Integrating chemosensors for amine-containing compounds into cross-linked dendritic hosts

Article abstract of DOI:10.1016/j.tet.2004.08.100

Trifluoroacetylazo dye 1, a known chemosensor for amines, has been integrated into cross-linked dendrimer hosts. Thus, boronic acid 16 was linked to iododye 9 via a Suzuki coupling reaction. In situ deprotection and alkylation with dendrons 3 and 4, conta

Full text of DOI:10.1016/j.tet.2004.08.100

Tetrahedron 60 (2004) 11191–11204
Integrating chemosensors for amine-containing compounds into
cross-linked dendritic hosts*
*
Eric Mertz, Stephanie L. Elmer, Amy M. Balija and Steven C. Zimmerman
Department of Chemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL 61801, USA
Received 2 March 2004; revised 23 June 2004; accepted 19 August 2004
Available online 6 October 2004
Abstract—Trifluoroacetylazo dye 1, a known chemosensor for amines, has been integrated into cross-linked dendrimer hosts. Thus, boronic
acid 16 was linked to iododye 9 via a Suzuki coupling reaction. In situ deprotection and alkylation with dendrons 3 and 4, containing 8
homoallyl or allyl ether groups, respectively, afforded dendrons 18 and 19 with chemosensor units at their focal point. Conversion of 18 (19)
to the bis-imine of butane 1,4-diamine, extensive cross-linking via the ring closing metathesis reaction with Grubbs catalyst 25, and
hydrolysis produced dendrimer hosts 28 and 29. Host-guest studies with a small library of amines and alcohols showed 28 and 29 to
selectively signal certain diamines but not due to template mediated imprinting.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Developing sensors that complex ions and molecules with a
distinct change in color or fluorescence (chemosensors) is a
topic of considerable current interest and technological
importance.2 A common approach is to covalently link a
recognition unit to a chromogenic reporter group.3 Alter-
natively, the chromogenic group may complex to the
recognition unit with the ligand of interest displacing it
and producing the sensor’s response.2c There are advantages
and disadvantages to both approaches.
2.1. Design of dendrons with focal point chromogenic
recognition units
In an effort to improve the performance of molecularly
imprinted polymers (MIPs)5 we have taken a ‘bottom–up’
approach in which a single binding site is imprinted into the
interior of a dendrimer (i.e., MID approach).6,7 To extend
this approach to new guests and integrate a chromogenic
reporter group into the dendrimer, attention was turned to
azo dye 1. Building upon earlier work by Simon,8 Mohr and
co-workers have extensively developed 1 and its analogs as
optical sensors for amines and alcohols.9 Upon reversibly
forming hemiaminal 2, or the corresponding zwitterion, 1
undergoes a shift in lmax of about 50 nm, corresponding to a
visible color change from red-orange to yellow (Scheme 1).
In the course of developing sensor applications, 1 has been
covalently linked to several polymer matrices and imbedded
in a thin layer of polyvinylchloride (PVC).9
We recently reported a cross-linked dendritic host for
diamines in which a chromogenic reporter group was
covalently integrated into the dendrimer framework.4 In this
case, the advantage of covalently linking the chromophore
within the binding unit was two-fold. First, the reporter
group was designed to signal binding by covalently
complexing the guest (vide infra), thus providing a direct
connection between the binding and signaling events.
Second, it was unclear what guests would bind making it
difficult to design a priori an appropriate displacement
assay. Herein we provide a full account of our efforts to
integrate reporter groups into cross-linked dendritic hosts,
including a comparison of two homologous dendritic
frameworks.
* See Ref. 1.
Keywords: Chemosensor; Dendritic host; Diamines.
* Corresponding author. Tel.: C1 217 333 6655; fax: C1 217 244 9919;
e-mail: sczimmer@uiuc.edu
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.100

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E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
2.2. Synthesis of dendrons with focal point chromogenic
recognition units
A number of dendrimers are known in which azobenzene
units are present at the core, peripheral sites, and within the
branching units.10 In the present case, the first objective was
to link azo dye 1 to dendrons 3 and 4; 3 being the key
compound used to synthesize cross-linked and cored
dendrimers11,12 and to imprint porphyrins within dendri-
mers.6,7,13 Because allyl ether-based dendron 4 is easier and
less expensive to prepare14 and might produce a more rigid
imprint, there was interest in comparing its performance to
that of 3. To retain the planar conjugation of the donor and
acceptor groups essential to the function of 1 it was decided
to attach dendron 3 through an aryl substituent ortho to the
azo-group. The aryl attachment was envisioned to occur
through a Suzuki coupling15 of iodide 9 and boronic acid 10.
Scheme 3.
The required boronic acid, 10, was envisioned to arise from
metal-halogen exchange of 11 followed by treatment with
triisopropyl borate. In the event, a modest yield of the
isomeric boronic acid 12 was obtained (Scheme 3).18 As a
model reaction 12 was coupled to 9 under Suzuki conditions
affording 13, whose X-ray structure analysis† (Fig. 1)
confirmed the structural assignment of both 9 and 13.
The synthesis of 9 is outlined in Scheme 2. Following the
procedure of Burton,16 4-fluorobromobenzene was con-
verted to the corresponding Grignard reagent which was
subsequently added to the lithium salt of trifluoroacetic
acid.17 The resulting ketone 5 was treated with ammonia to
afford amine 6.16 Iodination with iodine monochloride
afforded 7 with variable amounts of diiodide 8 which were
removed by chromatography. Diazotization and reaction
with N,N-dimethylaniline gave key intermediate 9.
Figure 1. ORTEP diagram from X-ray analysis of 13. Ellipsoids represent
50% probability and hydrogen atoms are removed for clarity.
Although dendrons 3 and 4 might be linked to 13 through
the 2,6-dimethoxy functionality, the less sterically con-
gested 3,5-isomer was preferred. By carefully maintaining
the temperature of both the metal-halogen exchange and
boronylation reactions at K78 8C, the conversion of 11 to
10 was accomplished in 65% yield. Coupling of 9 and 10
under Suzuki conditions afforded 14 in 80% yield.
However, attempts to demethylate the phenolic groups
resulted in low yields of product and decomposition of the
starting material.
An alternative route used TBDMS protecting groups. Thus,
11 was deprotected with boron tribromide, protected with
TBDMS-Cl, and boronylated to give 16 (Scheme 4).19 The
absence of signals corresponding to the boronic acid group
1
in the H NMR spectrum of 16 combined with the FD-MS
spectrum showing an m/zZ1092 (3!MK3H2O) suggested
that 16 trimerized to give cyclic boroxime structure 160.
Cross-coupling of 16 with 9 gave 17.
† CCDC 231899 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via www.ccdc.cam.ac.
uk/data_request/cif or by e-mailing data_request@ccdc.com.ac.uk.
Scheme 2.

E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
11193
2.3. Synthesis of didendrons using diamine templates
Two point covalent imprinting was examined by using 1,4-
diaminobutane (20) as a template. Although 20 likely
formed a 2:1 covalent complex with 18 (bis-carbinolamine,
see 2), it was not stable under the high-dilution conditions
needed for the intramolecular cross-linking reaction. It was
decided instead to link the two dendrons to the diamine core
through the bis-imine.20 A model study was undertaken to
find conditions under which butylamine (21) would react
with dye 1 (RZMe) to form imine 22. The most suitable
conditions found involved treating 1 with 21 and TiCl4 in
CH2Cl2,21 the product imine (22) obtained in 97% yield
(Scheme 6). Unfortunately, reaction of 18 with 1,3,5-
tris(aminomethyl)benzene in the presence of TiCl4 did not
produce the corresponding tris-imine dendrimer, rather
extensive degradation of 18 occurred.
Scheme 4.
Scheme 6.
The TBDMS groups in 17 could be removed in 77% yield
(TBAF, THF) and the resultant diol could be alkylated with
3 but in low yield despite exploring a range of conditions.
Ultimately, a deprotection—in situ alkylation protocol was
developed using KF and 18-crown-6 in THF (Scheme 5). By
this method, dendrons 18 and 19 were obtained in 44 and
54% yield, respectively. Evidence that the dye unit with-
stood the conditions of the alkylation reaction came from
the MALDI spectrum of 18, which indicated the correct
molecular weight (MWZ3004), with NaC and KC adducts
also present. Analytical size exclusion chromatography
(SEC) also indicated a molecular weight that was consistent
with alkylation product 18. 1H, 13C, and 19F NMR
spectroscopy indicated that 18 was formed with the
trifluoromethyl ketone group intact. Similarly, UV–Vis
spectroscopy indicated lmax of 18 to be 480.0 nm, consistent
with an unreacted trifluoromethyl ketone group.
In an attempt to find a more general way to attach templates
to 18 (19), an aza-Wittig strategy was chosen because of its
mild reaction conditions and compatibility with a variety of
functional groups.22 As shown in Scheme 7, this approach
was applied to 1,4-diazidobutane. The resultant didendron,
which would be imprinted with 1,4-diaminobutane, was
favored over the corresponding tridendron from 1,3,5-
tris(azidomethyl)benzene because of the known
rearrangement of aza-Wittig products of benzylamines.23
Furthermore, the smaller didendron would test the limits of
the monomolecular imprinting approach, determining
whether just two dendrons and two-point covalent binding
are sufficient for imprinting.
The synthesis of the target didendron and its subsequent
cross-linking is outlined in Scheme 7. Butane 1,4-diazide
was treated with triphenylphosphine and the resultant
bis(iminophosphorane) reacted immediately with either 18
or 19 to produce, respectively, bis-imines 23 and 24 in 69
and 32% yields. The didendrons were purified to homo-
geneity by first silica gel and then SEC. The ring closing
metathesis (RCM) mediated cross-linking of 23 and 24 was
performed at high dilution in benzene with Grubbs type I
catalyst 25. The cross-linked products, 26 and 27 were
purified by SEC giving product in 60 and 76% yield,
respectively. The extent of cross-linking in both 26 and 27
was examined by MALDI-MS. For 26 the highest
peaks corresponded to 14 cross-links (m/zZ5242.6,
MK14C2H4CNaC) and 15 cross-links (m/zZ5214.5,
MK15C2H4CNaC). In the MALDI spectrum of 26,
lower intensity peaks were also evident at m/z values
corresponding to 16 and 13 cross-links. The most intense
peak in the MALDI spectrum of 27 corresponded to 15
cross-links, while somewhat smaller peaks for 16 and 14
cross-links were also seen.
Scheme 5.

