yet they all contain the same metal ion in their active site.

A biological dinuclear copper site can bind dioxygen in a

side-on µ-η²:η²mode, as was established by X-ray crystal-

lography for oxy-hemocyanin (Figure 1, top).^[2]A similar

active site was recently observed by X-ray crystallography

in catechol oxidase^[10,11](Figure 1, bottom) and was sug-

gested to be present in other enzymes by similarities in EX-

AFS and UV/Vis spectroscopic features.^[12,13]The dinuclear

copper enzymes that bind and activate molecular oxygen

for reaction with exogenous substrates use the same metal-

containing active site for dioxygen binding as hemocyanin,

but combine it with a binding site for organic substrates

that is missing in hemocyanin.^[14,15]

Figure 1. Crystal structures of active sites: (top) Hemocyanin sub-

unit II from the horseshoe crab (Limulus polyphemus).^[5](bottom)

Catechol oxidase from sweet potatoes (Ipomoea batatas),^[10]a OH^–

ion coordinates between the Cu^Iions.

We have started a programme to develop synthetic mim-

ics for the dinuclear copper proteins and enzymes, not only

in order to better understand their mechanisms of action,

but also to develop new selective clean catalysts for oxi-

dation processes.^[16]In the design of these biomimetic cata-

lysts, we covalently attach ligands for catalytically active

metals to synthetic receptors such as diphenylglycoluril and

cyclodextrins. An abundance of synthetic copper complexes

that model biological oxygen binding and activation have

been reported.^{[1,3,4,17–20]}A ligand that has been used to

model biological tri-coordinated Cu^Isites such as the ones

shown in Figure 1 is bis(2-ethyl-1-pyridyl)amine (PY2, 1)

(Figure 2, top), which is synthetically easily accessible and

can be readily functionalised.^[21]Enzymes with tetracoordi-

[a] Department of Organic Chemistry, Institute for Molecules and

Materials, Radboud University Nijmegen,

1 Toernooiveld, 6525 ED Nijmegen, The Netherlands

[b] Department of Chemistry, The Johns Hopkins University,

3400 N. Charles Street, Baltimore, Maryland 21218, USA

Eur. J. Org. Chem. 2006, 2281–2295

2281

M. C. Feiters et al.

FULL PAPER

nate Cu ions are also found, e.g. Cu^IIin Cu,Zn superoxide N-dealkylation of the ligand, before it could attack exoge-

dismutase, which is coordinated by four histidine resi- nous substrates (Figure 4). One of the benzylic hydrogen

dues.^[22]A synthetic tetradentate ligand is tris(2-pyridyl- atoms of the m-xylyl linker is in close proximity to the reac-

methyl)amine (TPA, 2) (Figure 2, bottom).^[23]As shown in tive Cu^II₂O₂complex. This benzylic position is oxidized,

Figure 2, a µ-η²:η²dioxygen binding mode such as found leading to the formation of the aldehyde of the ligand and

in hemocyanin is observed for PY2, whereas a trans-µ-1,2 free PY2 (1).^[30]

peroxo dioxygen binding mode is observed for TPA.^[1,3,19]

Figure 2. Structure and dioxygen reactivity of the tri-coordinating

ligand 1 (top)^[21]and the tetra-coordinating ligand 2 (bottom).^[23]

A receptor referred to as a “molecular clip”, which was

previously designed by our group, is based on diphenyl-

glycoluril and selectively binds 1,3-dihydroxybenzenes (3, Figure 4. Oxidative N-dealkylation of 5·Cu^I₂·O₂.

Figure 3, top).^[13,24,25]This clip has been enlarged to a so-

called “molecular basket” by attachment of two crown

ether moieties (4, Figure 3, bottom).^[26,27]This molecular

We now report on the synthesis and characterization of

new biomimetic catalysts for dinuclear copper enzymes

based on the diphenylglycoluril basket (Figure 5). In the de-

sign of the first type of mimic, the m-xylyl linker in 5 is

replaced by an aliphatic butyl linker, affording the receptor

6 (PY2-appended receptor), which no longer contains ben-

zylic positions. For reasons of comparison the butyl linker

in the receptor 6 was selected to be approximately of the

same length as the m-xylyl linker in the receptor 5, but it is

of course much more flexible. In order to test the influence

of the linker length on the oxygen binding capacity and

oxidation reactivity of the dinuclear Cu^Icomplexes of these

receptors, receptor 7 was designed which only differs from

receptor 6 with respect to the length of the linker (ethyl vs.

butyl).

basket has two positions available (R) for attachment of

two ligand sets for Cu^Iions, creating the metal site in this

synthetic model.

In the second type of mimic a pyridyl linker is used in-

stead of an m-xylyl linker, affording the TPA-appended re-

ceptors 8 and 9, which contain two tetra-coordinating TPA

ligands instead of the tri-coordinating ligands in receptors

6 and 7. In 8 and 9, no benzylic hydrogen atoms are in close

proximity of the metal site. We expect a different reactivity

of receptors 6 and 8 towards dioxygen and substrates. The

reactivities of dinuclear Cu^Icomplexes of 6 and 8 towards

dioxygen and of the oxygenated complexes towards sub-

Figure 3. Molecular clip 3 and molecular basket 4.

We have previously reported on the dinuclear Cu^Icom- strates will be described elsewhere.^[31]The synthesis and

plex of a molecular basket in which two PY2 units are at- characterization of the receptors are described here, along

tached to the receptor by m-xylyl linkers (5, Figure 4).^[28,29]with detailed studies of the coordination of Cu^Ito the li-

Dioxygen was bound by this complex in a µ-η²:η²species, gands in the receptors 6 and 8 by as determined by NMR

which unfortunately was not stable and displayed oxidative spectroscopy.

2282

www.eurjoc.org

Eur. J. Org. Chem. 2006, 2281–2295

PY2- and TPA-Appended Diphenylglycoluril Receptors and Their Bis-Cu^IComplexes

FULL PAPER

Figure 5. Structures of target receptors.

two equiv. of [Cu^I(CH₃CN)₄](ClO₄) were dissolved in

dichloromethane and stirred for 10 minutes under standard

Schlenk conditions. The resulting complex was precipitated

by using diethyl ether as a non-solvent.^[35]Complex 6a was

obtained as a yellow solid that is very air sensitive in the

solid state, and even more air sensitive in solution. For the

in situ preparation of a solution of 6a, suitable for example

catalytic experiments or spectroscopy, one equiv. of recep-

tor 6 and two equiv. of [Cu^I(CH₃CN)₄](ClO₄) were dis-

solved in the desired solvent and then stirred for 10 minutes

under standard Schlenk conditions.

Results and Discussion

Synthesis

PY2-Appended Diphenylglycoluril Basket 6: The synthesis

of receptor 6 is depicted in Scheme 1. Tetrapodand 10^[32]

and compound 11 [tert-butyl N-(4-aminobutyl)carb-

amate]^[33]were heated to reflux in acetonitrile for six days

under Finkelstein conditions using sodium carbonate as a

base. As a result compound 12 was obtained via a double-

ring-closure reaction (60% yield).^[34]Compound 13, which

contains two primary amino groups for further function-

alization, was obtained in a yield of 90% by deprotection

Compound 7 was prepared in a similar fashion as 6 start-

of compound 12 in a solvent mixture of trifluoroacetic acid ing from the tetrapodand 10 (Scheme 2). Compounds 10

(TFA) and dichloromethane (1:1, v/v). Receptor 6 was pre- and 14 [tert-butyl N-(2-aminoethyl)carbamate] were heated

pared by double addition of the primary amino groups of at reflux temperatures under Finkelstein conditions to give

compound 13 to 2-vinylpyridine (4 molar equivalents) using 15 in 60% yield. Deprotection of 16 with TFA in dichloro-

one equiv. of acetic acid as a catalyst at high pressure methane gave compound 16 in 70% yield. Subsequent high-

(15 kbar) in a specialized setup. Receptor 6 was obtained in pressure addition of 2-vinylpyridine to 16 gave the receptor

a yield of 94% after basic work up and subsequent column 7. Unfortunately, this compound could not be obtained in

chromatography on activated alumina (eluent: 2% MeOH pure form due to decomposition during purification by col-

in CH₂Cl₂).

umn chromatography on activated alumina, evidenced by

The dinuclear Cu^Icomplex of receptor 6 (named 6a or the large number of unidentified aromatic signals in the

[6·Cu^I₂](ClO₄)₂) can be prepared by two methods. For prep- NMR spectrum. This experiment was not repeated to inves-

aration on a quantitative scale, one equiv. of 6 and tigate other means of purification.

Scheme 1. Synthesis of receptor 6 and its bis-Cu() complex 6a.

Eur. J. Org. Chem. 2006, 2281–2295

www.eurjoc.org

2283

M. C. Feiters et al.

FULL PAPER

Scheme 2. Synthesis of receptor 7.

TPA-Appended Diphenylglycoluril Baskets: The synthesis (hydroxymethyl)-2-pyridyl]methanol to give the protonated

of receptor 8 is shown in Scheme 3. Tetrapodand 10 was compound 20, which was deprotonated with NaHCO₃to

treated with benzylamine under the conditions described 2,6-bis(chloromethyl)pyridine 21. Compound 21 was sub-

above to yield compound 17, which was deprotected by re- sequently coupled to N,N-bis(2-pyridylmethyl)amine (pico-

duction under 20 bar of hydrogen pressure to give com- lylamine) by stirring in THF with diisopropylethylamine

pound 18.^[36]Instead of palladium on carbon with 4 bars (DIPEA) as a base for one week, affording 19 in a yield of

of hydrogen for 168 hours as in the literature procedure, 40%.

palladium hydroxide on carbon was used with 20 bars of

The substitution of the chlorine group in 19 by the sec-

hydrogen for 72 hours. The yield in both cases was around ondary amino nitrogen atoms of compound 18 was carried

70%, the reaction time was however shorter in the case of out under Finkelstein conditions with sodium carbonate as

the modified procedure. The desired receptor 8 was pre- a base and an excess of 19 (3 equiv.). The resulting receptor

pared by the reaction of 6-TPA-Cl 19 with compound 18. 8 was obtained in pure form after column chromatography

The synthesis of 19 has been described in the literature; it on activated alumina (2% MeOH in CH₂Cl₂) in a yield of

occurs through the chlorination of 6-TPA-OH in a multi- 60%. The dinuclear Cu^Icomplex of 8 (8a or [8·Cu^I₂]-

step process.^[37]To simplify this procedure a different route (ClO₄)₂) can be prepared using the two methods described

was used (Scheme 3), starting with the chlorination of [6- above for 6a, either on a quantitative scale or in situ, both

Scheme 3. Synthesis of receptor 8 and complex 8a.

