Molecular recognition: Comparative study of a tunable host-guest system by using a fluorescent model system and collision-induced dissociation mass spectrometry on dendrimers

Article abstract of DOI:10.1002/chem.200401230

Host-guest interactions between the periphery of adamantylurea- functionalized dendrimers (host) and ureido acetic acid derivatives (guest) were shown to he specific, strong and spatially well-defined. The binding becomes stronger when using phosphonic or

Full text of DOI:10.1002/chem.200401230

Molecular Recognition: Comparative Study of a Tunable Host–Guest System
by Using a Fluorescent Model System and Collision-Induced Dissociation
Mass Spectrometry on Dendrimers
Michael Pittelkow,[a, b] Christian B. Nielsen,[c] Maarten A. C. Broeren,[b]
Joost L. J. van Dongen,[b] Marcel H. P. van Genderen,[b] E. W. Meijer,*[b] and
Jørn B. Christensen*[a, b]
Abstract: Host–guest interactions be-
tween the periphery of adamantylurea-
functionalized dendrimers (host) and
ureido acetic acid derivatives (guest)
were shown to be specific,strong and
spatially well-defined. The binding be-
comes stronger when using phosphonic
or sulfonic acid derivatives. In the pres-
ent work we have quantified the bind-
ing constants for the host–guest inter-
actions between two different host
motifs and six different guest mole-
cules. The host molecules,which re-
semble the periphery of a poly(propy-
lene imine) dendrimer,have been
fitted with an anthracene-based fluo-
rescent probe. The two host motifs
differ in terms of the length of the
spacer between a tertiary amine and
two ureido functionalities. The guest
molecules all contain an acidic moiety
(either a carboxylic acid,a phosphonic
acid,or a sulfonic acid) and three of
them also contain an ureido moiety ca-
pable of forming multiple hydrogen
bonds to the hosts. The binding con-
stants for all 12 host–guest complexes
have been determined by using fluores-
cence titrations by monitoring the in-
crease in fluorescence of the host upon
protonation by the addition of the
guest. The binding constants could be
tuned by changing the design of the
acidic part of the guest. The formation
of hydrogen bonds gives,in all cases,
higher association constants,demon-
strating that the host is more than a
proton sensor. The host with the longer
spacer (propyl) shows higher associa-
tion constants than the host with the
shorter spacer (ethyl). The gain in asso-
ciation constants are higher when the
urea function is added to the guests for
the host with the longer spacer,indicat-
ing a better fit. Collision-induced disso-
ciation mass spectrometry (CID-MS) is
used to study the stability of the six
motifs using the corresponding third
generation dendrimer. A similar trend
is found when the six different guests
are compared.
Keywords: dendrimers
·
fluores-
cence spectroscopy · mass spec-
trometry · molecular recognition ·
supramolecular chemistry
[a] M. Pittelkow,Dr. J. B. Christensen
Department of Chemistry,University of Copenhagen
Universitetsparken 5,2100 (Denmark)
Fax : (+45)353-20-212
Introduction
Host–guest chemistry with dendrimers is an area of supra-
molecular chemistry that has developed fast in recent
years.[1–7] With the dendritic box as one of the first exam-
ples,[8] the field has developed towards systems that mimick
or interact with biological systems,that is,where the host–
guest chemistry involves binding to the surface of the den-
drimer,so-called exo complexation. One of the consequen-
ces of having a dendritic architecture is that a large number
of groups are presented at the surface of the structure. This
situation is well-suited for the study of multivalent interac-
tions in biological systems.[9,10] Some examples of previous
work are peptide dendrimers[7,11–13] and glycodendrim-
ers.[7,11,14–16] All of these systems,however,are based on co-
valent bonding of the surface groups to the dendritic struc-
E-mail: jbc@kiku.dk
[b] M. Pittelkow,M. A. C. Broeren,J. L. J. van Dongen,
Dr. M. H. P. van Genderen,Prof. Dr. E. W. Meijer,
Dr. J. B. Christensen
Laboratory of Macromolecular and Organic Chemistry
Eindhoven University of Technology
P.O. Box 513,5600 MB,Eindhoven (The Netherlands)
Fax : (+31)402-451-036
E-mail: e.w.meijer@tue.nl
[c] Dr. C. B. Nielsen
The Danish Polymer Center
RISØ National Laboratory
P.O. Box 49,4000 Roskilde (Denmark)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the authors.
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DOI: 10.1002/chem.200401230
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FULL PAPER
ture. Noncovalent binding to the surface of a dendrimer
gives rise to a dynamic system,for which the optimal bind-
ing motif for a target can be molded from a dendritic host
and an ensemble of guest molecules. An important first step
in this direction was the preparation of host–guest com-
plexes between dendrimers and peptides.[17]
Recently a series of new host–guest motifs for exo com-
plexation of poly(propylene imine) dendrimers was intro-
duced.[18–22] This design is outlined in Scheme 1,where X is a
the host moiety. These systems were studied in solution by
NMR spectroscopy[19,23] and in the gas phase by electrospray
mass spectrometry.[21] Determination of the association con-
stants for the different systems would be desirable to gain
further insight into the complexation.
However,quantification of the association constants of
large dendrimers capable of binding several guest molecules
(up to 32 for the fifth-generation poly(propylene imine)
dendrimer) is difficult due to multiple equilibrium consider-
ations. A relatively simple solution to this challenge is to
quantify the association constants on model host compounds
containing only one binding site. This approach furthermore
has the advantage that it should allow faster screening of
new potential host–guest combinations. Herein we present
the quantification of the association constants for the host–
guest interactions between two different host motifs that re-
semble the periphery of a poly(propylene imine) dendrimer
and six different guest molecules by attaching a fluorescence
probe to the host. Furthermore,these complexes were inves-
tigated with collision-induced decomposition mass spectrom-
etry to evaluate their relative stabilities in the gas phase.
The difference in solution phase and gas phase stabilities is
discussed.
Results and Discussion
Molecular design: In earlier work we observed strong indi-
cations,that,in a purely qualitative manner,the binding af-
finity of the host–guest system is tunable by rational design
of the guest molecules.[19–21] As a result,we have designed
and synthesized a system in which it is possible to quantify
the association constants by fluorescence spectroscopy. We
chose to simplify the system,as compared with the multi-
functional dendrimer systems,by choosing a model host sub-
strate that only contains one binding site. A well-known,
and thoroughly studied,fluorescence probe is the 9-methyl-
anthracenyl moiety. This can conveniently be attached to
the host by using the amine functionality in the binding
motif. In this way,two different hosts ( 1 and 2) were synthe-
sized
with
different
spacer lengths between
the tertiary amine and
the ureido moieties.