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E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
Scheme 7.
Consistent with previous investigations of cross-linked
dendrimers,7,11 the 1H NMR spectrum of 26 and 27 showed
significant broadening of signals due to the large number of
isomers formed during alkene metathesis. A new, broadened
signal in the d 5.65–5.40 ppm range is particularly
indicative of formation of the cross-links, as this peak
corresponds to the alkene protons of newly cross-linked
homoallyl ether groups. Similarly, the UV–Vis and 19F
NMR spectra of 23 (24) and 26 (27) indicated that alkene
metathesis did not affect either the azobenzene chromo-
phore or the imine linkages between the dendrimer core and
the dendrons.
spectrum of 28 was consistent with hydrolytic removal of
1,4-diaminobutane from the core of 26. MALDI also
revealed some degradation of the dendrimer’s cross-linked
periphery during the hydrolysis reaction. A distribution of
small peaks appeared below the molecular weight of fully
cross-linked isomers of 28. The molecular weight of these
peaks matches the mass of 28 with missing homoallyl
groups or their RCM counterparts. This impurity could not
be removed by silica gel chromatography, and it remained
in the sample of 28 used for complexation studies. In the
case of 27 it was found that a very short treatment with the
same aqueous acid fully removed the 1,4-diaminobutane
core, but without any degradation in the cross-linked allyl
ether periphery.
The 1,4-diaminobutane core in 26 (27) could be removed
under mild hydrolytic conditions (Scheme 7). Stirring a
solution of 26 (27) in THF with w1% aqueous HCl at room
temperature resulted in the hydrolyzed dendrimer 28 with
two unbound ketone groups in its core. The MALDI mass
Two dendrimers were prepared as controls (Scheme 8). The
first was synthesized identically to 28 except that 1,3-
bis(amino-ethyl) benzene (30) was chosen as the template

E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
11195
Scheme 8.
because diazide 31 could be readily synthesized in two steps
from commercially available 1,3-phenylenediacetic acid.4
More importantly, the availability of 28 and 32 would allow
application of a rigorous test of imprinting by comparing the
cross-reactivities of two dendrimers derived from different
templates, a method occasionally applied to MIPs.24
(RZC8H17) with primary amines in diethyl ether, and a
similar binding affinity was found.9 In our hands, titrations
of 1 (RZMe) in diethyl ether did not display clean
isosbestic behavior, possibly due to evaporation of solvent.
Ultimately THF was chosen for complexation studies
because titrations of 1 (RZMe) with butyl amine showed
both clean isosbestic points and strongly enhanced covalent
binding. Thus, addition of only 55 equiv of butyl amine to a
THF solution of 1 (RZMe) (29.6 mM) resulted in a 31.5 nm
blue shift in the absorbance spectrum of the dye. From
The second control dendrimer was prepared without a
template. Thus, cross-linking of 18 at a concentration of
10K3 M in benzene with catalyst 25 afforded a mixture of
cross-linked 18, cross-linked dimer 33, and cross-linked
trimer. Preparatory SEC readily separated the products, and
the MALDI-TOF spectrum of 33 confirmed its dimeric
structure and indicated 16 out of a possible 16 cross-links
(intermolecular and intramolecular) were formed. The
polystyrene-based molecular weight (MWPS) value of 33,
MWPSZ3646 is very close to that obtained for 28, MWPSZ
3620, and they exhibit nearly identical NMR spectra.
titration studies monitoring the loss of absorbance at lmax
Z
475 nm, a KassocZ790G210 MK1 was calculated. The
change in lmax and both 19F and 13C NMR spectra were
consistent with the formation of aminal 2 (RZMe).
In examining the cross-linked dendrimers, a simple screen-
ing assay was devised in which THF solutions of 28 were
prepared such that absorbance at 475 nm was ca. 0.4
(w20 mM). One equivalent of amine or alcohol guest was
added to each dendrimer solution, and the solutions were
mixed for 30 s. A UV–Vis spectrum was obtained for each
2.4. Complexation studies using small libraries of amine
and alcohol guests
solution, and the increase in absorbance at 425 nm (DA425
)
was recorded. As seen in Figure 2, a remarkably high level
of selectivity was observed for the simple alkyl diamine
guests.
Before performing complexation studies on the cross-linked
dendrimers, model titration experiments were carried out
using 1 (RZMe). Titration of a chloroform (CHCl3)
solution of 1 (RZMe) (15.6 mM) with 10,400 equiv of
butyl amine (21) in CHCl3 produced a 50 nm blue shift in
the dye’s absorbance spectrum. The overlaid spectra
obtained showed only an approximate isosbestic point at
438 nm, suggesting the presence of more than two discrete
species. The reactivity of 1 with 21 in CHCl3 appeared to be
quite low, and, without insuring full equilibration, a very
approximate 1:1 association constant (Kassoc) of 5 MK1 was
calculated in CHCl3.
Qualitatively, the binding profile for 29 with the same guests
and under the same conditions was very similar to that seen
in Figure 2. This result suggests that the allyl ether-based
dendrons, which are cheaper and easier to prepare,14 serve
as suitable substitutes for the homoallyl-based (Wendland-
type11) dendrons, at least in the systems studied here.
Evidence for two point covalent, but reversible, complexa-
tion through formation of a bis-aminal came from several
directions. First, a Job plot gave a maximum concentration
Mohr and co-workers performed titration studies of dye 1

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E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
Figure 2. Guest binding selectivity profile for 28. See text for details.
of complex with a 1:1 mixture of 20 and 28, consistent with
a 1:1 stoichiometry in the complex. A dilution study verified
the reversible nature of the 28$20 complex. A THF solution
of 28 (40.7 mM) and 35 (81.4 mM) gave lmax of 440 nm,
consistent with approximately 70% complexation. After the
addition of several aliquots of THF such that the
concentration of 28 was 5.1 mM and the concentration of
20 was 10.2 mM, the observed lmax shifted to 473.5 nm, near
to the lmax of uncomplexed 28. Finally, quantitative
determination of the binding constants showed a significant
increase in complex stability as a result of formation of the
second aminal.
variability can be attributed to the equilibration time used in
the binding titration. The enhanced stability of the 1$34
complex relative to 1$21 (butyl amine) was attributed to
an intramolecular hydrogen bond as in 39 and it is not
possible to rule out a 2:1 complex between 34 and 28 (29)
given the magnitude of the Kassoc for these host-
guest pairings (Scheme 9). On the other hand, the
increased stability of 28$20 and 29$20 relative to 1$20
and 28(29)$34 is consistent with two-point binding by 1,4-
diaminobutane.
In comparing the various Kassoc in Table 1, several trends are
apparent. First, 28 and 29 show very similar Kassoc values.
Although butyl amine appears to bind slightly stronger to
cross-linked dendritic host 29, its very slow reaction rate
with the dye chromophore (vide infra) meant that some
Scheme 9.
Table 1. Association constants (Kassoc) for 1, 28, and 29 and amine guestsa
Guest
Kassoc (MK1) for hosts 1 (RZMe), 28, 29
1
28
29
BuNH2 (21)
790G210
28,000G6000
N.D.
780G200
12,000b
N.D.
2300G1200
15,000G3000
26,000G3000
33,000G2500
34
35
20
4200G2600
27,000b
a At 25 8C in THF, monitoring lmaxZ475 nm with guest added to host and
waiting until full equilibration. Values for 1 taken from Ref. 25. Values
for BuNH2 complex with 28 and 29 assumed two independent binding
sites. N.D., not determined.
Is the remarkable selectivity seen in Figure 2 a result of
highly effective imprinting? As a first step toward answering
this question the binding of the same small library of guests
was examined with cross-linked dendrimer 32, which was
b Single determination.