2284

www.eurjoc.org

Eur. J. Org. Chem. 2006, 2281–2295

PY2- and TPA-Appended Diphenylglycoluril Receptors and Their Bis-Cu^IComplexes

FULL PAPER

Scheme 4. Synthesis of receptor 9.

1

under Schlenk conditions.^[31]Complex 8a was obtained as plex? All proton signals in the H NMR spectrum of the

a yellow solid that was very air sensitive in the solid state metal-free receptors 6 and 8 were assigned with the help

and in solution.

of COSY and 2D-NOESY experiments. The titrations of

The synthesis of receptor 9 (Scheme 4) is similar to that receptors 6 and 8 in CD₂Cl₂with [Cu^I(CH₃CN)₄]ClO₄were

of receptor 8, with the exception that a different chloro- carried out under exclusion of air, because air oxidation

TPA derivative is used, viz. 5-TPA-Cl (22). The synthesis of leads to the formation of paramagnetic Cu^IIcomplexes.

22 (Scheme 4) started with the bromination of methyl 6-

Copper Coordination to Receptor 6: The positions of all

methylnicotinate using N-bromosuccinimide to obtain com- peaks and the ∆δ values (shifts in the signals) for 6 to 6a

pound 23. Compound 24 was obtained by reaction of com- are listed in Table 1. The first observation from the NMR

pound 23 with picolylamine, as was described above for the spectrum (Figure 6 and Figure 7) is that a broadening oc-

preparation of 19. The resulting methyl ester was reduced curs upon addition of Cu^I, which obscures the coupling

with lithium aluminium hydride to the alcohol derivative patterns in some cases; this may be due to a self-exchange

25, which was chlorinated to give chloro-TPA derivative 22. electron-transfer reaction caused by a small impurity of

The substitution of the chlorine group in 22 by the second- paramagnetic Cu^IIin the Cu^Isalt.^[38]

ary amino nitrogen atoms of compound 18 was carried out

The NMR spectrum of the complex of receptor 6 with

under Finkelstein conditions with sodium carbonate as a one equivalent of Cu^Ishows only an average set of signals

base and an excess of 22 (3 equiv.). The resulting receptor for the pyridyl protons of 6, from which it can be concluded

9 was obtained in crude form. Column chromatography as that copper binding is dynamic in the sense that the Cu^I

used for receptor 8 was carried out using activated alumina ion moves between the two PY2 ligand sets. The NMR

(eluent: 2% MeOH in CH₂Cl₂); unfortunately this led to spectrum of the complex of 6 with two equivalents of Cu^I,

the decomposition of receptor 9 as indicated by many un- viz. 6a, shows significant shifts in the pyridyl region com-

identified peaks in the ¹H NMR spectrum. The lack of sta- pared to the metal-free receptor 6 (Table 1). The observed

bility of a 5-substituted TPA was also observed in the case downfield shifts in the pyridyl region are attributed to a

of compound 22, compared to the equivalent compound decrease in electron density on the pyridyl ring as a result

19. Apparently, a chloro substituent on the 5-position of of electron donation to the Cu^Iion. A more detailed de-

the pyridyl ring is much less stable than a chloro substituent scription of the changes observed in the NMR spectrum of

on the 6-position of this ring. This difference is most proba- 6 is presented below.

bly also the reason why receptor 9 is less stable than recep-

tor 8.

Upon the addition of a third equivalent of Cu^I, resolved

signals become visible for protons A and C in addition to

a peak at δ = 7.02 ppm, next to the signal for the phenyl

protons of glycoluril (marked by filled squares, ᭿). In the

aliphatic regions of the NMR spectrum several extra peaks

Characterization

¹H NMR titrations of ligands 6 and 8 with Cu^Iwere are observed: a peak near D⁰at δ = 4.15 ppm, and two

carried out in order to answer the following questions re- peaks at δ = 3.48 and 3.53 ppm. It is not clear to which

garding the coordination of Cu^I: (i) Is Cu^Icoordinated se- protons these peaks can be assigned. It is possible that the

lectively to the ligand sets or also non-selectively to the N four pyridyl nitrogen donors and two amino nitrogen do-

and O in the crown ether moieties? (ii) Is a non-symmetric nors from the two PY2 units of 6 (a total of 6 N donors)

complex formed upon coordination of one equivalent of are shared among three Cu^Iions, for example two N donors

Cu^I, or does exchange occur between the two ligand sets? per Cu^I. This type of coordination may result in the forma-

(iii) Can more than two equivalents of Cu^Icoordinate to tion of intra- or intermolecular dimers or oligomers,

the receptor and what is the structure of the resulting com- bridged by Cu^Iions. The additional peaks in the NMR

Eur. J. Org. Chem. 2006, 2281–2295

www.eurjoc.org

2285

M. C. Feiters et al.

FULL PAPER

Table 1. Chemical shift values for metal-free receptor 6, and its complexes with one, two (6a), and three equivalents of [Cu^I(CH₃CN)₄]

ClO₄.

Proton (symbol, Figure)

0 Equiv. (6)

1 Equiv.

2 Equiv. (6a)

3 Equiv.

∆δ 6 to 6a^[a]

PyH⁶(A, 6)

8.40

7.47

7.06

7.00

6.61

5.53

4.04

3.86

3.76

3.62

2.82

2.71

2.49

2.43

1.53

8.43

7.62

7.06

7.13

6.54

5.52

3.98

3.81

3.75

3.64

2.86

2.70

2.55

2.44

1.53

8.57

7.77

7.06

7.26

6.56

5.52

3.99

3.80

3.74

3.64

2.95

2.89

2.72

2.59

2.46

1.49

8.57+8.66

7.78

7.04

7.30

6.64

5.53

3.96

3.76

3.74

3.65

2.97

2.91

2.70

2.61

2.47

1.48

+0.17

+0.30

0

PyH⁴(C, 6)

ArH glycoluril (᭿, 6)

PyH^3/5(B, D, 3–6)

ArH side walls (᭹, 6)

NCH₂Ar out

+0.26

–0.05

–0.01

–0.05

–0.06

–0.02

+0.02

+0.13

+0.07

+0.01

+0.10

+0.03

–0.04

ArOCH₂out (D^o, 7)

ArOCH₂in (Dⁱ, 7)

CH₂O (E, 7)

NCH₂Ar in (᭹, 7)

PyCH₂CH₂N (J, 7)

PyCH₂CH₂N (I, 7)

NCH₂CH₂O (F, 7)

Py2-NCH₂(CH₂)₂CH₂(H, 7)

Py2-NCH₂(CH₂)₂CH₂(G, 7)

Py2-NCH₂(CH₂)₂CH₂

[a] + Sign, downfield shift; – sign; upfield shift.

1

Figure 6. H NMR spectra of metal-free receptor 6 (bottom trace)

with one, two (6a), and three equivalents of Cu^Iin the region of

8.5 to 6.4 ppm.

Figure 7. H NMR spectra of metal-free receptor 6 (bottom trace)

with one, two (6a), and three equivalents of Cu^Iin the region of

4.2 to 2.4 ppm.

2286

www.eurjoc.org

Eur. J. Org. Chem. 2006, 2281–2295

PY2- and TPA-Appended Diphenylglycoluril Receptors and Their Bis-Cu^IComplexes

FULL PAPER

spectrum point to a decrease in the symmetry of the com- ever no such shifts are observed (Table 1). From the above

plex; the structure of this complex is not yet clear.

it can be concluded that no coordination of Cu^Ito O- and

The signals of the phenyl protons of glycoluril (᭿) do not N donors in the crown ether region occurs; it is, however,

shift upon titration with Cu^I, in line with the distant position not exactly clear what causes the extra peaks in this region

with respect to the Cu^Ibinding site. The signal of the side- after addition of the third equivalent of Cu^I.

wall protons (marked by filled circles, ᭹, Figure 6), however,

Distinct downfield shifts were observed for the overlap-

shifts upfield upon the addition of a first equivalent of Cu^Iping signals of the protons of both methylene units (I) and

and shifts back after the addition of the third equivalent. The (J) of the 2-ethylpyridyl moieties upon addition of

observed upfield shift can be the result of the inclusion of a one equivalent of Cu^Iand the signals became resolved upon

pyridyl group, possibly copper-coordinated, in the cavity of the addition of the second equivalent. Together with the ob-

6. It is known that the association constant of an aromatic served downfield shift of the spacer H protons, this could

guest with clips and baskets increases with decreasing elec- point to the involvement of the amine N donor of the PY2

tron density on the guest.^[39,40]An increase was found in the ligand sets in copper coordination.

acidity of the hydroxy groups as well as the strength of the

Upon the addition of [Cu^I(CH₃CN)₄]ClO₄to 6 an in-

π–π stacking interactions of dihydroxybenzene substrates in creasing amount of acetonitrile, being partly displaced from

the presence of electron-withdrawing groups. The observed Cu^Iby the PY2 N donors, is found in the NMR spectra.

downfield shift of the signal of the side-wall protons of 6 can The integration of the acetonitrile signal, which would have

be a result of the expulsion of this pyridyl group from the given information about the exact number of acetonitrile

cavity of the Cu^I₃complex, induced by the less dynamic over- molecules that were displaced however, could not be carried

all structure described above.

out due to line broadening. The fact that line broadening

To establish if Cu^Ican also bind to the O- and/or N occurs may point to a slow exchange process between aceto-

donors of the crown ether moiety, the shifts in this region nitrile coordinated to copper and free acetonitrile in solu-

of the NMR spectrum were studied (Figure 7). An upfield tion. Furthermore, it may be caused by the presence of

shift was observed for the O-methylene D protons upon ad- some Cu^IIinstead of Cu^Ias described above.

dition of one equivalent of Cu^I; the signal remains un-

Based on the data presented above we can provide an-

changed after the addition of an additional equivalent. Se- swers to the questions stated in the beginning of this sec-

veral alternative explanations were considered for this up- tion: (i) Cu^Iis coordinated selectively to the pyridyl and

field shift. It could be due to the inclusion of a pyridyl amine N donor of the PY2 ligand sets, a conclusion that is

group in the cavity; however, because no downfield shift of in line with our EXAFS results,^[31](ii) in the complex of 6

these protons was observed after the addition of the with one equivalent of Cu^I, the binding of Cu^Iis dynamic,

third equivalent of Cu^I(expulsion of the pyridyl group) this and (iii) a non-symmetric complex is formed upon the ad-

cannot be the correct explanation. Another explanation of dition of three equivalents of Cu^Ito 6. In addition, it has

the observed upfield shift of the O-methylene D protons is been observed that one of the pyridyl groups, possibly coor-

a conformation change, such as distortions in the torsion dinated to Cu^I, can bind in the cavity of 6 and that this

angles of the oxyethylene chains in the crown ether moiety, pyridyl group is expelled upon the addition of a third equiv-

as has been described for a molecular basket appended with alent of Cu^I.

two chiral aza-R groups.^[41]In the case of coordination of

Copper Coordination to Receptor 8: The positions of all

Cu^Ito the O- and/or N donors, the signals of the other peaks and the ∆δ values found upon the titration of 8 with

protons in this region would also be expected to shift; how- Cu^Iare listed in Table 2. The first observation in the NMR

Table 2. Chemical shifts for metal-free receptor 8, and its complexes with one, two (8a), and three equivalents of [Cu^I(CH₃CN)₄]ClO₄.

