Avoiding steric congestion in dendrimer growth through proportionate branching: A twist on da Vincis rule of tree branching

Article abstract of DOI:10.1021/jo301718y

Making defect-free macromolecules is a challenging issue in chemical synthesis. This challenge is especially pronounced in dendrimer synthesis where exponential growth quickly leads to steric congestion. To overcome this difficulty, proportionate branchin

Full text of DOI:10.1021/jo301718y

Featured Article
pubs.acs.org/joc
Avoiding Steric Congestion in Dendrimer Growth through
Proportionate Branching: A Twist on da Vinci’s Rule of Tree
Branching
Xuyi Yue,† Marc B. Taraban,‡ Laura L. Hyland,‡ and Yihua Bruce Yu*,†,‡
†Department of Pharmaceutical Sciences, University of Maryland, 20 North Pine Street, Baltimore, Maryland 21201, United States
‡Fischell Department of Bioengineering, University of Maryland, 2330 Jeong H. Kim Engineering Building #225, College Park,
Maryland 20742, United States
S
* Supporting Information
ABSTRACT: Making defect-free macromolecules is a chal-
lenging issue in chemical synthesis. This challenge is especially
pronounced in dendrimer synthesis where exponential growth
quickly leads to steric congestion. To overcome this difficulty,
proportionate branching in dendrimer growth is proposed. In
proportionate branching, both the number and the length of
branches increase exponentially but in opposite directions to
mimic tree growth. The effectiveness of this strategy is
demonstrated through the synthesis of a fluorocarbon dendron
containing 243 chemically identical fluorine atoms with a MW of 9082 Da. Monodispersity is confirmed by nuclear magnetic
resonance spectroscopy, mass spectrometry, and small-angle X-ray scattering. Growing different parts proportionately, as nature
does, could be a general strategy to achieve defect-free synthesis of macromolecules.
identical chemical environments, and their 19F signals coalesce
INTRODUCTION
■
into a single peak for magnetic resonance imaging. Defects in
Defect-free synthesis of macromolecules remains a challenge in
fluorinated dendrimers would lead to split 19F signals, which
chemistry, especially for dendrimers, which are finding
can create chemical shift image artifacts. Hence, for 19F MRI
increased applications in chemistry, materials science, nano-
technology, as well as medicine and pharmacy.1−7 Dendrimers
applications, defect-free synthesis of fluorinated dendrimers is
essential.
are tree-like molecules composed of a core (“trunk”), several
interior layers (“branches”), and a periphery (“leaves”).8,9
We have previously made fluorinated asymmetric dendrimers
containing 27 fluorine atoms and conducted in vivo imaging
However, conventional dendrimer design grows dendrimers
disproportionately: the number of branches grows exponen-
tially, but the length of branches remains unchanged. The
length of branches refers to the number of covalent bonds
connecting adjacent branching nodes. Such a growth pattern
eventually leads to steric congestion and defect den-
studies.16 Each fluorinated asymmetric dendrimer comprises a
fluorocarbon dendron where the branching nodes are carbons
with 1→3 connectivity and a hydrophilic dendron where the
branching nodes are nitrogens with 1→2 connectivity.17 Using
conventional dendrimer design, we were able to grow the
drimers.10−14 In this work, we show that steric congestion
hydrophilic dendron for 4 generations without running into
steric congestion.18 However, when we tried to grow the
can be avoided using a bioinspired strategy called proportionate
fluorocarbon dendron, we encountered steric congestion and
branching. It is based on the observation that, in trees, branches
near the trunk are long but few, while branches near the leaves
incomplete growth. The fluorocarbon dendron is more prone
to steric congestion than the hydrophilic dendron for two
are many but short. Translating this observation into
reasons: higher branch multiplicity (3 vs 2) and bulkier
mathematical terms leads to proportionate growth of branch
peripheral group (−CF3 vs −OH).19 This difficulty with
lengths, which parallels da Vinci’s rule of proportionate growth
of branch diameters.15 Specifically, the number and the length
growing fluorocarbon dendrons prompted us to examine the
issue of dendrimer growth, and we came up with the strategy of
of branches in a dendrimer both grow exponentially but in
proportionate branching.
Using proportionate branching, fluorocarbon dendrons
containing 81 and 243 fluorine atoms, which could not be
obtained using conventional methods, were successfully
opposite directionsfrom the core to the periphery of a
dendrimer and from the periphery to the core, respectively,
to emulate tree growth.
We illustrate proportionate branching by making four
generations of fluorocarbon dendrons. The motivation for
making fluorocarbon dendrons is to use them as imaging agents
for 19F MRI. Fluorine atoms in a fluorinated dendrimer have
Received: August 13, 2012
Published: October 5, 2012
© 2012 American Chemical Society
8879
dx.doi.org/10.1021/jo301718y | J. Org. Chem. 2012, 77, 8879−8887