E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
11197
Figure 3. Guest binding selectivity profile using the same guests as in Figure 2 for (a) 32 after 30 s mixing (b) 28 after 12 h mixing. In (b) bar heights are only
approximately correlated with Kassoc as a result of concentration and kinetic differences, etc. See text for additional details.
synthesized from template 31. The imprinting of 32 with 31
would be expected to produce a very different selectivity
profile and, in particular, a higher affinity for 1,3-
bis(aminoethyl)benzene (30). In fact, the qualitative selec-
tivity profile for 32 (Fig. 3a) was very similar to that
observed for 28. More striking was the fact that a similar
selectivity trend (the entire library was not examined) was
seen with 33, whose preparation occurred without any
template.
dendrons or using larger (or more) dendrons to better imbed
the reporter chromophore within the imprint.
3. Conclusions
Azo dye 1, a useful chromogenic reporter group for amines,9
was successfully linked to the focal point of dendrons 18
and 19. Conversion to bis-imine dendrimers using an aza-
Wittig protocol, followed by cross-linking of the peripheral
alkenes and hydrolytic core removal created dendrimers
capable of reporting amine and alcohol binding at the
dendrimer core. The integration of chromogenic reporter
groups represents a compelling advance in the mono-
molecular dendrimer imprinting approach,6,7 although in
this particular case the dendrimers were too small to
produce imprinting. Another key finding is that the
dendrimers containing allyl ether peripheral groups
smoothly underwent RCM-mediated cross-linking and the
resultant dendritic structures behaved analogous to their
homoallyl ether derived analogs. The allyl ether based
systems are cheaper and more readily prepared.14
The possibility that the binding selectivity observed in
Figures 2 and 3a was kinetic in origin was examined by
allowing the solutions in Figure 2 to stand for 12 h prior to
measuring the A425 value. As seen in Figure 3b many of the
diamines give enhanced signal and even some of the
monoamines and alcohols show binding. This result clearly
implicates a kinetic effect in the binding ‘selectivity’
observed at short time periods. A careful kinetic analysis25
confirmed this conclusion and further showed it to originate
in an intramolecular general base catalyzed reaction similar
to that reported by Jencks for the addition of alkane
diamines to acetyl imidazole.26 Thus, rigid diamines like 30
cannot enjoy the transition state stabilization optimized in
35 and illustrated in 40.
Cross-linked dendrimer hosts containing the (trifluoro-
acetyl) azobenzene dye described herein have the potential
to achieve selective guest binding based solely on molecular
imprinting. For this to occur, it is necessary to develop a
better understanding of the relationship between the
dendrimer size and structure, including the number and
placement of the cross-linking functionality, and the
subsequent ‘memory’ of the template molecule.
Molecular modeling of 28 (29) is challenging because there
are many isomers that may be produced in the RCM-
mediated cross-linking reaction. Nonetheless, preliminary
modeling of 28 suggests that the two dendrons may cross-
link while leaving the dye moieties at the surface. Indeed,
the fact that the azo-dye is linked to the dendron through a
biphenyl linkage means that unless this rotation is hindered
by the dendritic framework, the trifluoroacetyl groups can
very significantly adjust their separation. Under these
circumstances one would expect the relaxed selectivity
observed qualitatively. Thus, future improvements on these
systems may involve linking the dye unit more rigidly to the
Once the rules of monomolecular imprinting with dye-
functionalized dendrimers are better understood, dendrimer-
based cross-linked hosts may find applications as sensors for
biologically significant amines such as amino acids, amino
sugars and alkaloid natural products. The strategies and

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E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
synthetic pathways outlined in this report may be applied to
dendrimers containing other dye molecules which are able
to report on other functional groups. The goal of building
cross-linked dendrimer hosts capable of selectively recog-
nizing any guest molecule imaginable may indeed be within
reach.6
4.2. Synthetic procedures
4.2.1. 1-[4-(4-Dimethylaminophenylazo)phenyl]-2,2,2-
trifluoroethanone (1, RZMe). A suspension containing
120 mg (640 mmol) of 6 and 1 mL of 6 N aqueous HCl was
prepared and cooled in an ice bath for 15 min. A solution of
42 mg (609 mmol) of sodium nitrite in 500 mL of distilled
water was added slowly, dropwise to the cooled suspension.
The suspension cleared to a slightly yellow solution which
was stirred for 15 min in an ice bath. This diazonium
mixture was added slowly, dropwise to an ice-cold solution
of 810 mL (6.40 mmol) N,N-dimethylaniline in 3.5 mL of
ethanol. The ethanol solution became a deep purple-red
color. The mixture was stirred in an ice bath for 3 h. The
mixture was warmed to room temperature and stirred for an
additional 1 h. Solvent was removed under vacuum, and the
red oily residue was partitioned between 100 mL of CH2Cl2
and 100 mL of saturated aqueous Na2CO3. The organic
layer was dried over Na2SO4, filtered, and evaporated to
yield a purple oily solid which was dry-loaded onto silica
gel. Flash chromatography (5% EtOAc–petroleum ether
(PE) stepped to 25% EtOAc–PE) afforded 140 mg (69%) of
1 as a shiny, crystalline purple solid. Additional purification
was accomplished by recrystallization from 20% EtOAc–
4. Experimental
4.1. General
All reactions were performed under N2 in glassware that
was oven dried at 105 8C prior to use. The full details of the
synthesis of 3 and 4 are described elsewhere.11,14 Reagents
and solvents used in reactions were obtained from
commercial sources and were used without further purifi-
cation except as follows: tetrahydrofuran (THF) was
distilled from sodium-benzophenone; N,N-dimethylform-
˚
amide (DMF) was dried over 4 A molecular sieves;
benzene, methylene chloride (CH2Cl2), chloroform
(CHCl3) and triethylamine were distilled from CaH2,
triisopropyl borate was distilled from sodium. All reactions
were monitored by TLC using silica gel 60 F254 plastic,
aluminum, or glass plates (Merck). Flash chromatography
was performed with 32–63 mm silica gel (Merck). Prepara-
tory size-exclusion chromatography (SEC) was performed
using a 2.25 ft!50 mm column of Bio-Beads S-X1 200–
400 mesh beads (Bio-Rad) with reagent grade toluene as the
eluent.
1
hexane: mp 159–160 8C; H NMR (400 MHz, CDCl3) d
8.18 (d, 1.5H, JZ7.8 Hz), 7.94 (apparent 0dt o0f AA0XX0, 2H,
JZ8.6, 2.2 Hz), 7.92 (apparent 0dt of AA XX , 2H, JZ9.0,
2.2 Hz), 6.77 (apparent d of AA XX0, 2H, JZ9.2 Hz), 3.14
(s, 6H); 13C NMR (125 MHz, CDCl3) d 157.6, 153.6, 144.1,
131.6, 129.6, 126.3, 122.8, 111.7, 40.5; 19F NMR
(400 MHz, CDCl3) d K71.79; IR (film) 1700.4, 1610.7,
1595.2; UV–Vis (EtOAc) lmaxZ472; MS (EI) m/zZ321.1
(MC); Anal. Calcd for C16H10F3N3O: C, 59.81; H, 4.39; N,
13.08. Found: C, 59.61; H, 4.19; N, 12.90.
1H NMR, 13C NMR, and 19F NMR data were obtained on
either 400 or 500 MHz Varian U400, U500, and 500NB
instruments. 1H NMR spectra obtained in CDCl3 were
referenced to 7.26 ppm. 13C NMR spectra obtained in
CDCl3 were referenced to 77.23 ppm. 19F NMR data are
either unreferenced or referenced to an external 1.0%
solution of trifluoroacetic acid. Chemical shifts are reported
in parts per million (ppm) and coupling constants are
reported in Hertz (Hz). IR spectra were collected on a
4.2.2. 1-(4-Amino-3-iodo-phenyl)-2,2,2-trifluoroetha-
none (7). To a solution of 168 mg (890 mmol) 4-amino-
a,a,a-trifluoroacetophenone 6 in 8 mL of 3 N aqueous HCl
and 2 mL water was added 40 mL (800 mmol) of iodine
monochloride. The resultant mixture was stirred at room
temperature for 12 h, at which time TLC (1:4 EtOAc–PE)
indicated nearly complete consumption of 6. The reaction
mixture was partitioned between 30 mL of EtOAc and
30 mL water, and saturated aqueous NaHCO3 was added
slowly to the suspension to neutralize. The organic layer
was separated, and the remaining aqueous layer was
extracted with 30 mL of EtOAc. The combined organic
layers were dried over anhydrous MgSO4, and then dry
loaded onto silica gel. Flash chromatography (15% EtOAc–
PE stepped to 20% EtOAc–PE) was used to isolate 154 mg
(62%) of 7 as a white solid. Further purification was
accomplished by recrystallization from 10% EtOAc–PE:
mp 114–116 8C; 1H NMR (400 MHz, CDCl3) d 8.37 (d, 1H,
JZ1.0 Hz), 7.85 (dq, 1H, JZ8.6, 0.7 Hz), 6.74 (d, 1H, JZ
8.6 Hz), 4.96 (bs, 2H); 13C NMR (125 MHz, CDCl3) d 177.3
(q, JZ34 Hz), 164.7, 153.1, 142.6, 132.5, 121.5, 117.1 (q,
JZ291 Hz), 113.2; MS (EI) m/zZ315.0 (MC), 246.0
(MCKCF3); Anal. Calcd for C8H5F3NIO: C, 30.50; H,
1.60; N, 4.45. Found: C, 30.39; H, 1.44; N, 4.33.
Mattson FTIR 5000 with major bands reported in cmK1
.
UV–Vis spectra were obtained using a Shimadzu UV-
2501PC recording spectrophotometer. Analytical SEC, used
to determine the purity of final dendrimer products, was
performed using a 2! styragel HR3, 1! styragel HR4E
column in THF with a 1.0 mL/min flow rate. Peak detection
was achieved using a Viscotek triple array 300 refractive
index detector, and SEC-derived molecular weights are
based on calibration with linear polystyrene. FDMS,
FABMS, EIMS data were collected by the mass spec-
trometry service at the University of Illinois, and MALDI-
TOF spectra were obtained using an Applied Biosystems
Voyager-DE STR mass spectrometer. The spectra of
dendrimers were obtained in a 2-(4-hydroxyphenylazo)-
benzoic acid (HABA) matrix. Elemental analysis was
performed by the microanalytical laboratory at the
University of Illinois. Melting points were measured with
a Thomas Hoover melting point apparatus and are
uncorrected.
Detailed procedures for the determination of Kassoc values
and for performing kinetic measurements can be found in
Refs. 4 and 25.
1-(4-Amino-3,5-diiodo-phenyl)-2,2,2-trifluoroethanone (8)
was isolated as a faster eluting side product during flash
1
chromatography: H NMR (400 MHz, CDCl3) d 8.32 (d,