Proton (symbol, Figure)

0 Equiv. (8)

1 Equiv.

2 Equiv. (8a)

3 Equiv.

∆δ 8 to 8a^[a]

PyH⁶(A, 8)

8.46 (d)

7.03

7.58

7.55

7.37 (dd)

7.08

6.64

5.55 (d)

4.14

3.96–3.70

3.82–3.80

3.71 (d)

2.89

8.54+8.46

6.94

7.53

8.55(d)

6.98

8.55^[b]

7.04

+0.09

–0.05

–0.03

+0.08

ca. –0.40

ca. +0.14

–0.03

–0.59

+0.05

+0.03

–

PyH⁵(B, 8)

PyH⁴(C, 8)

7.56^[b]

7.56

PyH^4Ј(CЈ, 8)^[d]

PyH³(D, 8)

7.62

7.66^[b]

7.18–7.15

ca. 7.49–7.53

7.05

6.05

5.60 (d)

4.17

4.00–3.66

3.78–3.72

3.68 (d)

3.31–3.26

7.71^[b]

7.18–7.15

ca. 7.49

7.06

6.05

5.59 (d)

4.12

4.00–3.50

3.80–3.74

3.67 (d)

3.38–3.20

7.25–7.15

ca. 7.65

7.05

PyH^3Ј(DЈ, 8)

ArH glycoluril (᭿, 8)

ArH side walls (᭹, 8)

NCHHAr out (ᮀ, 8)

ArOCHH out (E^o, 9)

ArOCHH in (Eⁱ, 9)

CH₂O (F, 9)

PyCH₂(H, 9)

NCHHAr in

CH₂N (G, 9)

6.05

5.60(d)

4.20–4.09

4.05–3.60

–

3.78–3.72

[c]

–0.03

+0.42

3.35–3.20

[a] + Sign, downfield shift; – sign; upfield shift. [b] An extra peak is observed. [c] Could not be clearly determined. [d] Signals for linker-

pyridyl groups are denoted with Ј to distinguish them from the ‘free’ pyridyl groups.

Eur. J. Org. Chem. 2006, 2281–2295

www.eurjoc.org

2287

M. C. Feiters et al.

FULL PAPER

spectra (Figure 8 and Figure 9) is that a broadening occurs

upon addition of Cu^I, analogous to what has been de-

scribed for receptor 6. Two sets of signals are observed in

the NMR spectrum (Table 2, Figure 8) for the pyridyl pro-

tons of a complex of 8 with one equivalent of Cu^I. The two

distinct sets of signals are best resolved for the A protons.

The signal of the metal-free receptor 8 at δ = 8.46 ppm is

broadened and shifts upon the addition of Cu^I, concomi-

tant with the appearance of a signal of the A protons of

Cu^I-coordinated pyridyl at δ = 8.55 ppm. The spectrum of

the complex with two equivalents of Cu^I, viz. 8a, shows

only one signal for the A protons at δ = 8.55 ppm. From

the combined results it can be concluded that Cu^Ibinding

in 8 is not dynamic, in contrast to what is observed for 6.

Hence the observed broadening is only due to the presence

of Cu^IIimpurities.

1

Figure 9. H NMR spectra of metal-free receptor 8 (bottom trace)

with one, two (8a), and three equivalents of Cu^Iin the region of

4.3 to 2.8 ppm.

for 6, possibly with the formation of intra- and intermo-

lecular complexes (see below). The three Cu^Iions in the

complex with 8, which contains two TPA units comprising

6 pyridyl N donors and 2 amine N donors, in contrast to

only 4 pyridyl N donors and 2 amine N donors in 6, each

have almost three N donors available instead of two in the

case of the complex with 6.

1

Figure 8. H NMR spectra of metal-free receptor 8 (bottom trace)

with one, two (8a), and three equivalents of Cu^Iin the region of

8.8 to 5.5 ppm.

Upon the addition of a third equivalent of Cu^I, resolved

The Cu^INMR titration does not show a significant shift

signals are observed for protons A, C and CЈ, pointing to of the signals of the phenyl protons of glycoluril (᭿) like in

a decrease in the symmetry of the complex, as also observed the case of 6. In the NMR spectrum of the complex of 8

2288

www.eurjoc.org

Eur. J. Org. Chem. 2006, 2281–2295

PY2- and TPA-Appended Diphenylglycoluril Receptors and Their Bis-Cu^IComplexes

FULL PAPER

with one equivalent of Cu^Ia small peak is observed at CЈ protons are protons of linker-pyridyl groups, which do

6.4 ppm, which can be attributed to residual metal-free re- not bind in the cavity and hence show no upfield shift. The

ceptor 8, indicating that less than one equivalent of Cu^Iper position of the signal for protons DЈ could not easily be

Cu binding site was actually present. For the complex of 8 determined from the spectrum. A COSY experiment of 8a

with one equivalent of Cu^I, a large upfield shift of showed the coupling of unidentified broad signals between

–0.59 ppm is observed for the signal of the side-wall pro- 7.49 and 7.53 ppm with two signals underneath the C/CЈ

tons. Upon the addition of additional equivalents the signal signal. These unidentified peaks might be attributed to the

remains unchanged. The observed upfield shift of the side- DЈ protons; the resulting downfield shift would be in line

wall protons could be the result of the inclusion of a pyridyl with the observations for CЈ.

group, possibly copper-coordinated, in the cavity of 8. A

To investigate possible coordination of Cu^Ito the O-

shift in the signals of the side-wall protons as a result of and/or N donors of the crown ether moieties the NMR

inclusion has also been observed for receptor 6. The shift spectrum of the crown ether region was studied. No down-

observed for the complex of 8 is of the same order of mag- field shift was visible for the spacer H protons, as was ob-

nitude as the shifts that are usually observed for complex- served in the case of 6, which could be an indication that

ation of 1,3-dihydroxybenzene guests in the cavities of mo- the amine N donor of the TPA units is not coordinated to

lecular clips and baskets, i.e. around –0.5 ppm.^[42]In con- copper. However, a large downfield shift (δ = 0.42 ppm) was

trast to what is found for 6, no downfield shift in the signal observed for the signal of the N-methylene G protons

of the side-wall protons is observed upon addition of a (Table 2, Figure 9), in contrast to 6, suggesting the partici-

third equivalent of Cu^I, indicating no change in the in- pation of the aza crown ether N donor in the coordination

clusion behavior in the cavity, hence no expulsion is ob- of Cu^I. It is proposed that copper is coordinated by two of

served. For receptor 6 it was observed that the binding of the three pyridyl groups of a TPA ligand set and by the

copper is dynamic in the complex with two equivalents of aza crown ether N donor, to give a tri-coordinated copper

copper, and not dynamic in the complex with three equiva- complex. The third pyridyl group of the TPA ligand set is

lents of copper (see above). In the case of receptor 8, how- not coordinated and forms a “free dangling” pyridyl group.

ever, the binding of copper is not dynamic in the complex This is in line with the conclusions from our EXAFS

with two equivalents of copper, and is dynamic in the com- study,^[31]which show that at least one of the pyridyl groups

plex with three equivalents of copper, wherein copper ex- of 8a is detached from the Cu^Iion.

changes rapidly on the NMR timescale between the ligands.

Similar results have been reported in the literature. It has

This would still enable one of the pyridyl groups, coordi- been shown by X-ray that in a complex of TPA with Cu^I

nated to copper or not, to be included in the cavity. A and an additional PPh₃ligand, one of the pyridyl groups is

reason for this difference between the receptors 6 and 8 is detached from the copper ion.^[43]Another report describes

that the latter contains more N donor ligands, which would NMR spectroscopic data for a Cu^Icomplex of TPA, show-

facilitate the coordination of a third Cu^Iion in the complex. ing that at room temperature broad signals are observed

Furthermore, there is a difference in the chelation, i.e. five- which sharpen upon cooling to –50 °C.^[44]This was ascribed

and four-membered chelate rings for the Cu^Icomplexes of to exchange processes that occur between the pyridyl arms,

6 and 8, respectively.

with one of the pyridyl groups dangling free at every mo-

The signals of the pyridyl protons shift downfield upon ment. In solution such free dangling pyridyl groups seem

coordination of Cu^Iand this downfield shift would compete to be more general than in the solid state. To further investi-

with an upfield shift that can be expected upon the in- gate whether inclusion behavior of a pyridyl group in the

clusion of a pyridyl group in the cavity. The “net” upfield cavity of the host is structurally possible, CPK modeling

shift for the signal of the pyridyl D protons upon the ad- was carried out, revealing that a pyridyl group, either coor-

dition of one equivalent of Cu^Ican be explained by the dinated to Cu^Ior not, can be included in the cavity. Our

larger upfield shift as a result of inclusion compared to the NMR study (see above) shows that inclusion of a pyridyl

downfield shift as a result of Cu^Icoordination. Upon the group in the cavity is dynamic and is favored by Cu^Icoordi-

addition of a second and a third equivalent this initial “net” nation to the pyridyl groups. A schematic representation of

upfield shift of the pyridyl D protons is completely can- this type of behavior is illustrated in Figure 10.

celled by the downfield shift as a result of the coordination

To obtain more evidence for the proposed inclusion be-

of additional Cu^I. The signals for the pyridyl B- and C pro- havior, binding studies were carried out with receptor 8 as

tons show the same effect, however, a smaller shift is ob- a host and olivetol (1,3-dihydroxy-5-pentylbenzene) as a

served, indicating that the pyridyl D protons are bound guest in dichloromethane. NMR studies were carried out

more deeply in the cavity than the B- and C protons. No using either 8 or 8a, with zero, one and ten equivalents of

NOE contacts have been observed between the pyridyl D olivetol. The signal of the side-wall protons of 8 or 8a is a

protons and the side-wall protons, possibly indicating a fast probe for complexation of a guest and is observed at δ =

exchange on the NMR timescale between different pyridyl 6.63 and 6.05 ppm, respectively. For 8 an upfield shift to

groups in and out of the cavity.