Host 1 is equivalent to
the binding motif of the
periphery of the poly-
(propylene imine) den-
Scheme 1. a) Schematic representation of the host–guest system studied
and b) third-generation adamantylurea-terminated poly(propylene imine)
dendrimer that is capable of binding eight guest molecules.
carboxylic acid,a phosphonic acid,or a sulfonic acid. The
adamantylurea-functionalized poly(propylene imine) den-
drimer (with the third generation shown in Scheme 1) serves
as a multivalent host for the guest molecules in a very selec-
tive manner,thus enabling the isolation of well-defined
complexes with one guest per host motif at the periphery of
the dendrimer. The complexation is due to a combination of
multivalent hydrogen bonding between the urea parts of the
guests and the host,and to an electrostatic interaction be-
tween the acidic part of the guest and the tertiary amine in
drimers and host
2
simply has an ethylene
spacer replacing the pro-
pylene spacer. Host
2
was prepared to study
the flexibility of the
host-binding motif.
The design of the orig-
inal type of host–guest
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E. W. Meijer,J. B. Christensen et al.
system,in which the guest has an ureido glycine tail that
binds to the host,opens the path to several structural modi-
fications. In earlier work it was shown that the ureido gly-
cine part can be substituted for a C-terminal peptide (in
which the carboxylic acid performs the electrostatic interac-
tion to the host) and the ureido part is replaced by an amide
from the peptide (that can form multiple hydrogen bonds to
the host). It has also been indicated,in a qualitative fashion,
that the binding strength of guests increases for complexes
in which the carboxylic acid part is substituted by a phos-
phonic acid or a sulfonic acid moiety. To
bles us to investigate the importance of rational design and
it makes it possible to rule out that the host–guest interac-
tion is more than merely a H+ sensor.
Synthesis: The two host molecules 1 and 2 were prepared
from the commercially available 9-(chloromethyl)anthra-
cene as outlined in Scheme 2. Reaction of 9-(chloromethyl)-
anthracene with the bis-boc-protected triamines[24] 9 and 10
yields,upon treatment with KI and K CO3,the light- and
2
acid-sensitive bis-boc protected triamines 11 and 12 in good
study this phenomenon in a systematic
manner and to quantify the binding
strengths,we prepared
a series of
chloroform-soluble guest molecules 3–5
bearing the above-indicated binding
motifs. The attachment of a trisdodecy-
loxy benzoic acid part to the guest mole-
cules serves only solubility purposes and
is identical for all guests in this study.
The guest molecules 6–8,which lack
the ureido moiety,and thus the ability to
form hydrogen bonds to the ureido part
of the hosts,were prepared as reference
compounds. The binding properties of
these guests rely solely on the electro-
static interaction with the tertiary amine
functionality of the host molecules.
Thus,this series of guest molecules ena-
Scheme 2. Synthesis of fluorescent hosts 1 and 2. Reagents and conditions: a) KI,K 2CO3,DMF,
68% (11),75% ( 12); b) TMSCl,PhOH,CH 2Cl2; c) AdNCO,CH Cl2,60% ( 1),96% ( 2) (two steps).
2
yields. Deprotection of the boc protection groups was per-
formed under very mild conditions by treatment with a mix-
ture of phenol and TMSCl in CH2Cl2.[25] After the deprotec-
tion and a basic workup,the crude triamines 13 and 14 were
allowed to react directly with adamantyl isocyanate to yield
the target host molecules (1 and 2) as white crystalline ma-
terials in high yields.
The synthesis of the carboxylic acid guest containing the
ureido functionality has been described elsewhere.[19] The
syntheses of the phosphonic acid guest 4 and the sulfonic
acid guest containing the ureido functionality (5) follow the
same overall synthetic strategy,and are outlined in Scheme 3.
The syntheses of the guest molecules lacking the ureido
functionalities proceeded by different protocols. The synthe-
sis of the carboxylic acid guest without the ureido function
(6) starts from methyl 11-bromoundecanoate (20;
Scheme 4),[28] which was treated with the gallic acid deriva-
tive[29] 15 to give the diester 21 in high yield. This diester
was selectively demethylated to give 6 by using LiI in pyri-
dine.[30,31]
The phosphonic acid guest 7 was prepared via the bro-
mide 23 by an Arbuzov reaction with trimethylphosphite
(Scheme 5). The bromide 23 was prepared from the gallic
acid precursor 15 via the acid fluoride 22 in a one-pot proce-
dure using fluoro-N,N,N’’,N’’-tetramethylformamidinium
hexafluorophosphate
(TFFH/4-dimethylaminopyridine
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Tunable Host–Guest Systems
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Scheme 3. Synthesis of guests 4 and 5. Reagents and conditions: a) DCC,DMAP,CHCl 3,67%; b) 1: HCl,diethyl ether,2: NaOH,3: tricarbonate; c)
aminomethanesulfonic acid,pyridine,62%; d) di- tert-butyl aminomethylphosphonate,CHCl 3,49%; e) TFA,CH 2Cl2,quant.
Fluorescence: Fluorescence titration experiments are an
ideal method to determine the binding constants of the six
guest molecules to the two host molecules.[34] These were
carried out by increasing the total concentration of the
highly soluble (in CHCl3) guest molecules in a solution with
a constant total concentration of host molecules and moni-
toring the increase in the fluorescence intensity. The fluores-
cence spectra from a titration (between host 1 and guest 3)
are shown in Figure 1. From the fluorescence spectra,we
see that the addition of more than 50 equivalents of guest
molecules does not lead to a further increase of the fluores-
cence intensity. Thus,this maximum in intensity ( Imax) indi-
cates that all the host molecules have bonded guest mole-
cules. Similarly,the lowest intensity measured ( I0) is due
only to the host molecule (no guest present). The degree of
Scheme 4. Synthesis of carboxylic acid guest 6. Reagents and conditions:
a) 15, K2CO3,DMF,99%; b) LiI,pyridine,51%.
complexation of host molecules is thus defined as a=(IÀI0)/
(ImaxÀI0) and from this value we can calculate the actual
guest concentration in the sample as [G]=CGÀaCH,where
CG is the total guest concentration and CH is the total host
concentration in the sample. By plotting the degree of com-
plexation as a function of the actual guest concentration
([G]) we obtain a Bjerrum S-diagram to which we can fit a
sigmoidal function and deduce the association constant (see
Figure 2). In the analysis described above we have assumed
(DMAP) as the coupling reagents.[32] Demethylation of 24
to yield 7 was carried out using TMSCl and NaI in refluxing
CH3CN.
The sulfonic acid guest 8 was prepared via 10-hydroxyde-
cane-1-sulfonic acid 25 through an ester-formation reaction
using TFFH/DMAP[32] in CH2Cl2.