E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
11199
2H, JZ0.7 Hz), 5.40–5.50 (bs, 2H); MS (EI) m/zZ440.9
(MC), 371.9 (MCKCF3).
6H), 3.07 (s, 6H); 13C NMR (125 MHz, CDCl3) d 180.2 (q,
JZ34 Hz), 158.1, 156.1, 153.0, 144.4, 135.5, 133.6, 130.0,
129.8, 129.2, 125.9, 117.8 (q, JZ292 Hz), 116.7, 111.5,
103.9, 56.0, 40.4; UV–Vis (CH2Cl2) lmaxZ460.5 nm; MS
(FAB) m/zZ458.2 (MCHC).
4.2.3. 1-[4-(4-Dimethylaminophenylazo)-3-iodo-phenyl]-
2,2,2-trifluoroethanone (9).
A solution of 50 mg
(720 mmol) of sodium nitrite in 5 mL of deionized water
was added slowly, dropwise to 10 mL of an ice-cold
solution of 235 mg (746 mmol) of 7 in a 6 N aqueous
solution of HCl. The resulting suspension was stirred at 0 8C
until it cleared to a yellow solution. This solution was added
slowly, dropwise to an ice-cold solution of 700 mL
(5.5 mmol) N,N-dimethylaniline in 25 mL of absolute
ethanol. During the addition process, the reaction mixture
became a deep red purple color. The mixture was warmed to
room temperature and stirred for 12 h. The mixture was
concentrated to a viscous dark red oil, which was partitioned
between 50 mL of CH2Cl2 and 50 mL of saturated aqueous
NaHCO3. The aqueous layer was extracted with two
additional 50 mL portions of CH2Cl2. The combined
organic layers were evaporated with silica (dry load).
Flash chromatography (15% EtOAc–PE stepped to 25%
EtOAc–PE) afforded 145 mg (44%) of 9 as a crystalline
purple solid. Additional purification was accomplished by
recrystallization from 30% EtOAc–PE to give purple
4.2.5. 1-[4-(4-Dimethylaminophenylazo)-3-(3,5-dimeth-
oxyphenyl)phenyl]-2,2,2-trifluoroethanone (14). To a
solution of 100 mg (223 mmol) 9 in 11 mL of benzene was
added 5.5 mL of a 2 M aqueous solution of Na2CO3. To the
resultant emulsion was added 21 mg (18 mmol) of
Pd(PPh3)4. The reaction mixture was charged with nitrogen,
and a solution of 160 mg (880 mmol) of 10 in 25 mL of
ethanol was added via syringe. The reaction mixture was
heated at 50–55 8C for 4 h at which time TLC (CH2Cl2)
indicated complete formation of product. The mixture was
cooled to room temperature and 2 mL of a 15% (v/v)
aqueous solution of H2O2 was added. The mixture was
stirred at room temperature for an additional 1 h, and then
partitioned between 50 mL water and 50 mL CH2Cl2. The
aqueous layer was extracted with 50 mL CH2Cl2. The
combined organic layers were dried over Na2SO4 and
evaporated over silica gel (dry load). Flash chromatography
with CH2Cl2 elution afforded 82 mg (80%) of 14 as a red
1
1
solid: mp 153–155 8C; H NMR (400 MHz, CDCl3) d 8.25
needles: mp 142–143 8C; H NMR (400 MHz, CDCl3) d
(s, 1H),08.11 (dq, 1H, JZ8.5, 0.7 Hz), 7.79 (apparent dt of
AA0XX , 2H, JZ9.3, 3.2 Hz), 7.79 (d, 1H, JZ8.5 Hz), 6.71
(apparent dq of AA0XX0, 2H, JZ9.5, 3.2 Hz), 6.64 (d, 2H,
JZ2.4 Hz), 6.54 (t, 2H, JZ2.2 Hz), 3.79 (s, 6H), 3.11 (s,
6H); 13C NMR (125 MHz, CDCl3) d 180.1 (q, JZ
180.1 Hz), 160.4, 155.0, 153.4, 144.5, 140.0, 139.9, 133.0,
130.2, 129.4, 126.5, 117.4, 117.0 (q, JZ29 Hz), 109.1,
100.5, 55.6, 40.5; MS (FAB) m/zZ458.2 (MCHC).
8.63 (d, 1H, JZ1.0 Hz), 8.06 (d, 1H, JZ1.0 Hz), 7.97 (dt,
2H, JZ9.3, 3.2 Hz), 7.67 (d, 1H, JZ8.6 Hz), 6.77 (dt, 2H,
JZ9.3, 3.2 Hz), 3.15 (s, 6H); 13C NMR (125 MHz, CDCl3)
d 179.0 (q, JZ35.9 Hz), 156.3, 153.9, 144.2, 141.8, 131.5
(q, JZ233 Hz), 130.9, 130.9, 127.1, 117.6, 111.7, 101.0,
40.5; UV–Vis (CHCl3) lmaxZ495.5; MS (EI) m/zZ447.2
(MC); Anal. Calcd for C16H13F3N3IO: C, 42.97; H, 2.93; N,
9.40. Found: C, 42.78; H, 2.90; N, 9.14.
4.2.6. 1,3-Bis-(tert-butyldimethylsilyloxy)-5-iodobenzene
(15). A solution of 2.05 g (8.70 mmol) 5-iodoresorcinol,
5.0 g (33 mmol) of tert-butyldimethylsilyl chloride, 2.0 g
(29 mmol) of imidazole, and 25 mL of DMF was stirred at
room temperature for 36 h. The reaction mixture was poured
into 80 mL of 5 8C water and the resulting suspension was
extracted twice with 80 mL portions of methylene chloride.
The combined organic layers were dried over Na2SO4,
filtered, and evaporated to yield an amber colored oil. Flash
chromatography (5% EtOAc–PE) afforded 4.03 g (100%) of
15 as a clear, slightly yellow oil: 1H NMR (400 MHz,
CDCl3) d 6.83 (d, 2H, JZ2.2 Hz), 6.27 (t, 1H, JZ2.2 Hz),
0.96 (s, 19H), 0.86 (s, 12H); 13C NMR (100 MHz, CDCl3) d
157.2, 123.1, 112.2, 93.7, 25.8, 18.4, K4.3; MS (EI) m/zZ
464.1 (MC), 407 (MCKtert-butyl).
4.2.4. 1-[4-(4-Dimethylaminophenylazo)-3-(2,6-dimeth-
oxyphenyl) phenyl]-2,2,2-trifluoroethanone (13). To a
solution of 150 mg (0.340 mmol) 9 in 16 mL of benzene
was added 8.2 mL of a 2 M aqueous solution of Na2CO3. To
the resultant emulsion was added 16 mg (14 mmol) of
Pd(PPh3)4. The reaction mixture was charged with nitrogen,
and a solution of 125 mg (690 mmol) 12 in 20 mL of ethanol
was added via syringe. The reaction mixture was heated at
50–55 8C for 12 h. The reaction mixture was cooled to room
temperature and stirred for 12 h. TLC (15% EtOAc–PE)
indicated little formation of a new product. An additional
125 mg (690 mmol) of 12 and an additional 16 mg
(14 mmol) of Pd(PPh3)4 were added to the reaction mixture
and stirring at 50 8C continued for 12 h. The reaction
mixture was cooled to room temperature and 1 drop of 15%
(v/v) aqueous H2O2 was added. The mixture was stirred at
room temperature for 1 h and partitioned between 50 mL of
water and 50 mL of diethyl ether. The aqueous layer was
extracted with 50 mL of EtOAc. The organic layer was
dried over MgSO4 and evaporated. The product was dry
loaded onto silica gel and flash chromatography (15%
EtOAc–PE) afforded 130 mg (84%) of 13 as a purple solid.
X-ray quality crystals were obtained by dissolving 13 in
20% EtOAc–PE and storing the resultant solution at 0 8C in
a capped vial for approximately 1 month. 1H NMR
(500 MHz, CDCl3) d 8.16 (s, 1H), 8.10 (dq, JZ8.6,
1.1 Hz, 1H), 7.79 (d, 1H, JZ8.6 Hz), 7.65 (AA ‘XX’,
apparent dt, JZ9.2, 3.2 Hz, 2H), 7.35 (t, JZ8.4 Hz, 2H)
6.67 (d, 2H, JZ10.0 Hz), 6.65 (d, 2H, JZ8.4 Hz), 3.64 (s,
4.2.7. 1,3-Bis-(tert-butyldimethylsilyloxy)phenylboronic
acid (16). To a solution of 3.1 g (6.7 mmol) of 15 in
40 mL of THF cooled to K78 8C was added dropwise
15 mL (10.5 mmol) of a 1.3 M solution of n-butyl lithium in
hexane. The resulting solution was stirred at K78 8C for
30 min. The cold solution was added rapidly, dropwise via a
canula to a K78 8C solution of 7 mL of triisopropyl borate
in 4 mL of THF. Care was taken to avoid contamination of
reagents with frost building up on the canula during the
dropwise addition process. The mixture was stirred for
10 min at K78 8C and at room temperature overnight. The
mixture was partitioned between 25 mL of a 1% (v/v)
aqueous solution of HCl and 250 mL EtOAc. The organic