The Journal of Organic Chemistry
Featured Article
synthesized. Small-angle X-ray scattering (SAXS) studies reveal
that these fluorocarbon dendrons have a dumbbell shape with
spherical symmetry, as designed. Our results demonstrate that
proportionate branching is an effective strategy to avoid steric
congestion in dendrimer synthesis.
the diameter of branches in the nth layer.15 Hence, from the
trunk to the leaves, the branches of a dendrimer or a tree get
proportionately shorter (our rule) or thinner (da Vinci’s rule).
Larger b is beneficial for avoiding steric congestion but
elevates synthesis difficulty. To strike a balance, it is sensible to
allow b to adopt any appropriate value between 1 and a,
including non-integers. The idea is that b should be no larger
than absolutely necessary. The optimal value of b depends on
branch multiplicity and peripheral group. While b can adopt a
non-integer value, ln, the number of bonds, cannot. The
solution is to let ln−1 float between [bln − 1, bln + 1]. The exact
integer value of ln−1 depends on the availability of starting
materials and the convenience of synthesis, thereby giving the
synthetic chemist some flexibility.
RESULTS AND DISCUSSION
■
Principle of Proportionate Branching. Proportionate
branching is characterized by a pair of constants, a and b; a is
the branch multiplicity for growing the number of branches,
and b is the length multiplier for growing the length of
branches. For a G-generation dendrimer, the number of
branching nodes in the nth layer is denoted as mn, and the
number of bonds between the nth and the (n−1)th layers as ln,
with 1 ≤ n ≤ G. The growth of mn starts at the core with m0 
1, and the growth of ln starts at the periphery with lG  1.
Subsequent growth of mn and ln, respectively, follows the
recursive formulas mn = a × mn−1 and ln−1 = b × ln. In other
words, mn and ln both grow exponentially but in opposite
directions, with mn growing from the core to the periphery and ln
growing from the periphery to the core.
Synthesis of Fluorinated Dendrons. With the propor-
tionate branching strategy in mind, we embarked on a
convergent synthesis of four generations of fluorocarbon
dendrons as shown in Scheme 1. For detailed structures of
Scheme 1. Convergent Synthesis of Fluorocarbon Dendrons
a
at 75% Proportionate Branching (a = 3, b = 2.5, c = 75%)
Branch multiplicity a is determined by the chemistry of the
branching atoms: a = 3 for 1→3 connectivity and a = 2 for 1→
2 connectivity. Length multiplier b satisfies 1 ≤ b ≤ a. We
define a proportionality constant c as
b − 1
a − 1
c =
× 100%
(1)
Figure 1 illustrates three levels of proportionate branching, 0,
50, and 100%. When b = 1, c = 0%. This is conventional
dendrimer growth. When b = a, c = 100%. In this case, mn × ln
= aG for 1 ≤ n ≤ G. Hence, at 100% proportionate branching,
the product of mn and ln is a constant. The essence of da Vinci’s
rule of tree branching is that mn × dn2 is a constant, where dn is
a
For the generation 4 dendron, 19F-243, (m0, m1, m2, m3, m4) = (1, 3,
9, 27, 81), (l1, l2, l3, l4) = (19, 8, 3, 1). The irregularity in ln values is
because b is a non-integer. The calculation of ln values is given in the
synthesis step of that compound.
the four fluorocarbon dendrons, see Figure S1 in the
Supporting Information. Since all branching atoms are
tetrahedron carbons, a = 3. On the basis of our experience
with16,18,20,21 and reported properties of22,23 the −CF3 and
−C(CF3)3 groups, we choose b = 2.5, hence c = 75%. The ln
values are given in Scheme 1.
To implement the convergent synthesis procedure outlined
in Scheme 1, we note that the first-generation dendron,
perfluoro-tert-butanol (19F-9), is commercially available. Hence
our synthesis endeavor starts with making the second-
generation dendron 19F-27 from 19F-9, as shown in Scheme
2. Pentaerythritol 1, which is commercially available at a low
price, was used as the branching unit to ensure a = 3. One of
the four hydroxyl groups in 1 was protected with tert-butyl
acrylate to afford 2 with a moderate yield. This step also
contributes three bonds to l2 (see Scheme 1). Three copies of
19F-9 (3) were then grafted onto the remaining three hydroxyl
Figure 1. Different levels of proportionate branching for G = 3
dendrimers. At 100% proportionate branching, m1 × l1 = m2 × l2 = m3
× l3 = aG; i.e., mn and ln are inversely proportional to each other for 1 ≤
n ≤ G, hence the name proportionate branching.
8880
dx.doi.org/10.1021/jo301718y | J. Org. Chem. 2012, 77, 8879−8887