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E. W. Meijer,J. B. Christensen et al.
quality of the sigmoidal fit to the experi-
mental data points (see Figure 2).[18,20]
The association constants for the 12 dif-
ferent complexes were obtained from the
sigmoidal curves by fitting a sigmoidal
function to the data points using nonlinear
regression (see Table 1).
Association constants for the binding of
ureido acetic acid guests substituted with
oligo(p-phenylene vinylenes) to a methyl-
analogue of 2 were reported previously.[22]
The association constants (in CDCl3) de-
termined by NMR titration were found to
be highly dependent on the length of the
oligomer,probably due to self-association
of the guests. The Ka values found were in
the range from 300 to 13000mÀ1.
Scheme 5. Synthesis of phosphonic acid guest 7. Reagents and conditions: a) TFFH,Et N,DMAP,
CH2Cl2,87%; b) 1: TFFH,Et 3N,CH 2Cl2,2: 10-bromodecanol,DMAP,90%; c) P(OEt) 3,110 8C,
three days,60%; d) TMSCl,NaI,CH 3CN,89%.
3
Table 1. Association constants for the complexes formed between hosts
1–2 and guests 3–8 and the required voltage for the dissociation of the
guests from the G3Ad dendrimer.
Complex Association constant
Mass spectrometry
range in which guest dissociates [V][a]
G3Ad
(”102 mÀ1
)
2
1
3
6
4
7
5
8
4.66Æ0.27 7.76Æ0.43
3.87Æ0.65 1.64Æ0.11
25–55
–
40–70
30–55
60–85
45–65
127Æ9
685Æ125
62.3Æ4.3 113Æ6
864Æ282 967Æ57
375Æ39
253Æ25
[a] Required voltage for dissociation of the guests from the G3Ad den-
drimer.
For the same binding motif,but with a different tail,we
find Ka =466mÀ1,which is in the interval previously report-
ed.
Figure 1. Fluorescence spectra of a titration between host 1 and guest 3.
Mass spectrometry: Recently we observed complexes of a
third-generation adamantylurea dendrimer (from now on re-
ferred to as D) with several guest molecules in the gas
phase using electrospray-ionization mass spectrometry.[21] It
was also possible to compare the binding strength of differ-
ent guest molecules in a qualitative manner using collision-
induced dissociation. In this technique an ion,consisting of
the dendrimer plus two different guest molecules,is selected
after it is accelerated. Subsequently the ion enters the colli-
sion cell,which contains argon gas. The ion collides with the
argon atoms,which,as a fraction of the ionꢁs kinetic energy
is transferred into internal energy,results in fragmentation
of the supramolecular complex. The guest molecule that dis-
sociates from the dendrimer first is more weakly bound to
the dendrimer than the other guest. This methodology is
comparable to the kinetic method developed by Cooks and
co-workers,which is a procedure for estimating thermo-
chemical information based on the rates of competitive dis-
sociations of mass-selected cluster ions.[35–38] However,in our
case,the conversion of collision energy to internal energy is
Figure 2. Bjerrum S-diagram for the host 1 and carboxylic acid guest 3.
1:1 stoichiometry between the guest and the host. This as-
sumption is confirmed by the fact that we only observe one
equivalence point in the Bjerrum S-diagram and the good
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Tunable Host–Guest Systems
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hard to quantify as multiple collisions occur in the collision
cell (see Experimental Section for details). Furthermore,
owing to the larger number of degrees of freedom in a
larger molecule,it is even more difficult to accurately deter-
mine the amount of internal energy upon ion activation.[39,40]
However,it is in our view valid to compare the binding of
guests 3–8 to dendrimer D in the gas phase in a qualitative
manner.
First,the six different complexes were made,each consist-
ing of four equivalents of guest 3–8 added to D. All samples,
except for guest 6, give mass spectra that show complexation
to the dendrimer,indicating that these complexes are stable
enough to be observed in the gas phase. A typical spectrum
is shown in Figure 3.
value of 1812.3. This means that 7 dissociates first from the
dendrimer as a neutral species and is the weaker binding
guest. The dissociation is not 100% selective as the peak of
(D·(71))3+ is present at m/z 1807.1; however,the intensity of
this ion is almost negligible. Guest 4 also starts to dissociate
when the voltage is further increased,resulting in bare
(D)3+ (m/z 1508.6) at roughly 70 V. This means that guest 4
binds stronger to host D than guest 7 in the gas phase. Thus,
the urea groups positively influence binding to the dendrim-
er. Some other peaks are also present in the mass spectra.
They correspond to the dendrimer that has lost one to four
adamantyl groups. Covalent bond dissociation of host D
starts to take place at higher voltages,resulting in the peaks
with a m/z value below 1508.6. Interestingly,covalent bond
dissociation can also occur while a guest molecule is still at-
tached. The ion with m/z 1761.9 corresponds to (D·(41))3+
which has lost one adamantyl group but still contains a guest.
A similar trend is observed for the sulfonic acid guests.
Collision-induced dissociation applied to (D·(51+81))3+
shows that guest 8 dissociates from the dendrimer first,re-
sulting in the ion with m/z 1812.3 (Figure 4). Subsequently
These results show that for the phosphonic and sulfonic
acid guests,the urea group is not required to obtain a com-
plex that is stable enough to survive the transfer from solu-
tion to the gas phase.
To investigate the influence of the urea groups on the
binding strength with D,collision-induced dissociation ex-
periments were performed to determine the relative binding
strength of 4 versus 7,and 5 versus 8. Therefore,a sample
containing two equivalents of 4 and two equivalents of 7
added to D was prepared. A further sample with two equiv-
alents of 5 and two equivalents of 8 added to D in chloro-
form was also prepared. Both samples gave complexes
showing the statistical combinations of guests bound to den-
drimer (not depicted). From the first sample,ion ( D·-
(41+71))3+ was selected and subjected to collision-induced
dissociation.
The applied voltage is a measure for the kinetic energy of
the ion prior to injection into the collision cell. The (D·-
(41+71))3+ ion remains stable until 25 V,but starts to frag-
ment when the voltage is further increased. The first major
product of fragmentation is (D·(41))3+,which has an m/z
Figure 4. Collision induced dissociation performed on ion (D·(51+81))3+
.
Guest 8 is depicted in green and guest 5 is depicted in blue. Besides non-
covalent fragmentation,severe covalent fragmentation of D results in ad-
ditional ions.
guest 5 dissociates. This again indicates that the guest mole-
cule without the urea group is the weaker binding guest in
the gas phase,which is in agreement with the fluorescence
experiments in chloroform. Unfortunately,the technique
could not be used to directly compare the difference in
binding strength between phosphonic acid guest 4 and sul-
fonic acid guest 5 (or guest 7 and 8),as these guest mole-
cules have an almost identical mass. Consequently it is not
possible to observe which guest molecule dissociates first.