11200
E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
layer was separated and the aqueous layer was extracted
with an additional 100 mL of EtOAc. The combined organic
layers were dried over Na2SO4, filtered, and evaporated to
yield an orange oily solid. The crude product was dry loaded
onto silica and flash chromatography (15% EtOAc-PE
stepped to 35% EtOAc–PE) afforded 1.44 g (56%) of 16 as a
white powder. Additional purification was accomplished by
precipitation from 1:1 EtOAc–PE: mp 234–240 8C; 1H
NMR (400 MHz, CDCl3) d 7.29 (d, 2H, JZ2.4 Hz), 6.59 (t,
1H, JZ2.4 Hz), 1.03 (s, 18H), 0.26 (s, 12H); 13C NMR
(100 MHz, CDCl3) d 156.7, 120.2, 117.0, 26.0, 18.5, K4.1;
MS (FD) m/zZ1092 (3!MK3!H2O); Anal. Calcd for
C54H99B3O9Si6: C, 59.32; H, 9.13. Found: C, 58.36; H,
9.06.
chromatography (PE stepped to 50% EtOAc–PE) afforded
660 mg (88%) of 18 as a viscous red oil. Additional
purification was accomplished using preparative SEC (yield
from prep. SEC was reduced to 44%): 1H NMR (400 MHz,
CDCl3) d 8.25 (s, 1H), 8.08 (d, 1H, JZ8.8 Hz), 7.79 (d, 2H,
JZ9.3 Hz), 7.76 (d, 1H, JZ8.6 Hz), 6.76 (d, 2H, JZ
1.9 Hz), 6.71 (t, 1H, JZ2.2 Hz), 6.65 (d, 8H, JZ2.0 Hz),
6.65–6.68 (m, 4H), 6.64 (d, 2H, JZ7.3 Hz), 6.55 (d, 19H,
JZ2.0 Hz), 6.52–6.55 (bt, 6H), 6.39 (t, 9H, JZ2.2 Hz),
5.87 (ddt, 18H, JZ17.1, 10.3, 6.6 Hz), 5.14 (ddt, 19H, JZ
17.1, 1.7, 1.2 Hz), 5.08 (dd, 19H, JZ10.3, 1.7 Hz), 4.96 (s,
4H), 4.92 (s, 25H), 3.97 (t, 36H, JZ6.8 Hz), 2.92 (s, 5H),
2.51 (q, 36H, JZ6.6 Hz); 13C NMR (126 MHz, CDCl3) d
180.0 (d, JZ35.0 Hz), 160.5, 160.3, 159.5, 155.0, 144.5,
139.9, 139.5, 139.4, 139.3, 134.6, 132.9, 129.4, 128.4,
126.5, 125.5, 117.3, 117.0 (d, JZ209 Hz), 111.6, 106.7,
106.6, 106.5, 106.1, 102.0, 101.8, 101.7, 101.1, 70.4, 70.2,
67.4, 40.3, 33.8; 19F NMR (400 MHz, CDCl3) d K71.79;
UV–Vis (CHCl3) lmaxZ480; MS (MALDI-TOF) m/zZ
3004.21 (MC); 3026.7 (MCNaC); 3043.8 (MCKC).
4.2.8. 1-[4-(4-Dimethylaminophenylazo)-3-(3,5-bis(tert-
butyldimethylsilyloxy)phenyl)phenyl]-2,2,2-trifluoroeth-
anone (17). To a solution of 500 mg (1.12 mmol) of 9 in
65 mL of benzene was added 32 mL of a 2 M aqueous
solution of Na2CO3. To the resultant emulsion was added
60 mg (52 mmol; 5 mol%) of Pd(PPh3)4. The reaction
mixture was charged with nitrogen, and a solution of
490 mg (1.28 mmol) of 16 in 25 mL ethanol was added via
syringe. The mixture was heated at 50–55 8C for 3 h. The
mixture was cooled to room temperature and stirred for
12 h. TLC (20% EtOAc–PE) indicated that some 9 still
remained so an additional 10 mg (8 mmol) of Pd(PPh3)4 and
50 mg (130 mmol) of 16 was added. Heating at 50–55 8C
resumed for 2 h. The reaction mixture was cooled to room
temperature and 1 mL of a 15% (v/v) aqueous solution of
H2O2 was added. The mixture was stirred at room
temperature for 1 h, and partitioned between 100 mL of
brine and 100 mL of diethyl ether. The ether layer was
washed with 100 mL water. The combined organic layer
was dried over Na2SO4, filtered, and evaporated to a red
film. The product was dry loaded onto silica and flash
chromatography (20% EtOAc–PE stepped to 25% EtOAc–
PE) afforded product which was further purified by
precipitation from PE to afford 660 mg (89%) of 17 as a
red powder: mp 100–102 8C; 1H NMR (400 MHz, CDCl3) d
8.18 (s, 1H), 8.09 (d, 1H, JZ8.6 Hz), 7.78 (dt, 2H, JZ3.2,
9.0 Hz), 7.74 (d, 1H, JZ8.6 Hz), 6.69 (dt, 2H, JZ3.2,
9.3 Hz), 6.58 (d, 2H, JZ2.2 Hz), 6.39 (t, 1H, JZ2.2 Hz),
3.10 (s, 6H), 0.96 (s, 18H), 0.18 (s, 11H); 13C NMR
(125 MHz, CDCl3) d 180.2 (q, JZ35.0 Hz). 156.2, 155.1,
153.3, 144.7, 139.9, 139.8, 133.1, 130.0, 129.4, 126.5,
117.4, 116.2, 117.0 (q, JZ291.8 Hz), 116.2, 111.6, 40.5,
27.2, 25.9, 18.4, K4.2; UV–Vis (CHCl3) lmaxZ495.5; MS
(FAB) m/zZ658.3 (MCHC); Anal. Calcd for C34H46F3-
N3O3Si2: C, 62.07; H, 7.05; N, 6.39. Found: C, 62.02; H,
7.10; N, 6.45.
4.2.10. 1-[4-(4-Dimethylaminophenylazo)-3-[{3,5-bis-
[3,5-bis(3,5-bis(2-propene-1-oxy)benzyloxy)benzyloxy]-
benzyloxy}phenyl]-2,2,2-trifluoroethanone (19). To
2.55 g (2.0 mmol) of 4 in 100 mL of THF was added
340 mg (5.9 mmol) of KF, 110 mg (410 mmol) of 18-crown-
6, and 530 mg (810 mmol) of 17. The mixture was heated to
60 8C for 16 h and an additional 178 mg (3.1 mmol) of KF
and 54 mg (200 mmol) of 18-crown-6 were added. The
mixture was stirred for an additional 24 h. The solvent was
removed at reduced pressure and the resultant red oil was
loaded onto a silica gel plug and eluted with 30% EtOAc–
PE. The crude product was further purified by preparative
1
SEC to afford 1.20 g (54%) of 19 as a red oil: H NMR
(400 MHz, CDCl3) d: 8.25 (d, 1H, JZ1.2 Hz), 8.09 (dd, 1H,
JZ9.6, 1.2 Hz), 7.80 (dt, 2H, JZ9.6, 2.4 Hz), 7.78 (d, 1H,
JZ8.8 Hz), 6.77 (d, 2H, JZ2.4 Hz), 6.66 (d, 8H, JZ
2.0 Hz), 6.58 (d, 18H, JZ2.4 Hz), 6.58 (d, 1H, JZ2.4 Hz),
6.44 (t, 8H, JZ2.4 Hz), 6.03 (ddt, 16H, JZ17.2, 10.4,
5.2 Hz), 5.34 (ddt, 16H, JZ17.2, 1.6, 1.2 Hz), 5.27 (ddt,
16H, JZ10.4, 1.6, 1.2 Hz), 4.94 (s, 24H), 4.50 (dt, 32H, JZ
5.2, 1.6 Hz), 2.94 (s, 6H); 13C NMR (100 MHz, CDCl3) d:
160.3, 160.2, 160.1, 159.5, 153.3, 144.5, 139.5, 139.2,
133.3, 129.4, 118.0, 111.7, 106.7, 106.6, 106.5, 106.4,
101.8, 101.7, 101.5, 70.4, 70.2, 69.1, 40.3; 19F NMR
(500 MHz, CDCl3) d: K71.40; UV–Vis (THF) lmax
Z
480.5; MS (MALDI-TOF) m/z 2782.0 (MC), 2805.0 (MC
NaC), 2821.4 (MCKC); SEC (THF) calcd MWZ3380.
Additionally 207 mg (21%) of the monoalkylated product
1
was obtained as a red oil: H NMR d 8.25 (d, 1H, JZ
1.2 Hz), 8.09 (dd, 1H, JZ9.6, 1.2 Hz), 7.80 (dt, 2H, JZ9.6,
2.4 Hz), 7.78 (d, 1H, JZ8.8 Hz), 6.77 (d, 2H, JZ2.4 Hz),
6.66 (d, 4H, JZ2.0 Hz), 6.58 (d, 9H, JZ2.4 Hz), 6.58 (d,
1H, JZ2.4 Hz), 6.44 (t, 4H, JZ2.4 Hz), 6.03 (ddt, 8H, JZ
17.2, 10.4, 5.2 Hz), 5.34 (ddt, 8H, JZ17.2, 1.6, 1.2 Hz),
5.27 (ddt, 8H, JZ10.4, 1.6, 1.2 Hz), 4.94 (s, 12H), 4.50 (dt,
16H, JZ5.2, 1.6 Hz), 2.94 (s, 6H).
4.2.9. 1-[4-(4-Dimethylaminophenylazo)-3-[{3,5-bis[3,5-
bis(3,5-bis(3-butene-1-oxy)benzyloxy)benzyloxy]benzyl-
oxy}phenyl]-2,2,2-trifluoroethanone (18). To a solution of
680 mg (500 mmol) of 3 in 35 mL of THF was added 32 mg
(550 mmol) of potassium fluoride, 54 mg (200 mmol) of 18-
crown-6, and 163 mg (248 mmol) of 17. The resultant
solution was stirred at 60 8C for 29 h. Twice over this
period, additional portions of 32 mg (550 mmol) of potas-
sium fluoride, and 54 mg (200 mmol) of 18-crown-6 were
added to the mixture. With minimal heating, the mixture
was evaporated over silica (dry-load). Flash
4.2.11. {4-[4-(1-Butylimino-2,2,2-trifluoroethyl)phenyl-
azo]phenyl}dimethylamine (22). To a solution of 150 mg
(467 mmol) of 1 in 8 mL of CH2Cl2 was added 150 mL
(1.52 mmol) of n-butyl amine. The resultant mixture was
cooled over an ice bath, and 260 mL (260 mmol) of a 1.0 M