The Journal of Organic Chemistry
Featured Article
a
a
Scheme 2. Synthesis of Two Versions of 19F-27 (5 and 8)
Scheme 4. Synthesis of 19F-81 (Compound 16)
a
a
The 8→16 step is 75% proportionate branching.
The 3→4 step is 75% proportionate branching.
Synthesis of 19F-243 was similar to that of 19F-81 in that
groups in 2 using the classic Mitsunobu reaction to give
compound 4. The combination of pentaerythritol and the
Mitsunobu reaction leads to l3 = 3, which lies in the range of
[2.5 × 1 − 1, 2.5 × 1 + 1]. This illustrates the principle that the
exact integer value of ln−1, which lies in the range of [bln − 1, bln
+ 1], is determined by a combination of starting material and
synthesis convenience. From 4, reduction of the ester group
with LiAlH4 gave the hydroxyl version of 19F-27 (compound 5).
Subsequent mesylation of the primary hydroxyl group in 5
afforded mesylate 6. Nucleophilic substitution of mesylate 6
with potassium thioacetate and then deprotection of the
resulting thioester bond in 7 afforded the sulfhydryl version of
19F-27 (compound 8).
pentaerythritol was used as the branching unit and grafting 19F-
81 onto pentaerythritol utilized the sulfide bond. To satisfy l1 =
19, the tetraoxyethylene tail in 16 was shortened to the
trioxyethylene tail in 20. However, direct growth from 20 to
19F-243 was hindered by unexpected difficulty in removing the
benzyl group in the trioxyethylene tail of 19F-81. To overcome
this difficulty, the benzyl group in 18 was replaced by the trityl
group in 21, which was converted to 23. The trityl group in 23
was easily removed by TFA to expose a free hydroxyl.
Subsequent transformation of this hydroxyl group in compound
24 to the sulfhydryl group in compound 27 proceeded
smoothly. Three copies of compound 27 were grafted onto
the tribromide compound 30 to give 19F-243 (compound 31)
with an 82% yield. In 19F-243, l1 = 19, which is at the lower end
of [2.5 × 8 − 1, 2.5 × 8 + 1] (Scheme 5).
With 19F-27 (8) in hand, we turned our attention to the
synthesis of 19F-81. Pentaerythritol was used as the branching
unit, and grafting 19F-27 onto pentaerythritol utilized the sulfide
bond. Model reactions showed that the reaction between 8 and
pentaerythritol tribromide proceeded smoothly under a
Cs2CO3/2-pentanone condition after various trials (Scheme
3; for condition optimization, see Supporting Information).
The target 19F-81 compound 16 can be successfully obtained
from tetraethylene glycol 13 (Scheme 4). The l2 in compound
16, which lies between [3 × 2.5 − 1, 3 × 2.5 + 1], was chosen
to be 8. This again is due to a combination of starting material
availability and synthesis convenience.
NMR spectroscopy shows that, as expected, all four
fluorinated dendrons emit a single unsplit sharp 19F signal
(see Supporting Information), attesting to their potential as
imaging agents for 19F MRI.
To illustrate the necessity of 75% proportionate branching,
we conducted the following control experiments (Scheme 6).
Attempts were made to graft three copies of compound 27
onto compound 15. If successful, this would have led to a 19F-
243 with l1 = 13, which is equivalent to b = 1.5 (13 is in the
range of [1.5 × 8 − 1, 1.5 × 8 + 1]), resulting in c = 25%. Such
attempts led to no reaction. Replacing bromide in 15 with the
more reactive triiodide compound 32 also led to no reaction
with 27. We then extended the three bromide side chains in
compound 15 by one oxyethylene unit to give another
tribromide compound 35. Successful grafting of three copies
of 27 to 35 would have led to a 19F-243 with l1 = 16, which is
equivalent to b = 2 (16 is in the range of [2 × 8 − 1, 2 × 8 +
1]), resulting in c = 50%. However, the reaction was incomplete
(see Supporting Information). This demonstrates that 75%
proportionate branching is necessary to avoid steric congestion
in the synthesis of these fluorocarbon dendrons.
Scheme 3. Model Reaction for Making 19F-81 Compounds
A previously reported strategy, developed by Xu and Moore
in 1993, overcomes steric congestion by growing ln linearly (i.e.,
l
n−1 = b + ln), where b is a constant.24 In contrast, proportionate
branching grows ln exponentially (i.e., ln−1 = b × ln), where b is a
constant. Linear growth of ln is synthetically simpler, but
exponential growth of ln is more likely to avoid steric
congestion. Indeed, in the synthesis of the fluorocarbon
dendrons from 19F-9 to 19F-243, linear growth of ln would
8881
dx.doi.org/10.1021/jo301718y | J. Org. Chem. 2012, 77, 8879−8887