6.53 and 6.26 ppm was observed upon addition of one and

The signal of the pyridyl CЈ protons show, in contrast to ten equivalents of olivetol, respectively, indicating olivetol

the B-, C- and D protons, only downfield shifts for each binding in receptor 8. For 8a a downfield shift to 6.07 and

addition of Cu^I. This can be explained by the fact that these 6.12 ppm was measured upon addition of one and

Eur. J. Org. Chem. 2006, 2281–2295

www.eurjoc.org

2289

M. C. Feiters et al.

FULL PAPER

clusion of a pyridyl group can be partially disrupted by the

addition of a guest, namely olivetol. However, binding of

one of the pyridyl groups is stronger than binding of oli-

vetol, perhaps due to the intramolecular (entropy) effect. In

addition, the aza crown ether N donors of receptor 8 were

shown to assist in copper coordination, whereas the spacer

N donors do not assist in copper coordination. In line with

our EXAFS results^[31]it is concluded that only two out of

the three pyridyl groups coordinate to the copper ion, while

one of the pyridyl groups is dangling free.

Experimental Section

General Prodecures: [Cu^I(CH₃CN)₄](ClO₄) was synthesized from

copper oxide according to a literature procedure by Kubas.^[45]Cau-

tion: Perchlorate salts are potentially explosive and should be han-

dled with care. Diethyl ether, THF, toluene and n-hexane were dis-

tilled under nitrogen from sodium benzophenone ketyl. Dichloro-

methane, chloroform, methanol and acetonitrile were distilled from

CaH₂. Triethylamine was dried with KOH. Diisopropylamine was

distilled from over ninhydrin and subsequently over KOH. 2-Vinyl-

pyridine was vacuum distilled. Ethyl acetate, hexane, chloroform

and dichloromethane used for column chromatography were rotary

evaporated prior to use. NaCO₃and NaI were oven-dried at

150 °C. All other solvents and chemicals were commercial materials

and were used as received. Merck Silica Gel (60H) and Aldrich

Figure 10. Schematic representation of inclusion of a pyridyl group

in the cavity of 8a.

ten equivalents of olivetol, respectively, indicating a change

in the inclusion behavior of the cavity of receptor 8a, poss-

ibly as a result of the binding of olivetol and the expulsion

of the pyridyl ligand.

Surprisingly, no NOE contacts between the protons of

the side walls and the protons of the pyridyl groups were Neutral Alumina 90 were used for column chromatography. Alu-

mina was activated to activity III according to the Brockmann

scale.^[46]To this end the alumina was dried overnight in a vacuum

oven at 150 °C. Subsequently 6% of water (w/w) was added, and

the mixture was equilibrated by rotation in a round-bottom flask

on a rotary evaporator, at atmospheric pressure. Merck Silica Gel

F254 plates and aluminum oxide 60 F254 neutral plates on plastic

or tin foil were used for thin layer chromatography.

detected with either 2D NOESY or ROESY experiments

(see Exp. Section for details).

Conclusions

Two new receptors, PY2-appended receptor 6 and TPA-

appended receptor 8, have been synthesized, as well as their

Cu^Icomplexes 6a and 8a. Furthermore, the design and

preparation of two other receptors, 7 and 9, have been de-

scribed; they were synthesized but could not be purified.

NMR studies have provided information about struc-

tural and dynamic aspects of the coordination of Cu^Ito

both 6 and 8. The coordination of pyridyl groups to Cu^I

in the complex of receptor 6 with one equivalent of Cu^Iis

dynamic and fast on the NMR timescale; exchange of pyri-

dyl groups to the Cu^Itakes place at room temperature. The

complex of receptor 8 with two equivalents of Cu^Idoes not

display this type of dynamic behavior, as distinct sets of

signals were observed for the protons of coordinated and

non-coordinated pyridyl groups.

Furthermore, large changes in the signals of the side-wall

protons of receptor 8 occurred, while only very small

changes were observed for receptor 6. These large changes

in the NMR spectrum of receptor 8 are ascribed to the

inclusion of one of the pyridyl groups of the ligand in the

receptor cavity. This inclusion is induced by coordination

of Cu^I, which decreases the electron density of the pyridyl

Melting points were determined with a Jeneval polarization micro-

scope THMS 600 hot stage and are uncorrected. Infrared spectra

were recorded with a BioRad FTS-25 spectrometer. NMR spectra

were recorded with Bruker WM-200, Bruker AM-300, Varian

Unity Inova 400 HR NMR or Bruker DRX-500 instruments.

Chemical shifts are reported in ppm downfield from internal stan-

dard (tetramethylsilane) at δ = 0.00 ppm in the case of ¹H NMR

spectra in CDCl₃, otherwise the solvent peak was used as a refer-

ence (CD₃OH: 3.31 ppm). In the case of ¹³C spectra, the solvent

peak was used as a reference (CDCl₃: 77.0 ppm). Abbreviations

used are: s = singlet, d = doublet, m = multiplet, br. = broad.

ESI-MS spectra were recorded with a Thermo Finnigan MAT900S

double-focusing mass spectrometer coupled to an ICIS data system

using ElectroSpray Ionization. EI and FAB mass spectra were re-

corded with a VG-7070E instrument. The matrix used for FAB was

3-nitrobenzyl alcohol. Elemental analysis were determined with a

Carbo Erba Ea 1108 instrument.

Syntheses: Compounds 10,^[32]11,^[33]14,^[33]20,^[30]and 23^[47]were

prepared according to literature procedures.

8,25-Bis(4-bis[2-(2-pyridyl)ethyl]aminobutyl)-36,37-diphenyl-

2,5,11,14,19,22,28,31-octaoxa-8,25,35,38,43,45-hexaazaoctacyclo-

[30.15.2.1^35,38.0^15,41.0^18,40.0^33,47.0^36,45.0^37,43]pentaconta-

group, thereby increasing its affinity for the cavity. This in- 1(47),15,17,32,40,48-hexaene-44,50-dione (6)

2290 Eur. J. Org. Chem. 2006, 2281–2295

www.eurjoc.org

PY2- and TPA-Appended Diphenylglycoluril Receptors and Their Bis-Cu^IComplexes

FULL PAPER

until the solids were dissolved. This in situ prepared solution was

used directly for spectroscopy, while for other purposes the product

was obtained as a solid by precipitation. The solution was concen-

trated under reduced pressure to ca. 1 mL, then diethyl ether (dis-

tilled and collected under nitrogen) was slowly layered on top of

the dichloromethane under argon. This solvent system was allowed

to equilibrate overnight in the freezer. The yellow precipitate was

collected by decantation. ¹H NMR (CDCl₃, 500 MHz): δ = 8.57

(m, 4 H, PyC⁶H), 7.77 (m, 4 H, PyC⁴H), 7.26 (m, 8 H, PyC³H,

PyC⁵H), 7.04 (m, 10 H, ArH glycoluril), 6.56 (s, 4 H, ArH side

wall), 5.52 (J = 15.6 Hz, 4 H, NCHHAr out), 3.98 (m, 4 H, Ar-

OCHH out), 3.8–3.74 (m, 4 H, ArOCHH in, 16 H, CH₂O), 3.64

(d, J = 16.5 Hz, 4 H, NCHHAr in), 2.97 (s, 8 H, PY2CH₂CH₂N),

2.89 (s, 8 H, PY2CH₂CH₂N), 2.72 (s, 8 H, NCH₂CH₂O), 2.59 (4

H, PY2NCH₂CH₂CH₂), 2.50 (4 H, ONCH₂CH₂CH₂), 1.49 [8 H,

NCH₂(CH₂)₂CH₂N]. C₈₄H₁₀₂Cl₂Cu₂N₁₂O₁₈·0.5CH₂Cl₂: calcd. C

56.13, H 5.74, N 9.29; found C 56.14, H 5.70, N 9.28.

A solution of compound 13 (275 mg, 0.27 mmol) was prepared in

a few mL of a 1:1 (v/v) mixture of MeOH and CH₂Cl₂. To this

were added 2-vinylpyridine (231 mg, 2.2 mmol, 8 equiv.) and acetic

acid (71 mg, 1.1 mmol, 4 equiv.). The yellow solution was transfer-

red to a 7.5-mL Teflon high-pressure vessel and a few grains of the

radical trap (5-(tert-butyl)-2-[4-(tert-butyl)-2-hydroxy-5-meth-

ylphenyl]sulfanyl-4-methylphenol) were added. After filling with

the solvent mixture and closing the cap tightly, the vessel was

placed in a special high-pressure apparatus and kept at 15 kbar and

50 °C for 16 h.^[29]After removal of the pressure the Teflon vessel

appeared dented because the volume was decreased during the re-

action. The bright red solution was concentrated in vacuo at room

temperature to yield a red brown oil. This oil was redissolved in

dichloromethane and extracted with aqueous base (NaOH). The

organic layer was dried with MgSO₄and the solvents evaporated.

The compound was obtained as a yellow solid in 94% yield after

column chromatography over alumina (activity III) (eluent: 2%

8,25-Bis(2-bis[2-(2-pyridyl)ethyl]aminoethyl)-36,37-diphenyl-

2,5,11,14,19,22,28,31-octaoxa-8,25,35,38,43,45-hexaazaoctacyclo-

[30.15.2.1^35,38.0^15,41.0^18,40.0^33,47.0^36,45.0^37,43]pentaconta-

1(47),15,17,32,40,48-hexaene-44,50-dione (7)

MeOH in CH Cl ). M.p. 156 °C. IR (KBr pellet): ν = 1710 and

˜

2

1590 (C=O), 1123 (C–O–C) cm^–1. H NMR (CDCl₃, 500 MHz): δ

= 8.50 (d, ^orthoJ = 4.0 Hz, 4 H, PyC⁶H), 7.52–7.49 (m, 4 H, PyC⁴H),

7.11 (m, 10 H, ArH glycoluril), 7.09–7.05 (m, 8 H, PyC³H, PyC⁵H),

6.62 (s, 4 H, ArH side wall), 5.65 (d, J = 16.0 Hz, 4 H, NCHHAr

out), 4.14–4.10 (m, 4 H, ArOCHH out), 3.98–2.83 (m, 4 H, Ar-

OCHH in, 16 H, CH₂O, 4 H, NCHHAr in), 2.94 (m, 8 H,

PyCH₂CH₂N), 2.88–2.81 (m, 8 H, NCH₂CH₂O), 2.60–2.56 [m, 8

H, NCH₂(CH₂)₂CH₂N], 1.30–1.27 [m, 8 H, NCH₂(CH₂)₂CH₂N].