E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
11201
CH2Cl2 solution of titanium tetrachloride was added slowly,
dropwise. During the dropwise addition process, the
solution became a lighter orange-red color and much
vapor evolved. The mixture warmed to room temperature,
and stirred for 12 h. An additional 100 mL (1.00 mmol) of
n-butyl amine and 240 mL (0.240 mmol) of a 1.0 M titanium
tetrachloride solution in CH2Cl2 were added to the mixture
which was stirred at room temperature for 2 h. The mixture
was filtered through a celite plug, the solvent was
evaporated, and the orange-red residue was re-dissolved in
diethyl ether. The solution was passed through another
celite plug, and solvent was evaporated to afford 171 mg
(97%) of 22 as a waxy, semi-crystalline red solid: mp 73–
bis(triphenylphosphoranylidene) was prepared by dis-
solving 70 mg (500 mmol) of 1,4-diazidobutane in 20 mL
of diethyl ether and adding 260 mg (1.00 mmol) of
triphenylphosphine. The mixture was heated to 30 8C for
5 h, cooled to room temperature, and evaporated to afford
crude yellow crystals weighing 300 mg (100%): 1H NMR d
7.61 (m, 12H), 7.46 (m, 6H), 7.39 (m, 12H), 3.03 (dt, 4H,
JZ18.5, 3.5 Hz), 1.58 (q, 4H, JZ3.5 Hz); MS (FD) m/z 609
(MC). To a solution of 300 mg (110 mmol) of 19 in 10 mL
of benzene was added 33 mg (54 mmol) of the bis-phosphor-
anylidene. The mixture was heated at 65 8C for 24 h, cooled
to room temperature, and the benzene evaporated. The
crude product was subjected to a silica gel plug eluted with
50% EtOAc–PE. The crude product purified by preparative
SEC to afford 97 mg (32%) of 24 as an orange oil: 1H NMR
(500 MHz, CDCl3) d 7.76 (d, 4H, JZ9.0 Hz), 7.71 (d, 2H,
JZ1.5 Hz), 7.41 (dd, 2H, JZ8.0, 1.5 Hz), 7.22 (dd, 2H, JZ
8.0, 1.5 Hz), 6.74 (d, 4H, JZ2.0 Hz), 6.63 (d, 28H, JZ
2.0 Hz), 6.55 (d, 32H, JZ2.0 Hz), 6.51 (t, 14H, JZ2.0 Hz),
6.41 (t, 16H, JZ2.0 Hz), 6.00 (ddt, 32H, JZ17.5, 10.5,
5.5 Hz), 5.36 (ddt, 32H, JZ17.5, 1.5, 1.5 Hz), 5.24 (ddt,
32H, JZ10.5, 1.5, 1.5 Hz), 4.91 (s, 48H), 4.99 (s, 8H), 4.47
(dt, 64H, JZ5.5, 1.5 Hz), 3.47 (m, 4H), 2.88 (s, 12H), 1.70
(m, 4H); 13C NMR (100 MHz, CDCl3) d 160.3, 160.2,
160.1, 159.5, 139.4, 139.3, 125.9, 106.7, 106.4, 101.9,
101.6, 70.2, 69.1, 69.0, 40.2; 19F NMR (500 MHz, CDCl3) d
K70.869; MS (MALDI-TOF) m/z 5615.6 (MC), 5638.4
(MCNaC), 5650.8 (MCKC); SEC (toluene) MWPSZ
5616.
1
74 8C; H NMR (400 MHz, CDCl3) d 7.91 (d, 2H, JZ
8.1 Hz), 7.91 (d, 2H, JZ9.0 Hz), 7.35 (d, 2H, JZ8.3 Hz),
6.76 (apparent d of AA0XX0, 2H, JZ9.0 Hz), 3.44 (td, 2H,
JZ7.1, 1.7 Hz), 3.10 (s, 6H), 1.66 (quintet, 2H, JZ7.3 Hz),
1.31 (sextet, 2H, JZ7.8 Hz), 0.89 (t, 3H, JZ7.3 Hz); 13C
NMR (100 MHz, CDCl3) d 157.9 (d, JZ34 Hz), 154.1,
153.0, 143.7, 130.9, 128.8, 125.6, 123.1 (q, JZ300 Hz),
122.5, 111.6, 53.4, 40.5, 32.5, 20.6, 14.0; IR (film) 1700.4,
1610.7, 1595.2; MS (EI) m/zZ376.3 (MC).
4.2.12. N,N0-Bis-{1-[4-(4-dimethylaminophenylazo)-3-
[{3,5-bis[3,5-bis(3,5-bis(3-buteneoxy)benzyloxy)benzyl-
oxy]benzyloxy}phenyl]-phenyl]-2,2,2trifluoroethylid-
ene}butane-1,4-diamine (23). A solution of 19 mg
(73 mmol) of triphenylphosphine in 1 mL of diethyl ether
was added in portions to a solution of 5 mg (40 mmol) of
1,4-diazidobutane in 1 mL of diethyl ether. The resulting
solution was stirred at 35 8C for 2.5 h. Ether was evaporated
and the residue was immediately combined with a solution
of 225 mg (75 mmol) of 18 in 5 mL of benzene. The
resultant mixture was refluxed for 17 h, cooled to room
temperature, and the solvent removed to afford an orange oil
which was partially purified on a silica plug eluting with a
solvent mixture of 40% EtOAc–0.5% triethylamine-PE. The
eluted orange-red material was further purified using
preparative SEC. SEC fractions containing pure dendrimer
were concentrated, and fractions containing impure den-
drimer were subjected to additional preparative SEC runs.
The combined purified fractions afforded 180 mg (69%) of
23 as an orange oil: 1H NMR (400 MHz, CDCl3) d 7.79 (d,
4H, JZ9.0 Hz), 7.73 (d, 2H, JZ8.3 Hz), 7.44 (s, 2H), 7.23
(dd, 2H, JZ6.8, 1.2 Hz), 6.76 (d, 4H, JZ2.2 Hz), 6.69 (bt,
2H, JZ1.8 Hz), 6.65 (d, 30H, JZ2.2 Hz), 6.64 (d, 4H, JZ
10 Hz), 6.55 (d, 36H, JZ2.2 Hz), 6.54 (t, 12H, JZ2.4 Hz),
6.40 (t, 18H, JZ2.2 Hz), 5.87 (ddt, 32H, JZ17.1, 10.5,
6.6 Hz), 5.15 (ddt, 34H, JZ17.1, 1.7, 1.5 Hz), 5.09 (ddt,
34H, JZ10.3, 1.7, 1.2 Hz), 4.94 (s, 8H), 4.92 (s, 50H), 3.97
(t, 72H, JZ6.6 Hz), 3.49 (bt, 4H), 2.89 (s, 12H), 2.50 (q,
72H, JZ6.6 Hz), 1.72 (m, 4H); 13C NMR (126 MHz,
CDCl3) d 160.5, 160.3, 159.5, 139.5, 139.3, 139.2, 134.6,
129.7, 125.9, 117.3, 111.6, 106.7, 106.1, 101.8, 101.6,
101.1, 70.4, 70.2, 67.4, 40.2, 33.8, 28.3; 19F NMR
4.2.14. Cross-linking of dendrimer 23 (26). To a solution
of 110 mg (18 mmol) of 23 in 1.8 L of benzene was added
38 mg (46 mmol, 8 mol% per alkene) of 25. The resulting
solution was stirred at room temperature for 24 h. The
mixture was slowly poured through a silica gel plug with
benzene. A dark black layer remained on the top of the silica
plug. An orange band was eluted from this top layer with
500 mL of 5% EtOAc–CH2Cl2. The orange colored eluent
was collected and evaporated to a thick brown oil. The crude
product was redissolved in 250 mL of benzene and filtered
through another silica gel plug using 5% EtOAc–CH2Cl2 as
the eluent. Concentration of the orange colored eluent
afforded an orange oil. Two successive preparative SEC
columns afforded 60 mg (60%) of 26 as a yellow-orange oil:
1H NMR (400 MHz, CDCl3) d 7.80–7.60 (bs, 8H), 6.70–
6.20 (bd, 85H), 6.00–5.80 (bs, 8H), 5.70–5.40 (bs, 28H),
5.20–5.00 (bs, 13H), 5.00–4.40 (bs, 55H), 4.10–3.60 (s,
64H), 3.60–3.50 (bs, 12H), 2.90–2.60 (bs, 14H), 2.60–2.20
(bs, 61H); 19F NMR (400 MHz, CDCl3) d K70.93, K71.40;
UV–Vis (CHCl3) lmaxZ436.5; MS (MALDI-TOF) m/zZ
5640.0 (16 cross-linksCNaC), 5667.0 (15 cross-linksC
NaC), 5694.3 (14 cross-linksCNaC), 5706.6 (14 cross-
linksCKC).
4.2.15. Cross-linking of dendrimer 24 (27). To a solution
of 140 mg (25 mmol) of 24 in benzene was added 53 mg
(64 mmol, 8 mol% per alkene) of 25. The reaction was
stirred at room temperature for 24 h and slowly poured
through a 3 cm !3 in. silica gel plug equilibrated with
benzene. The column was eluted with 1.0 L of 5% EtOAc–
CH2Cl2. The brown colored eluent was collected and
evaporated to an brown oil which was redissolved in
500 mL benzene and filtered through another silica gel plug
(400 MHz, CDCl3) d K71.46; UV–Vis (CHCl3) lmax
Z
435.5; MS (MALDI-TOF) m/zZ6061.99 (MC); 6085.57
(MCNaC); 6100.91 (MCKC).
4.2.13. N,N0-Bis-{1-[4-(4-dimethylaminophenylazo)-3-
[{3,5-bis[3,5-bis(3,5-bis(2-propeneoxy)benzyloxy)benz-
yl-oxy]benzyloxy}phenyl]-phenyl]-2,2,2-trifluoroethyli-
dene}-butane-1,4-diamine (24). 1,4-Butanediamine, N,N0-