However,there are indications that the sulfonic acid guests
bind stronger than the phosphonic acid guests based on the
applied voltage. The acceleration voltage required for the
ions to start fragmenting is higher for (D·(51+81))3+ than for
(D·(41+71))3+. This indicates that sulfonic acid guests 5 and
8 bind stronger to host D than phosphonic acid guests 4 and
7. These observations are further supported by the degree of
Figure 3. ESI Mass spectrum of a sample containing four equivalents of 5
added to D in chloroform. 4+ ions: red,3 + ions: blue,2 + ions: green.
The number indicates the amount of guest that is bound to the dendrim-
er.
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E. W. Meijer,J. B. Christensen et al.
covalent fragmentation. While for the (D·(41+71))3+ ion the
adamantyl groups dissociate to some extent,severe covalent
dissociation of the adamantyl groups of D is observed for
(D·(51+81))3+,eventually resulting in host D that has lost
one to ten adamantyl groups at 85 V. This also indicates that
the sulfonic acid guests bind stronger. In conclusion,two
general trends are observed from the mass spectrometry
measurements. When we compare two guest molecules with
identical acid head groups that only differ in the presence of
the ureido moiety (3 versus 6, 4 versus 7, 5 versus 8),the
guests with the ureido functionality always bind stronger
(Table 1). For guests 3 and 6 this is represented in the fact
that no stable complexes are observed for guest 6. Further-
more,when the acid strength of the guest is increased so
that all contain the ureido groups (3 versus 4 versus 5),the
binding strength also increases.
not the sulfonic acid. This provides strong evidence for the
fact that the association constants for the urea-modified
guests are due to a better recognition of the guest and not
merely a matter of the acidic moiety being more acidic
when a urea function is present at the b-carbon atom to the
acidic function.
In our attempts to fully understand the dendrimer-based
multivalent supramolecular complexes,we studied the gas-
phase stabilities of the complexes as well. It is tempting to
compare these results with the fluorescence model studies in
solution. However,discrepancies between gas-phase binding
and binding strengths in aqueous media have often been ob-
served.[41,42] The main reasons are that electrostatic interac-
tions and dipolar noncovalent interactions are strengthened
in the absence of solvent shielding,while hydrophobic inter-
actions become less important in the absence of solvent.[41]
In our case we compare the gas-phase experiments to those
in chloroform instead of aqueous media. Chloroform is an
aprotic solvent,and a non-competing solvent to acid–base
and hydrogen-bonding interactions due to the low dielectric
constant.[43–46] Therefore,some comparisons between chloro-
form and the gas phase can be made. With this in mind we
find that the mass spectrometry results in the gas phase are
in reasonable agreement with the fluorescence experiments
in chloroform. In all cases the guest molecules with urea
groups bind stronger than the guest molecules without urea
groups. Furthermore,an increase in binding strength is ob-
served when the acidity of the head group becomes stron-
ger.
In conclusion,we have presented design and synthetic
procedures for a series of novel guest molecules for supra-
molecular functionalization of specific host molecules. Also,
two novel piner-type fluorescence host molecules have been
designed and synthesized. Finally,we have presented a
simple method for evaluating a new host–guest system
based on a combination of noncovalent interactions using a
simple fluorescent probe. The host–guest system is highly
flexible with respect to the host motif,and the association
constants can be tuned by varying the design of the guest.
The relatively high association constants of this all-organic
host–guest system makes it an appealing alternative in the
construction of supramolecular materials that can compete
with metal-based and natural supramolecular materials.
The results presented herein complement earlier findings
for this host–guest motif in large dendrimers both in solu-
tion and in the gas phase.
Discussion and Conclusions
The results of the fluorescence studies in chloroform depict-
ed in Table 1 clearly show that the guest molecules contain-
ing the urea functionality bind stronger to both host mole-
cules (1 and 2) than the guest molecules lacking the urea
functionality. Thus,from these results we conclude that we
actually observe molecular recognition and not just differen-
ces in pKa values among the guests. Also,it is evident from
the results in Table 1 that the three designed guests (3, 4,
and 5) bind slightly stronger to host 1 than to host 2,though
these differences are minor. The effect is most pronounced
for the phosphonic acid guest 4 that binds approximately
five times stronger to host 1 than to host 2.
In general,the gain in binding strength,when going from
the guests lacking the urea functionality (6–8) to the guests
having the urea function incorporated (3–5),is larger for
host 1 than for host 2. For host 1 (the host containing propyl
spacers) the association constants are 4–5 times higher for
the guests with the urea functionality but only 1–2 times
higher in the case of host 2 (the host containing ethyl
spacers). This,combined with the fact that the binding
strength in general is slightly higher,strongly suggest that
guests fit better with the cavity of host 1 than the cavity of
the host 2. This conclusion can be drawn because the gain in
association constant has an entropy and an enthalpy contri-
bution,and we assume that the enthalpies are comparable,
which is reasonable because the main contribution to the
enthalpy term is the electrostatic interaction. As the host–
guest complexes represent a more highly ordered state than
the guest and the host on their own,the entropy of the reac-
tion will constitute a negative contribution to the association
constant. This cost of entropy is larger for the host with the
longer spacer groups because it has more degrees of free-
dom,and this must mean that the gain in binding strength is
due to a better fit.
Experimental Section
General methods: Solvents were HPLC grade and were used as received.
1H NMR and 13C NMR spectra were recorded on a 300 MHz NMR
1
(Varian) apparatus (300 MHz for H NMR and 75 MHz for 13C NMR) or
on a 400 MHz NMR (Bruker) apparatus (400 MHz for 1H NMR and
100 MHz for 13C NMR). Proton chemical shifts are reported in ppm
downfield from tetramethylsilane (TMS) and carbon chemical shifts in
ppm downfield of TMS using the resonance of the deuterated solvent as
internal standard. Melting points were measured on a Büchi B-140 appa-
An important point to note is that the two sulfonic acid
guests 5 and 8 are present as their pyridinium salts. This
makes the pyridinium ion the acidic part of the guest and
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Tunable Host–Guest Systems
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ratus and are uncorrected. Elemental analysis was performed by Mrs
Karin Linthoe on a Perkin-Elmer Series II,2400 elemental analyser.
Fast-atom bombardment (FAB) mass spectra were recorded on a Jeol
JMS-HX 110A Tandem Mass Spectrometer in the positive ion mode
using m-NBA as the matrix. HRMS were recorded on a Micromass Q-
TOF apparatus using the electrospray ionization (ESI) technique. All
column chromatography was performed on Merck Kiselgel 60 (0.015–
0.040 mm) using the dry column vacuum chromatography (DCVC) tech-
nique.[49] All fluorescence measurements were performed by using Spec-
trosolve grade solvents and the solutions were degassed for 15 min prior
to use. Emission spectra were measured on a FLS920 spectrometer from
Edinburgh Instruments. The instrument is fitted with a 450-W Xe lamp
for steady-state measurements. The detecting system comprises a single-
photon-counting PMT detector in a Peltier cooled housing. All spectra
were measured in a perpendicular geometry using 1-cm quartz cuvettes.
elemental analysis (%) calcd for C43H57N5O2: C 76.41,H 8.50,N 10.36;
found: C 76.20,H 8.61,N 10.36.