¹³C NMR +HETCOR (CDCl₃, 75.5 MHz): δ = 160.7 [N(C=O)N

glycoluril], 157.4 (PyC²), 150.9 (ipso-C of Ar side walls), 149.1

(PyC⁶), 136.0 (PyC⁴), 134.2/128.8/128.4 (Ar glycoluril), 123.3

(PyC⁵), 121.0 (PyC³), 114 (Ar side walls), 85.0 (N₂CPh–CPh,

glycoluril), 69.7/69.3/69.0 (CH₂O), 55.8/53.7/53.5 (CH₂N), 36.9

(NCH₂Ar glycoluril), 36.1 (PyCH₂), 25.2 [NCH₂(CH₂)₂CH₂N].

MS-FAB: m/z = 1438.78 [M+H]⁺. C₈₄H₁₀₂N₁₂O₁₀: calcd. C 78.84,

H 8.03, N 13.13; found C 78.97, H 8.04, N 12.99.

1

A solution of 16 (135 mg, 0.14 mmol) in a few mL of MeOH/

CH₂Cl₂(1:1) was prepared. To this were added 2-vinylpyridine

(115 mg, 1.1 mmol, 8 equiv.) and acetic acid (35 mg, 0.55 mmol,

4 equiv.). The yellow solution was transferred to a 7.5-mL Teflon

high-pressure vessel and a few grains of radical trap (5 (tert-butyl)-

2-[4-(tert-butyl)-2-hydroxy-5-methylphenyl]sulfanyl-4-methylphe-

nol) were added. The vessel was completely filled with the solvent

mixture, and the cap was tightly screwed. This vessel was placed in

a special high-pressure apparatus and kept at 15 kbar and 50 °C

for 16 h. The orange solution was evaporated at room temperature

to yield a yellow-brown oil. The compound decomposed during

column chromatography on activated alumina (activity ) (eluent:

2% MeOH in CH₂Cl₂).

Cu^I₂Complex of Receptor 6 (6a)

8,25-Bis{4-[(tert-butoxycarbonyl)amino]butyl}-36,37-diphenyl-

2,5,11,14,19,22,28,31-octaoxa-8,25,35,38,43,45-hexaazaoctacyclo-

[30.15.2.1^35,38.0^15,41.0^18,40.0^33,47.0^36,45.0^37,43]pentaconta-

1(47),15,17,32,40,48-hexaene-44,50-dione (12)

This complex was either prepared in situ or by precipitation; the

product obtained was the same for both methods. A magnetic stir-

ring bar, compound 6 (10.8 mg, 7.5 mmol) and [Cu^I(CH₃CN)₄]-

(ClO₄) (4.9 mg, 2 equiv.) were transferred to an Schlenk flask. Five

cycles of evacuation and filling with pre-dried nitrogen were ap-

plied. In a separate flask 15 mL of distilled dichloromethane (or

acetone) was collected under nitrogen and transferred to the solids

under nitrogen. The resulting yellow solution was stirred for 10 min

A solution of 10 (380 mg, 0.38 mmol) in 100 mL of freshly distilled

and degassed acetonitrile was prepared; then NaI (4.1 g,

28.2 mmol) and Na₂CO₃(1.6 g, 15.1 mmol) was added to this solu-

tion. Compound 11 (1 equiv., 71.5 mg) was added to this white

suspension, and the reaction mixture was refluxed for 16 h. A solu-

tion of 11 (2 equiv., 143 mg) in 6 mL acetonitrile was slowly added

Eur. J. Org. Chem. 2006, 2281–2295

www.eurjoc.org

2291

M. C. Feiters et al.

FULL PAPER

to the solution over the next 36 h. The resulting suspension was

refluxed for 96 h. The acetonitrile was removed under reduced pres-

sure, and the residue was redissolved in 500 mL of chloroform. The

organic solution was washed twice with water (500 mL), once with

NaHCO₃(satd. 500 mL), and once again with water (500 mL). The

organic layer was evaporated under reduced pressure and the prod-

uct redissolved in 2 mL of distilled chloroform. The resulting solu-

tion was added dropwise to 50 mL of distilled n-hexane while stir-

ring. The white precipitate was collected by filtration and purified

by column chromatography on silica with MeOH/Et₃N/CHCl₃

(10:1:89, v/v) as the eluent. The product (R_f0.2) was obtained as

To a solution of the tetrapodand 10 (2 g, 2.02 mmol) in 500 mL

of freshly distilled and degassed acetonitrile was added NaI (20 g,

134 mmol) and Na₂CO₃(6.5 g, 61 mmol). Compound 14 (1 equiv.,

323 mg) was added to this white suspension, and the reaction mix-

ture was refluxed for 16 h. A solution of 14 (2 equiv., 646 mg) in

6 mL acetonitrile was slowly added to the solution over the next

36 h. The resulting suspension was refluxed for another four days.

The acetonitrile was removed under reduced pressure, and the resi-

due was redissolved in 500 mL of chloroform. This was extracted

twice with water (500 mL), washed with saturated aqueous

NaHCO₃(500 mL) and water (500 mL). The organic layer was

evaporated under reduced pressure, and the product was redis-

solved in 2 mL of distilled chloroform. This solution was added

dropwise to 50 mL of distilled hexane while stirring. The white pre-

cipitate that was formed was filtered off and dried. The product

was obtained as a white solid in 52 % yield after column

chromatography on silica (eluent: 10% MeOH and 1% Et₃N in

a white solid in a yield of 60%. M.p. 184 °C. IR (KBr pellet): ν =

˜

3373 (br., NH), 2927 (br., CH), 1713 (C=O), 1170–1135 (C–O),

1068 (C–N) cm^–1. ¹H NMR (CDCl₃, 300 MHz): δ = 7.09 (m, 10

H, ArH glycoluril), 6.71 (s, 4 H, ArH side walls), 5.65 (d, J =

16.1 Hz, 4 H, NCHHAr out), 4.90 (br., 2 H, NHC=O Boc group),

4.20–4.13 (m, 8 H, ArOCH₂), 3.99–3.78 (m, 16 H, CH₂O), 3.71 (d,

J = 16.1 Hz, 4 H, NCHHAr in), 3.14 (m, 4 H, Boc-HNCH₂), 2.88

(m, 8 H, O–CH₂CH₂N), 2.62 [m, 4 H, Boc-HN(CH₂)₃CH₂N], 1.68

[m, 8 H, NCH₂(CH₂)₂CH₂N], 1.45 [s, 18 H, C(CH₃)₃]. ¹³C NMR

(CDCl₃, 75.5 MHz): δ = 157.3 [NH(C=O)], 156.0 [N(C=O)N

glycoluril], 150.0 (Ar glycoluril), 134.2/128.9/128.4/113.9 (Ar side

walls, Ar glycoluril), 85.0 (N₂CPh–CPh), 78.9 (NCH₂Ar), 70.2

(CH₂NHC=O), 69.6/69.4 (CH₂O), 55.4/53.7/40.4 (CH₂N), 37.0

[C(CH₃)₃], 28.5 [NCH₂(CH₂)₂CH₂N], 27.9 (CH₃). MS: m/z = 1219

[M+H]⁺. C₆₄H₉₀N₈O₁₄: calcd. C 79.62, H 9.11, N 11.26; found C

79.98, H 8.98, N 11.03.

CHCl ). M.p. 207 °C. IR (KBr pellet): ν = 3365 (br., NH), 2929/

˜

3

2871 (br., CH), 1712 (C=O). ¹H NMR (CDCl₃, 200 MHz): δ =

7.08 (m, 10 H, ArH glycoluril), 6.70 (s, 4 H, ArH side wall), 5.76

(br., 2 H, NHC=O Boc group), 5.64 (d, J = 16.0 Hz, 4 H,

NCHHAr out), 4.16–4.07 (m, 8 H, ArOCH₂), 4.00–3.66 (m, 16 H,

CH₂O, 4 H, NCHHAr in), 3.21–3.19 (m, 4 H, Boc-HNCH₂), 2.89–

2.83 (m, 8 H, O–CH₂CH₂N), 2.72–2.67 (m, 4 H, Boc-

HNCH₂CH₂N), 1.39 [s, 18 H, C(CH₃)₃]. ¹³C NMR (CDCl₃,

50.3 MHz): δ = 157.5 [NH(C=O)], 156.6 [N(C=O)N glycoluril],

150.7 (Ar glycoluril), 134.0/128.5/113.8 (Ar side walls, Ar

glycoluril), 85.0 (CPh–CPh), 78.6 (NCH₂Ar), 70.0 (CH₂NHC=O),

69.6/69.3 (CH₂O), 54.3/53.9 (CH₂N), 36.9 [C(CH₃)₃], 28.4 (CH₃).

MS: m/z = 1186 [M+Na]⁺. C₆₂H₈₂N₈O₁₄: calcd. C 79.28, H 8.79,

N 11.93; found C 79.34, H 8.71, N 11.95.