11202
E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
eluting with 5% EtOAc–CH2Cl2. The product was evapor-
ated to an orange oil. Two successive preparative SEC
columns afforded 98 mg (76%) of 27 as a yellow-orange oil:
1H NMR (400 MHz, CDCl3) d 7.80–7.60 (bs, 10H), 6.70–
6.20 (bd, 94H), 6.00–5.60 (bs, 32H), 5.20–5.00 (bs, 56H),
5.00–4.40 (bs, 64H), 3.60–3.10 (bs, 4H), 2.90–2.60 (bs,
12H), 1.80–1.60 (bs, 4H); 19F NMR (400 MHz, CDCl3) d
K70.88, K71.34; UV–Vis (THF) lmaxZ443.5; MS
(MALDI-TOF) m/zZ5186.4 (16 cross-linksCNaC),
5214.5 (15 cross-linksCNaC), 5230.6 (15 cross-linksC
KC), 5242.6 (14 cross-linksCNaC); SEC (toluene)
MWPSZ2460.
extracted with 50 mL of ether, and the combined organic
layers were washed with 50 mL of a saturated aqueous
solution of sodium bicarbonate. The organic layers were
dried over Na2SO4, filtered, and evaporated to yield a
yellow oil. Flash chromatography using 25% EtOAc–PE as
the eluent isolated 820 mg (63%) 31 as a clear oil: 1H NMR
(400 MHz, CDCl3) d 7.28 (t, 1H, JZ7.6 Hz), 7.11 (dd, 2H,
JZ7.6, 1.5 Hz), 7.08 (t, 1H, JZ1.5 Hz), 3.51 (t, 4H,
JZ7.1 Hz), 2.89 (t, 4H, JZ7.1 Hz); MS (EI) m/zZ131.8
(MK2N3).
4.2.19. N,N0-Bis-{1-[4-(4-dimethylaminophenylazo)-3-
[{3,5-bis[3,5-bis(3,5-bis(3-buteneoxy)benzyloxy)benzyl-
oxy]benzyloxy}phenyl]-phenyl]-2,2,2-trifluoroethylid-
ene}-1,3-bis(aminoethyl)benzene (32). A solution of
25 mg (95 mmol) of triphenylphosphine in 2 mL of diethyl
ether was added in portions to a solution of 10 mg (46 mmol)
of 31 in 1 mL of diethyl ether. The resulting solution was
stirred at 35 8C for 2.5 h. The solvent was evaporated and
the residue was immediately combined with a solution of
410 mg (136 mmol) 18 in 10 mL of benzene. The mixture
was refluxed for 24 h, cooled to room temperature and
concentrated to an orange oil which was partially purified on
a silica plug eluting with a solvent mixture of 30% EtOAc–
0.1% triethylamine-PE. The eluted orange-red material was
further purified using preparative SEC. SEC fractions
containing pure dendrimer were concentrated, and fractions
containing impure dendrimer were subjected to additional
preparative SEC runs. Combined purified fractions from all
SEC runs provided 120 mg (42%) of product as an orange
oil: 1H NMR (400 MHz, CDCl3) d 7.75 (d, 4H, JZ9.0 Hz),
7.57 (d, 2H, JZ8.1 Hz), 7.20 (s, 2H), 7.08 (t, 1H, JZ
7.4 Hz), 6.89 (d, 2H, JZ7.6 Hz), 6.84 (s, 1H), 6.76 (dd, 2H,
JZ8.3, 1.5 Hz), 6.69 (d, 5H, JZ2.0 Hz), 6.66 (bt, 2H, JZ
2.0 Hz), 6.63 (d, 27H, JZ2.2 Hz), 6.60 (d, 4H, JZ9.3 Hz),
6.53 (d, 35H, JZ2.2 Hz), 6.54 (m, 14H), 6.40 (t, 17H, JZ
2.2 Hz), 5.85 (ddt, 32H, JZ17.1, 10.3, 6.6 Hz), 5.13 (ddt,
35H, JZ17.1, 1.9, 1.5 Hz), 5.06 (ddt, 35H, JZ10.3, 1.9,
1.2 Hz), 4.94 (s, 8H), 4.92 (s, 48H), 3.97 (t, 70H, JZ
6.8 Hz), 3.67 (t, 2H, JZ6.9 Hz), 2.91 (t, 4H, JZ6.9 Hz),
2.87 (s, 10H), 2.51 (qt, 72H, JZ6.8, 1.4 Hz); 13C NMR
(126 MHz, CDCl3) 160.4, 160.3, 159.4, 152.8, 151.4, 144.2,
140.3, 139.5, 139.3, 139.2, 134.6, 130.5, 129.6, 128.8,
128.6, 127.3, 125.9, 117.3, 111.6, 110.6, 106.7, 106.1,
101.8, 101.6, 101.1, 70.3, 70.2, 67.4, 55.0, 40.2, 33.7, 27.2;
19F NMR (400 MHz, CDCl3) d K70.99; UV–Vis (CHCl3)
lmaxZ436.5; MS (MALDI-TOF) m/zZ6137.1 (MC);
6159.2 (MCNaC); 6174.1 (MCKC).
4.2.16. Cross-linked dendrimeric host 28. To a solution of
60 mg (11 mmol) of 26 in 20 mL of THF was added 10 mL
of 1% (v/v) aqueous solution of HCl. The mixture quickly
turned from orange-yellow to red and 1 mL of CHCl3 was
added to ensure homogeneity. The mixture was stirred at
room temperature for 15 h. The mixture was poured into
25 mL of a 10% (v/v) aqueous solution of HCl. The
resulting suspension was extracted three times with 20 mL
of CHCl3. The combined organic layers were washed with a
saturated aqueous solution of sodium bicarbonate. The
organic layer was dried over anhydrous Na2SO4, filtered,
and evaporated to 46 mg (65%) of 28 as a red film.
Purification (with some loss in yield) was accomplished by
silica gel flash chromatography using 10% EtOAc–CH2Cl2
as the eluent: 1H NMR (400 MHz, CDCl3) d 8.30–7.90 (bd),
7.80–7.60 (bs, 1H), 6.80–6.00 (bd, 27H), 6.00–5.70 (bs,
2H), 5.70–5.10 (bs, 8H), 5.20–5.00 (bs, 3H), 5.00–4.40 (bs,
16H), 4.10–3.50 (s, 20H), 2.90–2.60 (bs, 2H), 2.60–2.20 (bs,
20H); 19F NMR (400 MHz, CDCl3) d K70.62, K71.44;
UV–Vis (THF) lmaxZ480.0, 3 (475 nm)Z25,400 MK1
;
MS (MALDI-TOF) m/zZ5585.4 (16 cross-linksCNaC),
5612.0 (15 cross-linksCNaC), 5639.7 (14 cross-linksC
NaC), 5667.7 (13 cross-linksCNaC).
4.2.17. Cross-linked dendrimeric host 29. To a solution of
17 mg (3 mmol) of 27 in 10 mL of THF was added 5 mL of a
1% (v/v) aqueous solution of HCl and 1 mL of CHCl3. The
reaction mixture was stirred at room temperature for 5 min.
The mixture was poured into 10 mL of a 10% (v/v) aqueous
solution of HCl. The resultant residue was extracted three
times with 10 mL of CHCl3. The combined organic layers
were washed with a saturated aqueous solution of sodium
bicarbonate, dried over sodium sulfate, filtered, and
evaporated. The crude product was loaded onto a silica
gel column (5!15 cm2) eluting with 1 L of 10% EtOAc–PE
to afford 14 mg (82%) of 29 as a red oil: 1H NMR
(400 MHz, CDCl3) d 7.80–7.20 (bs, 10H), 6.70–6.10 (bs,
94H), 6.10–5.70 (bs, 32H), 5.00–4.80 (bs, 56H), 4.80–4.40
(bs, 64H), 2.90–2.60 (s, 12H); 19F NMR (400 MHz, CDCl3)
d K70.62; UV–Vis (THF) lmaxZ477.0; MS (MALDI-
TOF) m/zZ5135.2 (16 cross-linksCNaC), 5162.2 (15
cross-linksCNaC), 5178.2 (15 cross-linksCKC); SEC
(toluene) MWPSZ2920.
4.2.20. Cross-linked dendrimeric host 32. To a solution of
110 mg (18 mmol) of the dendrimer described in Section
4.2.19 in 1.7 L of benzene was added 38 mg (46 mmol, 8%
per mol alkene) of 25. The resulting solution was stirred at
room temperature for 24 h and slowly poured through a
3 cm !3 in. silica gel plug that was pre-equilibrated with
benzene. A dark black layer remained on the top of the silica
plug. An orange band was eluted from this top layer with
500 mL of 3% EtOAc–CH2Cl2. The orange colored eluent
was collected and evaporated to a thick brown oil. Two
successive preparative SEC columns afforded 31 mg (30%)
of cross-linked dendrimer as a yellow-orange oil: 1H NMR
(400 MHz, CDCl3) d 7.80–7.40 (bs), 6.90–6.00 (bd, 85H),
6.00–5.80 (bs, 1H), 5.70–5.40 (bs, 27H), 5.20–5.00 (bs, 3H),
4.2.18. 1,3-Bis(azidoethyl)benzene (31). To a solution of
1.9 g (5.9 mmol) of 1,3-benzenediethanol dimethane-sul-
fonate in 15 mL of DMF was added 0.95 g (15 mmol) of
sodium azide. The resultant mixture was stirred at 50 8C for
12 h, cooled to room temperature, and partitioned between
50 mL of ether and 100 mL of water. The aqueous layer was