1-(2-{Anthracen-9-ylmethyl-[2-(3-adamantylureido)ethyl]amino}ethyl)-3-
adamantylurea (2): Synthesized as compound 1 from precursor 11. The
product was purified by dry column vacuum chromatography (from hep-
tane to EtOAc with 20% increments,followed by EtOAc to 20%
MeOH in EtOAc with 3% increments) to yield 2 as an off-white solid.
Yield 0.62 g,60%; m.p. 140–142 8C; 1H NMR (300 MHz,CDCl 3): d=
8.25–8.38 (m,3H),7.94–7.98 (m,2H),7.40–7.55 (m,4H),4.50 (br s,2H),
4.42 (br s,2H),4.05 (br s,2H),3.05–3.10 (m,4H),2.57–2.62 (m,4H),
1.95–1.98 (m,6H),1.88–1.92 (m,12H),1.8–1.86 ppm (m,12H);
13C NMR (75 MHz,CDCl 3): d=157.9,131.6,129.4,128.0,126.5,125.4,
125.3,125.1,125.0,54.9,51.2,50.9,42.6,38.1,36.7,29.8 ppm; MS (posi-
tive-ion mode FAB): m/z: 648.9 [M+H]+; elemental analysis (%) calcd
for C41H53N5O2: C 76.01,H 8.25,N 10.81; found: C 76.21,H 8.41,N
10.66.
The ESI mass spectra of the dendrimer complexes were recorded with a
Q-Tof Ultima GLOBAL mass spectrometer (Micromass,Manchester,
UK) equipped with a Z-spray source. The samples (10 mL) were injected
in the flow injection analysis (FIA) mode. The HPLC-grade chloroform
6-(3-Phosphonomethylureido)hexyl 3,4,5-tris-dodecyloxybenzoate (4):
Compound 19 (0.400 g,0.39 mmol) was dissolved in dry dichloromethane
(10 mL) and trifluoroacetic acid (TFA; 10 mL) was added under a nitro-
gen atmosphere to the stirring solution using a syringe. After the reaction
mixture had been stirred for 3 h at room temperature,the solvent was re-
moved in vacuo. The resulting off-white solid was dried in a vacuum
was pumped with a Shimadzu LC-10 ADvp at a flow rate of 30 mLminÀ1
.
Electrospray ionization was achieved in the positive-ion mode by applica-
tion of 5 kV on the needle. The source block temperature was maintained
at 608C and the desolvation gas was heated to 608C. Argon collision gas
was introduced into the central hexapole collision cell of the mass spec-
trometer in collision-induced dissociation (CID) experiments. The pres-
sure in the collision cell corresponds to approximately 0.8 mTorr (1”
10À6 bar). With a collision cell length of 18.5 mm,multiple collisions
occur in the collision cell.[39,47,48]
1
oven at 708C overnight; yield 0.355 g (100%); m.p. 206–2088C; H NMR
(400 MHz,CDCl ): d=7.22 (s,2H),4.25 (m,2H),3.99 (m,6H),3.57 (m,
3
2H),3.15 (m,2H),1.69–1.84 (m,8H),1.40–1.54 (m,8H),1.24–1.38 (m,
52H),0.84–0.91 ppm (t, J=5.8 Hz,9H); 13C NMR (100 MHz,CDCl 3):
d=167.0,160.5,153.2,142.7,125.0,108.5,73.8,69.5,65.2,40.8,32.2,30.6,
30.0,29.95,29.90,29.85,29.70,29.60,28.9,26.6,26.4,26.3,25.7,23.0,
14.4 ppm; elemental analysis (%) calcd for C51H95N2O9P: C 67.20,H
10.52,N 3.07; found: C 67.47,H 10.19,3.02; MS (negative-ion mode
FAB): m/z: 910 [MÀH]À.
For the regular mass spectrometry experiments all complexes were pre-
pared by adding four equivalents of guest to the dendrimer in a total con-
centration of 1 mgmLÀ1 in chloroform. To 400 mL of each of these solu-
tions was added 100 mL of a 1% acetic acid in chloroform solution. For
the MS/MS experiments,two equivalents of each guest molecule were
added to the dendrimer in a total concentration of 1 mgmLÀ1 in chloro-
form. To 400 mL of these solutions was added 100 mL of a 1% acetic acid
in chloroform solution. This mixture was immediately injected in the
mass spectrometer. The small amount of acetic acid is used to protonate
the dendrimer interior. When no acetic acid is used,no ions are observed
in the mass spectrum. When too much acetic acid is used,the solvent de-
stroys the supramolecular aggregate and only bare dendrimer D is ob-
served. Under these conditions,we mostly observed the 4 + and 3+ ions
as well as small amounts of the 2+ ion. As the 3+ ions are often the
predominant species,all MS/MS experiments were performed with this
ion. MS/MS experiments performed on the 2+ ion gave different voltag-
es of dissociation,but never changed the order of dissociation when two
different guests were compared when bound to the same dendrimer.
Pyridinium {3-[6-(3,4,5-tris-dodecyloxybenzoyloxy)hexyl]ureido}methane-
sulfonate (5): tert-Butyl protected amine 17 (1.0 g,1.1 mmol) was dis-
solved in anhydrous CH2Cl2 (15 mL) and a solution of HCl in diethyl
ether (5 mL,1 m) was added. The solution was stirred for 1 h at room
temperature. The mixture was made strongly alkaline with aqueous
NaOH (30 mL,2 m) and the organic phase was separated. The aqueous
phase was extracted with chloroform (2”30 mL),and the combined or-
ganic phases were dried over Na2SO4 and concentrated in vacuo. The
crude amine was redissolved in anhydrous chloroform (10 mL) and a so-
lution of di-tert-butyl tricarbonate[27] (0.30 g,1.1 mmol) dissolved in anhy-
drous chloroform was added. This was stirred at room temperature over-
night (a characteristic peak at 2250 cmÀ1 in the IR spectrum of the crude
mixture confirmed the presence of an isocyanate). The reaction mixture
was concentrated under reduced pressure. The crude isocyanate was re-
dissolved in pyridine (10 mL),and aminomethane sulfonic acid (134 mg,
1.2 mmol) was added to the reaction mixture. This reaction mixture was
heated to 608C for 36 h. The reaction mixture was concentrated under re-
duced pressure. The crude product was redissolved in chloroform and fil-
tered. The mother liquor was concentrated under reduced pressure yield-
ing a white solid that was fractionally recrystallized from ethanol to yield
1-(3-{Anthracen-9-ylmethyl-[3-(3-adamantyl-ureido)propyl]amino}prop-
yl)-3-adamantylurea (1): Compound 12 (2.65 g,5.16 mmol) dissolved in
dry CH2Cl2 (50 mL) was added to a mixture of TMSCl (5.61 g,6.55 mL,
51.63 mmol) and phenol (4.86 g,51.63 mmol) in dry CH 2Cl2 (50 mL).