8,25-Bis(4-aminobutyl)-36,37-diphenyl-2,5,11,14,19,22,28,31-

o c t a o x a - 8 , 2 5 , 3 5 , 3 8 , 4 3 , 4 5 - h e x a a z a o c t a c y c l o -

[30.15.2.1^35,38.0^15,41.0^18,40.0^33,47.0^36,45.0^37,43]pentaconta-

1(47),15,17,32,40,48-hexaene-44,50-dione (13)

8,25-Bis(2-aminoethyl)-36,37-diphenyl-2,5,11,14,19,22,28,31-

o c t a o x a - 8 , 2 5 , 3 5 , 3 8 , 4 3 , 4 5 - h e x a a z a o c t a c y c l o -

[30.15.2.1^35,38.0^15,41.0^18,40.0^33,47.0^36,45.0^37,43]pentaconta-

1(47),15,17,32,40,48-hexaene-44,50-dione (16)

A solution of 12 (860 mg, 0.71 mmol) in 5 mL of dichloromethane

was slowly added to TFA/CH₂Cl₂(10 mL/5 mL) at 0 °C. The solu-

tion was stirred for 1 h at 0 °C after which 250 mL of dichlorometh-

ane was added. The organic solution was washed twice with NaOH

(250 mL) and concentrated in vacuo. The residue was redissolved

in 2 mL of distilled chloroform and added dropwise to distilled n-

hexane while stirring. The white precipitate was collected by fil-

tration and obtained in a yield of 90%. M.p. dec. Ͼ210 °C. IR

(KBr pellet): ν = 3434 (NH), 2931 (CH), 1700/1692 (C=O) cm^–1.

˜

¹H NMR (MeOH/CDCl₃, 400 MHz): δ = 7.15 (s, 10 H, ArH

glycoluril), 6.84 (s, 4 H, ArH side walls), 5.48 (d, J = 15.7 Hz, 4 H,

NCHHAr out), 4.32–4.30 (m, 8 H, ArOCH₂), 4.03–3.74 (m, 16

H, CH₂O, 4 H, NCHHAr in), 2.83–2.82 (m, 4 H, NH₂CH₂, 8 H,

OCH₂CH₂N), 2.62 [m, 4 H, NH₂(CH₂)₃CH₂N], 1.68 [m, 8 H,

NCH₂(CH₂)₂CH₂N]. ¹³C NMR (MeOH/CDCl₃, 75.5 MHz): δ =

157.3 [N(C=O) glycoluril], 150.5 (Ar glycoluril), 133.2/128.7/128.0/

114.7 (Ar side walls, Ar glycoluril), 85.5 (N₂CPh–CPh), 78.9

(NCH₂Ar), 70.0/69.8/68.6 (CH₂N), 54.9/54.1 (CH₂O), 40.0/37.0

[NCH₂(CH₂)₂CH₂N]. MS: m/z = 1019 [M+H]⁺.

A solution of 15 (120 mg, 0.10 mmol) was dissolved in 5 mL of

dichloromethane. A mixture of TFA/CH₂Cl₂(10 mL/5 mL) was co-

oled in ice to 0 °C. The solution of 15 was slowly added to the

solvent mixture, and the resulting solution was stirred for 1 h at

0 °C. After the reaction 250 mL of dichloromethane was added,

and the solution was extracted twice with NaOH (250 mL). The

organic layer was evaporated under reduced pressure; the residue

was redissolved in 2 mL of distilled chloroform and added dropwise

to stirring distilled hexane. The white precipitated was filtered off

8,25-Bis{2-[(tert-butoxycarbonyl)amino]ethyl}-36,37-diphenyl-

2,5,11,14,19,22,28,31-octaoxa-8,25,35,38,43,45-hexaazaoctacyclo- and the product was obtained in a yield of 80 %. M.p. dec.

[30.15.2.1^35,38.0^15,41.0^18,40.0^33,47.0^36,45.0^37,43]pentaconta-

1(47),15,17,32,40,48-hexaene-44,50-dione (15)

Ͼ220 °C. IR (KBr pellet): ν = 3426 (NH), 2923 (CH), 1697 (C=O).

˜

¹H NMR (MeOH/CDCl₃, 200 MHz): δ = 7.16 (m, 10 H, ArH

2292

www.eurjoc.org

Eur. J. Org. Chem. 2006, 2281–2295

PY2- and TPA-Appended Diphenylglycoluril Receptors and Their Bis-Cu^IComplexes

FULL PAPER

glycoluril), 6.77 (s, 4 H, ArH side wall), 5.46 (br., 1 H, NH₂), 5.48

(d, J = 15.9 Hz, 4 H, NCH₂Ar out), 4.23–4.20 (m, 8 H, ArOCH₂),

3.97–3.73 (m, 16 H, CH₂O, 4 H, NCH₂Ar in), 2.96–2.76 (m, 16 H,

NH₂CH₂). MS: m/z = 985 [M+Na]⁺.

glycoluril], 150.8 (Ar glycoluril), 149.0 (PyC⁶), 136.8–136.4

(PyC^3/3Ј), 128.5–127.1 (Ar glycoluril), 122.9 (PyC⁴), 122.0

(PyC^5/5Ј), 121.2 (PyC^4Ј), 120.8/113.9 (Ar side walls), 70.1–69.4

(CH₂O), 61.5–60.2 (CH₂Py), 54.1 (CH₂CH₂N), 37.0 (NCH₂Ar

glycoluril). MS-FAB: m/z = 1480.0 [M+2 H]⁺. No satisfactory ele-

mental analysis could be obtained. However, a satisfactory high-

resolution mass spectrum was obtained. HR-MS [MH⁺]: calcd. For

C₈₆H₉₃N₁₄O₁₀: 1481.71991; found 1481.72082 (–0.61 ppm).

36,37-Diphenyl-2,5,11,14,19,22,28,31-octaoxa-8,25,35,38,43,45-

hexaazaoctacyclo[30.15.2.1^35,38.0^15,41.0^18,40.0^33,47.0^36,45.0^37,43]penta-

conta-1(47),15,17,32,40,48-hexaene-44,50-dione (18)

Cu^I₂Complex of Receptor 8 (8a) (Figure 10): This complex was

either prepared in situ or by precipitation; the product obtained

was the same for both methods. Compound 8 (11.1 mg, 7.5 mmol)

and [Cu^I(CH₃CN)₄](ClO₄) (4.9 mg, 2 equiv.) were transferred to a

Schlenk flask equipped with a magnetic stirring bar. Five cycles of

evacuating and filling with pre-dried nitrogen were applied. In a

separate flask 15 mL of distilled dichloromethane (or acetone) was

collected under nitrogen and transferred to the solids under nitro-

gen. The resulting yellow solution was stirred for 10 min until the

solids were dissolved. This in situ prepared solution was used di-

rectly for spectroscopy, while for other purposes the product was

obtained as a solid by precipitation. The solution was concentrated

under reduced pressure to ca. 1 mL, and under argon diethyl ether

(distilled and collected under nitrogen) was slowly layered on top

of the dichloromethane. This solvent system was allowed to equili-

brate overnight in the freezer. The yellow precipitate was collected

This compound was prepared according to a modified literature

procedure.^[36]Compound 17 (1.5 g, 1.4 mmol) was dissolved in

25 mL of acetic acid. To this solution was added a large excess

of palladium hydroxide on carbon (ca. 1 g). The resulting black

suspension was transferred to an autoclave and stirred for 72 h at

55 °C under 20 bar of hydrogen. The reaction mixture was filtered

through celite, and the resulting yellow solution was concentrated.

The solvent was evaporated twice with toluene (100 mL) to remove

acetic acid. The residue was dissolved in 2 mL of distilled chloro-

form and added dropwise to distilled n-hexane while stirring. The

white precipitate was obtained in a yield of 70%. Characterization

was consistent with the literature.^[36]

1

by decantation. H NMR (CD₂Cl₂, 500 MHz): δ = 8.62 (m, 4 H,

PyC⁶H), 7.70 (m, 4 H, PyC^4ЈH), 7.61 (m, 42 H, PyC⁴H), 7.24 (m,

8 H, PyC³H, PyC^3ЈH), 7.13 (m, 10 H, ArH glycoluril), 6.99 (m, 4

H, PyC⁵H), 6.12 (s, 4 H, ArH side wall), 5.67 (J = 16 Hz, 4 H,

NCHHAr out), 4.21 (m, 4 H, ArOCHH out), 4.10–3.70 (m, 4 H,

ArOCHH in, 16 H, CH₂O, 12 H, PyCH₂), 3.75 (d, J = 16 Hz, 4

H, NCHHAr in), 3.41–3.30 (br., 8 H, CH₂N).

8,25-Bis[(6-{[bis(2-pyridylmethyl)amino]methyl}-2-pyridyl)methyl]-

36,37-diphenyl-2,5,11,14,19,22,28,31-octaoxa-8,25,35,38,43,45-

hexaazaoctacyclo[30.15.2.1^35,38.0^15,41.0^18,40.0^33,47.0^36,45.0^37,43]penta-

conta-1(47),15,17,32,40,48-hexaene-44,50-dione (8)

2,6-Bis(chloromethyl)pyridine·HCl (20): A flask containing [6-(hy-

droxymethyl)-2-pyridyl]methanol (0.99 g, 7.1 mmol) was cooled in

ice to 0 °C. Thionyl chloride (15 mL) was added with an addition

funnel over a period of 1 h. After warming to room temperature

the reaction mixture was heated to reflux for 4 h; then cooled to

room temperature, and 10 mL of toluene were slowly added in or-

der to precipitate the product. After vacuum filtration the product

was washed at least four times with toluene to remove excess of

thionyl chloride. Finally, the product was obtained as a white solid.

The product was not characterized but used directly in the next

reaction to obtain 21.