E. Mertz et al. / Tetrahedron 60 (2004) 11191–11204
11203
5.00–4.30 (bs, 42H), 4.10–3.00 (s, 64H), 3.00–2.60 (bs, 5H),
2.60–2.00 (bs, 48H); 19F NMR (400 MHz, CDCl3) d
K70.93; UV–Vis (CHCl3) lmaxZ438.5; MS (MALDI-
TOF) m/zZ5688.1 (16 cross-links), 5713.0 (16 cross-
linksCNaC), 5739.0 (15 cross-linksCNaC). To a solution
of 30 mg (5.2 mmol) of the dendrimer prepared above in
10 mL of THF was added 5 mL of a 1% (v/v) aqueous
solution of HCl. The mixture quickly turned from orange-
yellow to red and 1 mL of CHCl3 was added to ensure
homogeneity. The mixture was stirred at room temperature
for 4 h and poured into 10 mL of a 10% (v/v) aqueous
solution of HCl. The resulting suspension was extracted
three times with 30 mL CHCl3. The combined organic
layers were washed with a saturated aqueous solution of
sodium bicarbonate, dried over Na2SO4, filtered, and
evaporated to a red oil. Flash chromatography (10%
EtOAc–CH2Cl2) afforded 17.4 mg (60%) of 32 as a red
James B. Beil, Annabelle Benin, Brian G. Carter, and
Denise M. Junge for assistance with preparative work.
References and notes
1. Taken in part from the Ph.D. Thesis of Eric Mertz, University
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1
film: H NMR (400 MHz, CDCl3) d 8.40–7.80 (bd, 2H),
7.80–7.40 (bs, 5H), 6.80–6.00 (bd, 90H), 6.00–5.70 (bs,
3H), 5.70–5.10 (bs, 32H), 5.20–5.00 (bs, 4H), 5.00–4.40 (bs,
54H), 4.10–3.60 (s, 64H), 2.90–2.60 (bs, 8H), 2.60–2.20 (bs,
66H); 19F NMR (400 MHz, CDCl3) d K70.62, K71.44;
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of 110 mg (36 mmol) 18 in 15 mL of benzene was added
38 mg (46 mmol, 8 mol% per alkene) of 25. The resulting
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achieved using flash chromatography with 20% EtOAc–
CH2Cl2: 1H NMR (400 MHz, CDCl3) d 8.30–8.20 (bs, 1H),
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Acknowledgements
Funding of this work by the National Institutes of Health
(GM61067) is gratefully acknowledged. The authors thank
Melissa J. Witmer for early work on the X-ray analysis and

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