This reaction mixture was stirred overnight under an N2 atmosphere at
room temperature. Water (50 mL) was added and the mixture was acidi-
fied with aqueous HCl (2m). After vigorous stirring for 1 h,the phases
were separated and the aqueous phase was washed with CH2Cl2 (2”
75 mL). The aqueous phase was made strongly alkaline by addition of
aqueous NaOH (12m) and extracted with CH2Cl2 (3”75 mL). The organ-
ic phases were concentrated in vacuo to yield the crude deprotected tria-
mine as a slightly yellow oil. This was redissolved in dry CH2Cl2 (50 mL)
and adamantyl isocyanate (1.92 g,10.84 mmol) was added and the reac-
tion mixture was stirred overnight at room temperature under N2. The re-
sulting precipitate was filtered off,washed with cold CH 2Cl2,and recrys-
tallized from EtOH to yield 1 as a white solid. Yield 3.30 g,96%; m.p.
156–1588C; 1H NMR (300 MHz,CDCl 3): d=8.25–8.35 (m,3H),7.90–
7.95 (m,2H),7.40–7.50 (m,4H),4.80 (br s,2H),4.45 (s,2H),4.20 (br s,
2H),2.95–2.98 (m,4H),2.57–2.62 (m,4H),1.95–1.98 (m,6H),1.88–1.92
5
as
(400 MHz,CDCl 3): d=9.05 (d, J=4.9 Hz,2H),8.39 (t, J=7.8 Hz,1H),
7.94 (t, J=7.8 Hz,2H),7.22 (s,2H),4.37 (br s,2H),4.23 (t, J=6.8 Hz,
2H),3.96–4.02 (m,8H),3.09 (t, J=6.8 Hz,2H),1.67–1.84 (m,8H),1.41–
1.51 (m,6H),1.20–1.39 (m,54H),0.87 ppm (t,9H);
13C NMR (100 MHz,
a
white solid. Yield 0.70 g,62%; M.p. 158–160 8C; 1H NMR
CDCl3): d=166.7,159.3,153.1,145.7,142.9,142.5,127.2,125.2,108.2,
73.7,69.4,65.2,57.7,40.6,32.2,30.6,30.1,30.0,29.95,29.9,29.8,29.7,29.6
(2”),28.9,26.7,26.4,26.3,25.8,23.0,14.4 ppm; MS (negative-ion mode
FAB): m/z: 910 [MÀpyridinium]À; elemental analysis (%) calcd for
C56H99N3O9S: C 67.89,H 10.09,N 4.24; found: C 67.53,H 9.92,N 3.91.
10-Carboxydecyl 3,4,5-tris-dodecyloxybenzoate (6): LiI (0.57 g,4.2 mmol,
dried in vacuo overnight at 1708C) was co-evaporated twice with dry pyr-
idine (25 mL). The resulting anhydrous LiI was redissolved in pyridine
(25 mL),and ester 21 (0.50 g,0.57 mmol) was added to the solution. The
reaction mixture was heated to reflux for 48 h. After the reaction mixture
was cooled to room temperature,water (50 mL) was added and acidifica-
tion performed with aqueous HCl (4m). This was extracted with CH2Cl2
(m,12H),1.80–1.86 ppm (m,16H);
13C NMR (75 MHz,CDCl 3): d=
157.9,131.5,129.4,126.5,125.0–125.4,124.8,55.5,51.4,50.9,42.7,38.2,
36.7,29.9,27.0 ppm; MS (positive-ion mode FAB): m/z: 676.9 [M+H]+;
Chem. Eur. J. 2005, 11,5126 – 5135
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
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E. W. Meijer,J. B. Christensen et al.
(3”50 mL) and the combined organic phases were evaporated to dryness
in vacuo and purified by dry column vacuum chromatography (heptane
to 1:1 heptane/EtOAc with 5% increments) to yield 6 as a white solid.
Yield 0.25 g,51%; m.p. 55–57 8C; 1H NMR (400 MHz,CDCl 3): d=7.22
(s,2H),4.24 (t,2H),3.97 (t,6H),2.31 (t,2H),1.68–1.78 (m,8H),1.58–
1.62 (m,2H),1.41–1.45 (m,8H),1.23–1.40 (m,58H),0.83 ppm (t,9H);
13C NMR (100 MHz,CDCl 3): d=177.5,166.4,152.7,142.3,124.94,107.9,
73.4,69.1,65.0,33.5,31.8,30.2,28.6–29.6,25.9,24.6,22.6,14.0 ppm; MS
(negative-ion mode FAB): m/z: 857.3 [MÀH]À; elemental analysis (%)
calcd for C54H98O7: C 75.47,H 11.49; found: C 75.37,H 11.69.
DMF (15 mL) under N2. The reaction mixture was stirred overnight at
room temperature. Water (40 mL) was added and the reaction mixture
was extracted with CH2Cl2 (2”50 mL). The combined organic phases
were evaporated to dryness and purified by dry column vacuum chroma-
tography (heptane to 50% EtOAc in heptane with 5% increments) to
yield 12 as a pale yellow solid. Yield 0.782 g,68%; m.p,113–115 8C;
1H NMR (300 MHz,CDCl 3): d=8.38–8.44 (m,3H),7.98–8.02 (m,2H),
7.40–7.44 (m,4H),4.63 (br s,2H),4.48 (s,2H),2.94–2.97 (m,4H),2.56–
2.60 (m,4H),1.63 (t,4H),1.40 ppm (br s,18H);
CDCl3): d=156.3,134.3,131.6,131.5,129.4,127.4,126.2,125.2,124.9,
13C NMR (75 MHz,
79.0,51.6,51.5,39.1,28.6,27.2 ppm; MS (positive-ion mode FAB):
m/z:
3,4,5-Tris-dodecyloxybenzoic acid 10-phosphonodecyl ester (7): Com-
pound 24 (0.923 g,1.0 mmol) and NaI (0.30 g,2.0 mmol) was suspended
in CH3CN (10 mL) and TMSCl (0.25 mL,1.96 mmol) was added under
N2 at room temperature using a syringe. The reaction mixture was heated
to 508C for 15 min,water (50 mL) was added and the reaction mixture
was stirred vigorously for 5 h. The reaction mixture was then extracted
with CH2Cl2 (3”50 mL) and the combined organic phases dried
(Na2SO4),filtered,and concentrated in vacuo. The residue was recrystal-
lized from acetone to yield a white solid. Yield 0.80 g,89%; m.p. 62–
648C; 1H NMR (400 MHz,CDCl 3): d=10.42 (br s,2H),7.24 (s,2H),
4.27 (t,2H),4.00 (t,8H),1.75–1.83 (m,12H),1.40–1.46 (m,8H),1.26–
522.5 [M+H]+; elemental analysis (%) calcd for C31H43N3O4: C 71.37,H
8.31,N 8.05; found: C 71.42,H 8.51,N 7.70.