To a solution of 18 (50 mg, 0.07 mmol) in 10 mL of acetonitrile

was added 6-TPA-Cl (23, 45 mg, 2.2 equiv.), Na₂CO₃(285 mg,

40 equiv.), and NaI (400 mg, 40 equiv.). The resulting suspension

was refluxed for 120 h. After cooling to room temperature the reac-

tion mixture was concentrated in vacuo and redissolved in dichlo-

romethane (200 mL). The organic layer was washed twice with

water and once with saturated aqueous NaHCO₃. The organic

layer was dried with Na₂SO₄instead of MgSO₄, because magne-

sium ions will irreversibly coordinate to TPA. After concentration

the residue was redissolved in 2 mL of chloroform and added drop-

wise to distilled n-hexane while stirring. The product precipitated

as a light yellow solid and was obtained in pure form after column

chromatography on activated alumina (activity III) (eluent: 2%

MeOH in CH₂Cl₂) with a yield of 60%. M.p. 86 °C. IR (KBr pel-

2,6-Bis(chloromethyl)pyridine (21): The hydrochloric acid salt 20

was dissolved in 200 mL of water and solid NaHCO₃was added

slowly until a pH of 7 was reached. The product precipitated out

and was filtered and washed repeatedly with water. The product

was recrystallized from petroleum ether (40–64 °C) and the pure

product was obtained as colourless needles in a yield of 53% for

the last two steps. M.p. 71 °C. IR (KBr pellet): ν = 3020, 2980,

˜

1600, 1570, 1470 (Pyr) cm^–1. ¹H NMR (CDCl₃, 200 MHz): δ =

7.81–7.73 (t, ^orthoJ = 7.9 Hz, 1 H, Py-CH⁴), 7.46–7.26 (d, ^orthoJ =

7.5 Hz, 2 H, Py-CH^3,5), 4.67 (s, 4 H, Py-CH₂Cl). ¹³C NMR

(CDCl₃, 50.3 MHz): δ = 156 (PyC^2,6H), 138 (PyC⁴H), 122

(PyC^3,5H), 46 (PyCH₂Cl). MS: m/z = 175 [M + H]⁺. C₇H₇Cl₂N:

calcd. C 47.76, H 4.01, N 7.96; found C 47.73, H 3.73, N 7.81.

let): ν = 1709 and 1572 (C=O) cm^–1. ¹H NMR (CDCl , 500 MHz):

˜

3

δ = 8.53 (d, ^orthoJ = 4.7 Hz, 4 H, PyC⁶H), 7.66–7.58 (m, 10 H,

{[6-(Chloromethyl)-2-pyridyl]methyl}bis(2-pyridylmethyl)-

PyC^4/4Ј/3H), 7.50–7.42 (m, 2 H, PyC^3ЈH), 7.13–7.10 (m, 10 H, amine (19): A solution of bis(2-pyridylmethyl)amine (picolyl-

PyC^5/5ЈH, ArH glycoluril), 6.65 (s, 4 H, ArH side walls), 5.67 (d, J

= 16.0 Hz, 4 H, NCHHAr out), 3.96–3.93 (m, 4 H, ArOCHH out),

amine) (0.41 g, 2.1 mmol), compound 21 (0.36 g, 1 equiv.) and di-

isopropylethylamine (DIPEA, 1 g, 3.7 equiv.) in 10 mL of distilled

3.90–3.75 (m, 4 H, ArOCHH in, 16 H, CH₂O, 12 H, PyCH₂N), THF was transferred to a pressure vessel. After stirring under ex-

3.72 (d, ^orthoJ = 16.4 Hz, 4 H, NCHHAr in), 2.95 (m, 8 H,

NCH₂CH₂). ¹³C NMR (CDCl₃, 75.5 MHz): δ = 159.5 [N(C=O)N

clusion of air for one week a precipitate of DIPEA–HCl was

formed. After decanting and evaporation the crude product was

Eur. J. Org. Chem. 2006, 2281–2295

www.eurjoc.org

2293

M. C. Feiters et al.

FULL PAPER

obtained as a brown oil. Column chromatography (neutral alumina

90, activation III) with a gradient eluent of EtOAc/hexane (55:45

to 45:55, v/v) provided the product as white solid in a yield of 40%.

solution of 24. The resulting mixture was stirred overnight at room

temperature after which it was cooled again to 0 °C. Subsequently,

1 mL of water, 1 mL of 10% NaOH, and 1 mL of water were added

M.p. 98 °C. IR (KBr pellet): ν = 3500/3400 (N–H), 1591/1436 dropwise. The resulting mixture was stirred at room temperature

˜

(Pyr). ¹H NMR (CDCl₃, 200 MHz): δ = 8.54 (d, ^orthoJ = 4.9 Hz,

for 1 hour after which it was extracted with diethyl ether. The mix-

^metaJ = 1.0 Hz, 2 H, PyC⁶H), 7.69 (d, J = 7.8 Hz, 1 H, PyC^4ЈH), ture was filtered through a plug of celite and washed with 25 mL

7.66 (dd, ^orthoJ = 7.5 Hz, ^metaJ = 1.2 Hz, 2 H, PyC⁴H), 7.58 (d, J = of diethyl ether. The resulting ether layer was dried with NaSO₄

7.6 Hz, 2 H, PyC³H), 7.54 (d, J = 7.6 Hz, 1 H, PyC^3ЈH), 7.33 (d,

J = 7.6 Hz, 1 H, PyC^5ЈH), 7.15 (dd, J = 6.0 Hz, 2 H, PyC⁵H), 4.65

(s, 2 H, PyCH₂-Cl), 3.90 (s, 6 H, PyCH₂-N). C₁₉H₁₉ClN₄: calcd. C

67.35, H 5.65, N 16.54; found C 67.40, H 5.50, N 16.12.

and evaporated in vacuo to yield a yellow oil. Due to the instability

of the product it was used directly without further purification in

the following step. ¹H NMR (CDCl₃, 300 MHz): δ = 8.53 (d, ^orthoJ

= 6.6 Hz, 1 H, PyC⁶H), 7.69–7.56 (m, 4 H, Py-H), 7.17–7.14 (m, 2

H, Py-H), 4.70 (s, 2 H, CH₂OH), 3.88 (s, 2 H, NCH₂PyCH₂OH),

3.74 (s, 4 H, NCH₂Py).

8,25-Bis[(5-{[bis(2-pyridylmethyl)amino]methyl}-2-pyridyl)methyl]-

36,37-diphenyl-2,5,11,14,19,22,28,31-octaoxa-8,25,35,38,43,45-

hexaazaoctacyclo[30.15.2.1^35,38.0^15,41.0^18,40.0^33,47.0^36,45.0^37,43]penta-

conta-1(47),15,17,32,40,48-hexaene-44,50-dione (9)

[5-(Chloromethyl)-2-pyridyl]-N,N-bis(2-pyridylmethyl)methanamine

(22): A solution of 25 (ca. 0.43 mmol), prepared as described above

in 5 mL of chloroform was added dropwise at 0 °C to a solution

of SOCl₂(256 mg, 5 equiv.) in 10 mL of chloroform. The resulting

mixture was stirred overnight at room temperature and evaporated

in vacuo to give a greenish foam. The product was dissolved in

5 mL of THF and DIPEA (600 mg) was added under argon at

0 °C. The resulting mixture was stirred for 3 h at room temperature,

filtered through a plug of celite and washed with 25 mL of THF.

The resulting solution was evaporated in vacuo to yield 22 as a

brown oil that slowly crystallizes upon standing. The product was

used directly in the following reaction (to prepare 9) without fur-

ther purification because of the satisfactory NMR spectrum. ¹H

NMR (CDCl₃, 200 MHz): δ = 8.53 (d, ^orthoJ = 6.6 Hz, 1 H,

PyC⁶H), 7.69–7.57 (m, 4 H, Py-H), 7.16–7.13 (m, 2 H, Py-H), 4.57

(s, 2 H, CH₂Cl), 3.88–3.85 (s, 4 H, NCH₂Py).

To a solution of 22 (approx. 145 mg, 0.43 mmol), NaCO₃(750 mg,

20 equiv.) and NaI (1 g, 20 equiv.) in 20 mL of acetonitrile was

added compound 18 (125 mg, 1/3 equiv.). The resulting suspension

was heated to reflux for 120 h. After cooling of the reaction mixture

the solvent was evaporated and the residue was dissolved in dichlo-

romethane (200 mL). The organic layer was washed twice with

water and once with saturated aqueous NaHCO₃, dried with

Na₂SO₄(magnesium will irreversibly coordinate to TPA) and evap-

orated in vacuo. The residue was dissolved in 2 mL of chloroform

and added dropwise to about 25 mL of distilled hexane while stir-

ring. The product precipitated as a beige solid. It decomposed dur-

ing an attempt to purify it by column chromatography on activated

alumina (activity III, eluent: 2% MeOH in CH₂Cl₂).

NMR Titration Experiments: NMR titrations were carried out with

a Bruker DRX 500 instrument at 298 K. The Cu^I-containing solu-

tions were prepared in a glove box under nitrogen, because of the

air sensitivity of these complexes. For the titration of Cu^Ito recep-

tor 6 two solutions were prepared: A) Compound 6 (2.95 mg) in

2 mL of CD₂Cl₂(1.03 m), and B) 6 (2.95 mg) and [Cu^I(CH₃-

CN)₄](ClO₄) (2.05 mg) in 2 mL of CD₂Cl₂(1.03 and 3.13 m resp.).

Four NMR tubes were prepared with 0.6/0.4/0.2/0.0 mL of A and

0.0/0.2/0.4/0.6 mL of B, affording samples with 0/1.01/2.03/

3.04 equiv. of Cu^I, respectively.

For the titration of Cu^Ito receptor 8, two solutions were prepared

in oxygen-free and dry CH₂Cl₂, A) Compound 8 (1.0 m); B) [Cu^I-

(CH₃CN)₄](ClO₄) (2 m). These two solutions were mixed under

argon in the desired ratios by use of syringes, and the resulting

solutions of Cu^Icomplexes of 8 were stirred for 5 min and concen-

trated in vacuo outside the glove box. The dry residues were trans-

ported back into the glove box and redissolved in CD₂Cl₂after

which the NMR tubes where filled. The NMR tube for the NOESY

and ROESY experiment was sealed under vacuum by melting to

prevent oxidation by air during the experiments. The NOESY mix-

ing times used in the experiments were 50 ms and 200 ms, the

ROESY mixing time used was 300 ms. The relaxation delay in all

experiments was 1.5 s.

Methyl 6-{[Bis(2-pyridylmethyl)amino]methyl}nicotinate (24): A

solution of N,N-bis(2-pyridymethyl)amine (156 mg, 0.8 mmol), 23

(185 mg, 1 equiv.) and diisopropylethylamine (DIPEA, 130 mg,

3.7 equiv.) in 10 mL of dry THF was transferred to a pressure ves-

sel. After stirring under exclusion of air for one week a precipitate

of DIPEA–HCl was formed. After decanting and evaporation the

crude product was obtained as a brown oil. After two crystalli-

zations from petroleum ether 40:65 (v/v) the product was isolated

as a white solid in a yield of 18% (this low yield is probably due

to the second crystallization, which was necessary to remove impu-

1

rities). H NMR (CDCl₃, 200 MHz): δ = 9.16 (d, ^paraJ = 0.5 Hz, 1

H, PyC^6ЈH), 8.64 (br. d, ^orthoJ = 4.8 Hz, 2 H, PyC⁶H), 8.19–8.14

(dd, ^orthoJ = 7.9 Hz, ^metaJ = 2.2 Hz, 1 H, PyC^4ЈH), 7.79–7.70 (dt,

^orthoJ = 7.5 Hz, 2 H, PyC⁵H), 7.63 (d, ^orthoJ = 9.4 Hz, 1 H, PyC^3ЈH),

7.54 (d, ^orthoJ = 8.0 Hz, 2 H, PyC³H), 7.28–7.2 (dt, ^orthoJ = 8.0 Hz,

^metaJ = 1.3 Hz, 2 H, PyC⁴H), 4.04 (s, 4 H, NCH₂Py), 3.96 (s, 2 H,

NCH₂PyЈ).