6-tert-Butoxycarbonylaminohexyl 3,4,5-tris-dodecyloxybenzoate (17): tert-
Butyl (6-hydroxyhexyl)carbamate[26] (5.0 g, 23.0 mmol), 3,4,5-tridodecy-
loxybenzoic acid 15[29] (15.5 g,23.0 mmol),and DMAP (1.0 g,8.2 mmol)
were dissolved in anhydrous chloroform (250 mL). DCC (5.0 g,
24.2 mmol) was added and the reaction mixture was stirred for three
days at room temperature. TLC (dichloromethane, Rf =0.3) showed the
formation of a new adduct that was both UV and ninhydrin active. Dicy-
clohexylurea (DCU) was removed by filtration,and the mixture was con-
centrated in vacuo. The product was purified by column chromatography
(Silica Gel) using dichloromethane as eluent; yield 13.5 g (67%) of a
white solid. M.p. 44–458C; 1H NMR (400 MHz,CDCl 3): d=7.24 (s,2H),
4.51 (br s,1H),4.28 (t, J=6.6 Hz,2H),4.01 (t, J=5.9 Hz,6H),3.11 (m,
2H),1.70–1.85 (m,8H),1.44 (s,9H),1.24–1.27 (m,60H),0.88 ppm (t,
J=6.6 Hz,9H); 13C NMR (100 MHz,CDCl 3) 166.7,156.2,153.0,142.6,
125.2,108.2,73.7,69.4,65.2,40.7,32.2,30.6,30.2,30.0,29.9,29.85,29.8,
29.65,29.6,29.55,28.9,28.6,26.7,26.35,26.3,25.9,22.9,14.3 ppm; MS
(positive-ion mode FAB): m/z: 874 [M+H]+; elemental analysis (%)
calcd for C54H99NO7: C 74.16,H 11.43,N 1.60; found: C 74.51,H 11.09,
N 1.68.
1.35 (m,56H),0.87 ppm (t,9H);
13C NMR (100 MHz,CDCl 3) d 166.4,
152.7,142.3,124.9,108.0,73.4,69.1,65.0,31.8,30.2,29.6,29.55,29.5,29.4,
29.35,29.3,29.2,29.0,28.7,26.1,26.0,25.9,22.6,14.0 ppm; MS (negative-
ion mode FAB): m/z: 893.6 [MÀH]À; elemental analysis (%) calcd for
C53H99O8P: C 71.10,H 11.15; found: C 70.81,H 11.22.
Pyridinium 10-(3,4,5-tris-dodecyloxybenzoyloxy)-decane-1-sulfonate (8):
[50]
Carboxylic acid 15 (1.40 g,2.07 mmol) and TFFH
(0.55 g,2.07 mmol)
were suspended in CH2Cl2 (50 mL),and Et 3N (1.44 mL,10.3 mmol) was
added using a syringe. The reaction mixture was stirred for 30 min and
then alcohol 25 (0.50 g,2.10 mmol) and DMAP (50 mg) was added. The
reaction mixture was stirred overnight and was then evaporated to dry-
ness in vacuo. Water (50 mL) was added and acidified by addition of con-
centrated HCl,and the mixture was then extracted with CH 2Cl2 (3”
60 mL). The combined organic phases were evaporated to dryness and
recrystallized from acetone. This yielded the free sulfonic acid,which was
converted to the corresponding pyridinium salt by dissolving it in pyri-
dine (25 mL) and evaporating to dryness in vacuo. The resulting oil was
crystallized from acetone to yield 8 as a white solid. Yield 1.72 g,85%;
m.p. 49–528C; 1H NMR (300 MHz,CDCl 3): d=8.88–8.92 (m,1H),8.38–
8.42 (m,1H),8.18–8.22 (m,1H),7.94–7.97 (m,1H),7.24 (br s,2H),
6.63–6.68 (m,1H),4.21 (t,2H),3.98 (t,6H),3.16 (br s,1H),3.05–3.10
(m,2H),2.95 (t,2H),1.67–1.80 (m,10H),1.20–1.35 (m,64H),0.85 ppm
(t,9H); 13C NMR (75 MHz,CDCl 3): d=167.1,153.0,142.6,140.1,127.2,
125.6,108.4,106.8,73.8,69.5,65.3,52.0,46.3,40.4,32.2,30.5,29.5–30.0,
6-[3-(Di-tert-butoxyphosphorylmethyl)ureido]hexyl 3,4,5-tris-dodecyloxy-
benzoate (19): To a solution of crude isocyanate 18,prepared from com-
pound 17 (1.0 g,1.1 mmol) as described for compound 5,was added a so-
lution of di-tert-butyl aminomethylphosphonate[50] (0.3 g,1.3 mmol) in
chloroform (5 mL). After 1 h the isocyanate peak in the IR spectrum had
disappeared. The reaction mixture was concentrated in vacuo and the
crude product was purified by column chromatography (silica gel) using
ethyl acetate as eluent. The product 19 (Rf =0.5) was isolated as a white
solid; yield 0.552 g (49%); 1H NMR (400 MHz,CDCl 3): d=7.23 (s,2H),
5.50 (m,1H),5.45 (m,1H),4.27 (t,
J=6.6 Hz,2H),4.00 (t, J=6.6 Hz,
6H),3.51 (dd, J=5.9 Hz and J(H,P)=11.7 Hz,2H),3.16 (m,2H),1.68–
1.84 (m,8H),1.41–1.52 (m,8H),1.21–1.37 (m,70H),0.88 ppm (t,
J=
7.3 Hz,9H); 13C NMR (100 MHz,CDCl 3): d=166.7,158.5,153.0,142.7,
125.2,108.2,73.7,69.5,65.2,53.6,40.5,38.8,32.2,31.2,30.7,30.6,30.55,
29.95,29.90,29.85,29.80,29.65,29.60,29.55,26.8,26.3,26.2,25.9,22.9,
14.4 ppm; elemental analysis (%) calcd for C59H111N2O9P: C 69.22,H
10.95,N 2.74; found: C 68.87,H 10.66,N 2.67.
29.0,28.9,26.5,25.0,23.0,14.7 ppm; MS (negative-ion mode FAB):
m/z:
894.4 [MÀHPy]À; elemental analysis (%) calcd for C58H103NO8S: C 71.48,
H 10.65,N 1.44; found: C 71.67,H 10.74,N 1.45.
tert-Butyl {2-[Anthracen-9-ylmethyl-(2-tert-butoxycarbonylaminoethyl)-
amino]ethyl}carbamate (11): 9-(Chloromethyl)-anthracene (0.50 g,
2.21 mmol),boc-protected triamine 9[24] (0.74 g,2.43 mmol),KI (0.37 g,
2.21 mmol),and K 2CO3 (0.31 g,2.21 mmol) was suspended in dry DMF
(25 mL) and stirred overnight at room temperature under N2. Water
(40 mL) was added and the mixture was extracted with CH2Cl2 (2”
50 mL). The combined organic layers were evaporated to dryness and pu-
rified by dry column vacuum chromatography (heptane to 1:1 EtOAc/
heptane with 5% increments) to yield 11 as a pale yellow solid. Yield
0.81 g,75%; m.p. 138–140 8C; 1H NMR (300 MHz,CDCl 3): d=8.31–8.36
(m,3H),7.92–7.95 (m,2H),7.36–7.49 (m,4H),4.55 (br s,1H),4.50 (s,
2H),3.01–3.09 (m,2H),2.56–2.63 (m,2H),1.29 ppm (br s,18H);
13C NMR (75 MHz,CDCl 3): d=155.8,131.3,131.0,129.3,129.1,127.7,
125.9,124.8,124.3,78.8,53.4,51.1,38.3,28.3 ppm; MS (positive-ion mode
FAB): m/z: 494.7 [M+H]+; elemental analysis (%) calcd for C29H39N3O4:
C 70.56,H 7.96,N 8.51; found: C 70.40,H 8.13,N 8.46.
10-Methoxycarbonyldecyl 3,4,5-tris-dodecyloxybenzoate (21): Carboxylic
acid 15[29] (2.08 g,3.08 mmol),methyl 11-bromoundecanoate
(
20)[28]
(0.860 g,3.08 mmol) and K 2CO3 (0.47 g,3.4 mmol) was suspended in
DMF (50 mL) and heated to 1008C for 18 h. After cooling the reaction
mixture to room temperature,it was poured into ice water (100 mL).
This was extracted with petroleum ether (b.p.<508C,2”50 mL),dried
over Na2SO4 and evaporated to dryness yielding a white solid material.
Recrystallization from acetone yields the title compound as a white crys-
talline material. Yield 2.67 g,99%; m.p. 42–43 8C; 1H NMR (400 MHz,
CDCl3): d=7.20 (s,2H),4.25 (t,2H),3.95 (t,6H),3.62 (s,3H),2.25 (t,
2H),1.68–1.76 (m,8H),1.58–1.62 (m,2H),1.41–1.46 (m,8H),1.23–1.40
(m,58H),0.88 ppm (t,9H);
13C NMR (100 MHz,CDCl 3): d=174.1,
166.4,152.6,142.2,124.9,107.9,73.4,69.1,65.1,54.3,34.0,31.8,30.2,
29.0–29.6,28.6,26.0,25.9,24.8,22.6,14.0 ppm; MS (positive-ion mode
FAB): m/z: 872.8 [M+H]+; elemental analysis (%) calcd for C54H98O7: C
75.64,H 11.54; found: C 75.40,H 11.56.
tert-Butyl
{3-[Anthracen-9-ylmethyl-(3-tert-butoxycarbonylaminoprop-
yl)amino]propyl}carbamate (12): 9-(Chloromethyl)-anthracene (0.50 g,
2.21 mmol),boc-protected triamine 10[24] (0.804 g,2.43 mmol),K 2CO3
(0.31 g,2.21 mmol) and KI (0.367 g,2.21 mmol) was suspended in dry
10-Bromodecyl 3,4,5-tris-dodecyloxybenzoate (23): Carboxylic acid 15[29]
[50]
(27.04 g,40.05 mmol) and TFFH
(11.64 g,40.06 mmol) was dissolved in
CH2Cl2 (300 mL) and Et3N (12.16 g,16.70 mL,120.2 mmol) was added by
5134
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Tunable Host–Guest Systems
FULL PAPER
using a syringe to the stirring solution under N2. The reaction mixture
was stirred for 30 minutes and then 10-bromo-1-decanol (11.40 g,
48.06 mmol) was added followed by DMAP (10%,0.48 g,4 mmol). The
reaction mixture was stirred overnight,and water (400 mL) was added.
The phases were separated and the organic phase was dried (Na2SO4),fil-
tered,and evaporated to dryness. The product was purified by filtering
[14] R. Roy, Trends Glycosci. Glycotechnol. 2003, 15,291.
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1
34–358C; H NMR (400 MHz,CDCl ): d=7.24 (s,2H),4.28 (t,2H),4.01
3
(t,6H),3.40 (t,2H),1.70–1.90 (m,10H),1.45–1.50 (m,10H),1.26–1.30
(m,56H),0.88 ppm (t,9H);
13C NMR (100 MHz,CDCl 3): d=166.4,
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152.7,142.3,125.0,107.9,73.4,69.1,65.0,33.9,32.7,31.8,30.2,29.6,29.5,
29.4,29.3,29.2,29.1,28.6,28.0,26.0,25.9,22.6,14.0 ppm; MS (DI):
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m/z:
893.5 ([M]+); elemental analysis (%) calcd for C53H97BrO5: C 71.19,H
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10-(Dimethoxyphosphoryl)decyl 3,4,5-tris-dodecyloxybenzoate (24): Bro-
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3
bottomed flask fitted with a Claisen-type condenser and heated to 1108C
for three days. All volatiles were evaporated in vacuo and the product
purified by dry column vacuum chromatography (heptane to EtOAc with
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358C; 1H NMR (400 MHz,CDCl 3): d=7.23 (s,2H),4.20 (t,2H),3.95
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152.7,142.3,124.9,108.0,74.0,69.0,65.0,52.2,31.8,30.2,29.6,29.55,29.5,
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Na2SO3 (1.79 g,14.2 mmol) in water (10 mL) was added. This mixture
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(400 MHz,D 2O): d=3.50 (t,2H),2.81 (t,2H),1.64 (m,2H),1.45 (m,
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We acknowledge Associate Prof. M. F. Nielsen for useful discussions. M.
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Received: December 1,2004
Published online: June 30,2005
Chem. Eur. J. 2005, 11,5126 – 5135
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