Acknowledgments

The authors thank René Aben (Nijmegen) for assistance with the

high-pressure reactions, and Johan Visser (Nijmegen) for assistance

with the synthesis. This research was funded by the Dutch Research

Council (NWO) through its chemical branch (CW, formerly SON)

with a grant in the Supramolecular Technology programme to

M.C.F. and R.J.M.N.; K.D.K. gratefully acknowledges research

support from the USA National Institutes of Health (GM 28962).

(6-[Bis(2-pyridylmethyl)amino]methyl-3-pyridyl)methanol (25): Ar-

gon was led through a solution of 24 (150 mg, 0.43 mmol) in 10 mL

of dry, freshly distilled diethyl ether for 20 min. A solution of Li-

AlH₄(29 mg, 1.8 equiv.) in 3 mL of dry, freshly distilled diethyl

ether was prepared and added dropwise under argon at 0 °C to the

2294

www.eurjoc.org

Eur. J. Org. Chem. 2006, 2281–2295

PY2- and TPA-Appended Diphenylglycoluril Receptors and Their Bis-Cu^IComplexes

FULL PAPER

[26] J. W. H. Smeets, H. C. Visser, V. E. M. Kaats-Richter, R. J. M.

Nolte, Recl. Trav. Chim. Pays-Bas 1990, 109, 147–153.

[27] A. P. H. J. Schenning, B. de Bruin, A. E. Rowan, H. Kooijman,

A. L. Spek, R. J. M. Nolte, Angew. Chem. Int. Ed. Engl. 1995,

34, 2132–2134.

[28] R. J. M. Klein Gebbink, C. F. Martens, M. C. Feiters, R. J. M.

Nolte, Chem. Commun. 1997, 389–390.

[29] R. J. M. Klein Gebbink, C. F. Martens, P. J. A. Kenis, R. J. Jan-

sen, H.-F. Nolting, V. A. Solé, M. C. Feiters, K. D. Karlin,

R. J. M. Nolte, Inorg. Chem. 1999, 38, 5755–5768.

[30] R. J. M. Klein Gebbink, Supramolecular Metallobiosite Ana-

logues, PhD Thesis, University of Nijmegen, 1998.

[31] V. S. I. Sprakel, M. C. Feiters, W. Meyer-Klaucke, M. Klopstra,

J. Brinksma, B. L. Feringa, K. D. Karlin, R. J. M. Nolte, Dal-

ton Trans. 2005, 3522–3534.

[1]

[2]

[3]

K. D. Karlin, A. D. Zuberbühler, Bioinorganic Catalysis 1999,

2^nded. (Eds.: J. Reedijk, E. Bouwman), 469–534.

E. I. Solomon, P. Chen, M. Metz, S.-K. Lee, A. E. Palmer, An-

gew. Chem. Int. Ed. 2001, 40, 4570–4590.

L. M. Mirica, X. Ottenwaelder, T. D. P. Stack, Chem. Rev.

2004, 104, 1013–1045.

E. A. Lewis, W. B. Tolman, Chem. Rev. 2004, 104, 1047–1076.

K. A. Magnus, B. Hazes, H. Ton-That, C. Bonaventura, J. Bon-

aventura, W. G. J. Hol, Proteins-Struc. Funct. Gen. 1994, 19,

302–309.

M. C. Feiters, Comments Inorg. Chem. 1990, 11, 131–174.

G. L. Woolery, L. Powers, M. Winkler, E. I. Solomon, K.

Lerch, T. G. Spiro, Biochim. Biophys. Acta 1984, 788, 155–161.

J. P. Klinman, Chem. Rev. 1996, 96, 2541–2561.

S. T. Prigge, B. Eipper, R. Mains, L. M. Amzel, Science 2004,

304, 864–867.

T. Klabunde, C. Eicken, J. C. Saccettini, B. Krebs, Nat. Struct.

Biol. 1998, 5, 1084–1090.

C. Gerdemann, C. Eicken, B. Krebs, Acc. Chem. Res. 2002, 35,

183–191.

M. C. Feiters, W. Meyer-Klaucke, G. Godette, C. Bonaventura,

C. Gielens, G. Préaux, Proceedings of the XIIth International

Conference on Invertebrate Dioxygen Binding Proteins, Roscoff,

France, July 24–28, 2000, contribution no. 3 (CD-ROM, 2002).

[4]

[5]

[6]

[7]

[8]

[9]

[32] H. K. A. C. Coolen, P. W. N. M. van Leeuwen, R. J. M. Nolte,

J. Am. Chem. Soc. 1995, 117, 11906–11913.

[33] A. P. Krapcho, C. S. Kuell, Synth. Commun. 1990, 20, 2559–

[10]

[11]

[12]

2564.

[34] J. W. H. Smeets, R. P. Sybesma, F. G. M. Niele, A. L. Spek,

W. J. J. Smeets, R. J. M. Nolte, J. Am. Chem. Soc. 1987, 109,

928–929.

[35] K. D. Karlin, M. S. Haka, R. W. Cruse, G. J. Meyer, A. Fa-

rooq, Y. Gultneh, J. C. Hayes, J. Zubieta, J. Am. Chem. Soc.

1988, 110, 1196–1207.

[36] J. W. H. Smeets, L. van Dalen, V. E. M. Kaats-Richter, R. J. M.

Nolte, J. Org. Chem. 1990, 55, 454–461.

[37] Z. He, P. J. Chaimungkalanont, D. C. Craig, S. B. Colbran, J.

Chem. Soc., Dalton Trans. 2000, 9, 1419–1430.

[38] C. M. Groeneveld, J. van Rijn, J. Reedijk, G. W. Canters, J. Am.

Chem. Soc. 1988, 110, 4893–4900.

[39] J. N. H. Reek, A. H. Priem, H. Engelkamp, A. E. Rowan,

J. A. A. W. Elemans, R. J. M. Nolte, J. Am. Chem. Soc. 1997,

119, 9956–9964.

[40] G. C. Dol, S. Gaemens, M. Hietikko, P. C. J. Kamer,

P. W. N. M. Van Leeuwen, R. J. M. Nolte, Eur. J. Inorg. Chem.

1998, 1975–1985.

[41] R. Schuurman, Chiral Receptors Derived from Diphenyl-

glycoluril, An Approach to Enantioselective Supramolecular Ca-

talysis, PhD Thesis, University of Nijmegen, 1994, chapter 7.

[42] J. N. H. Reek, J. A. A. W. Elemans, R. J. M. Nolte, J. Org.

Chem. 1997, 62, 2234–2243.

[43] Z. Tyeklar, R. R. Jacobson, N. Wei, N. N. Murthy, J. Zubieta,

K. D. Karlin, J. Am. Chem. Soc. 1993, 115, 2677–2689.

[44] M. Schatz, M. Becker, F. Thaler, F. Hampel, S. Schindler, R. R.

Jacobson, Z. Tyeklár, N. N. Murthy, P. Ghosh, Q. Chen, J.

Zubieta, K. D. Karlin, Inorg. Chem. 2001, 40, 2312–2322.

[45] G. J. Kubas, Inorg. Synth. 1979, 19, 90–92.

[46] H. Brockmann, H. Schodder, Ber. Dtsch. Chem. Ges. 1941,

74B, 73.

[47] Z. Tyéklar, R. R. Jacobson, N. Wei, N. N. Murthy, J. Zubieta,

K. D. Karlin, J. Am. Chem. Soc. 1993, 115, 2677–2689.

Received: November 4, 2005

[13] E. I. Solomon, U. M. Sundaram, T. E. Machonkin, Chem. Rev.

1996, 96, 2563–2605.

[14] D. E. Wilcox, A. G. Porras, Y. T. Hwang, K. Lerch, M. E.

Winkler, E. I. Solomon, J. Am. Chem. Soc. 1985, 107, 4015–

4027.

[15] C. W. G. van Gelder, W. H. Flurkey, H. J. Wichers, Phytochem-

istry 1997, 45, 1309–1323.

[16] M. C. Feiters, Met. Ions Biol. Syst. (Ed.: A. H. Sigel), Marcel

Dekker, New York, 2001, 38, 461–655.

[17] S. Schindler, Eur. J. Inorg. Chem. 2000, 11, 2311–2326.

[18] N. Kitajima, Y. Moro-oka, Chem. Rev. 1994, 94, 737–757.

[19] L. Quant Hatcher, K. D. Karlin, J. Biol. Inorg. Chem. 2004, 9,

669–683.

[20] V. S. I. Sprakel, M. C. Feiters, R. J. M. Nolte, Eur. J. Inorg.

Chem., Microreview, in preparation.

[21] C. X. Zhang, H.-C. Liang, E.-i. Kim, J. Shearer, M. E. Helton,

E. Kim, S. Kaderli, C. D. Incarvito, A. D. Zuberbühler, A. L.

Rheingold, K. D. Karlin, J. Am. Chem. Soc. 2003, 125, 634–

635.

[22] K. Djinovic-Carugo, A. Battistoni, M. Carri, F. Polticelli, A.

Desideri, G. Rotilio, A. Doca, K. Wilson, M. Bolognesi, Acta

Crystallogr., Sect. D 1996, 52, 176–188.

[23] R. R. Jacobson, Z. Tyeklar, A. Farooq, K. D. Karlin, S. Liu, J.

Zubieta, J. Am. Chem. Soc. 1988, 110, 3690–3692.

[24] R. P. Sijbesma, R. J. M. Nolte, Top. Curr. Chem. 1995, 175, 26–

56.

[25] A. E. Rowan, J. A. A. W. Elemans, R. J. M. Nolte, Acc. Chem.

Res. 1999, 32, 995–1006.

Published Online: March 15, 2006

Eur. J. Org. Chem. 2006, 2281–2295

www.eurjoc.org

2295

Article Doi

Synthesis and characterization of PY2- and TPA-appended diphenylglycoluril receptors and their bis-CuI complexes

DOI: 10.1002/ejoc.200500865

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.200500865

Full text of DOI:10.1002/ejoc.200500865

Products guided by the article

R&D Labs maybe for 124042-45-1

Relevant to this article

Hot Product