The Journal of Organic Chemistry
Featured Article
a
Scheme 5. Synthesis of 19F-243 (Compound 31)
dendrimers with low branch multiplicity (a = 2) while
exponential growth of ln is developed for dendrimers with
high branch multiplicity (a = 3).
Small-Angle X-ray Scattering Characterization. Small-
angle X-ray scattering (SAXS) was used to characterize the
shape of these fluorocarbon dendrons. To this end, the
fluorocarbon dendrons were dissolved in trifluoroethanol
(TFE) at a concentration of 276 mM for compound 3 (19F-
9), 92.1 mM for compound 5 (19F-27), 30.7 mM for compound
16 (19F-81), and 10.2 mM for compound 31 (19F-243). Note
that, in all samples, the molar concentration of fluorine is 2488
mM. All samples are colorless clear solutions.
SAXS profiles of I(Q) versus Q of the four compounds are
shown in Figure 2, where I(Q) is the scattering intensity and Q
Figure 2. I(Q) vs Q SAXS profiles of 19F-243 (red) and 19F-81 (blue)
after solvent subtraction and background correction; the scattering
profiles of 19F-27 (green) and 19F-9 (black) are shown for comparison.
Inset plot shows the linear region of Guinier plot of lnI(Q) vs Q2 for
globular particles, for the Q range where QRg < 1.3 (Q range ∼ 0.039−
0.072 Å−1 for 19F-81 and ∼0.021−0.054 Å−1 for 19F-243). Colors in
the inset correspond to the main figure. Statistical error bars
correspond to one standard deviation and represent error in scattering
intensity estimation.
a
The 8→20 (or 23) and 27→31 steps are both 75% proportionate
branching.
Scheme 6. Control Experiments for Growing 19F-243 with l1
= 13 and 16, Which Respectively, Represent 25 and 50%
Proportionate Branching for the 19F-81→19F-243 Step
is the amplitude of the scattering vector and is equal to (4π/
λ)sin(θ/2), where θ is the scattering angle and λ is the
wavelength of the incident X-ray (0.689 Å). Of these four
compounds, only 19F-81 (MW = 2941 Da) and 19F-243 (MW =
9082 Da) are large enough to give sufficient scattering intensity
at the aforementioned concentrations. 19F-243 gave much
stronger X-ray scattering than 19F-81 in the lower Q region,
indicative of much larger scattering particles.
The linearity in the Guinier plot suggests monodispersity for
both 19F-81 and 19F-243 in TFE solution. Indeed, indirect
Fourier transform of the scattering profiles results in pairwise
distance distribution P(r) functions with good quality (fitting
quality of the P(r) functions was ∼0.7−0.8, which indicates
good fit; for an ideal fit, the criterion is 1.025). In the case of
19F-81, the P(r) profile describes an elongated slightly
asymmetrical object. In the case of 19F-243, the P(r) profile
has two pronounced maxima and is characteristic for distinct
dumbbell shaped particles. From the r value at which P(r) = 0,
the maximum linear dimension of each particle, dmax, could be
have led to l3 = 3 (19F-9→19F-27), l2 = 8 (19F-27→19F-81), and
l1 = 13 (19F-81→19F-243). However, we have shown that for
the 19F-81→19F-243 step, l1 = 13 resulted in no growth at all.
Hence, for these fluorocarbon dendrons, linear growth of ln
cannot effectively overcome steric congestion. This is hardly
surprising because linear growth of ln was developed for
8882
dx.doi.org/10.1021/jo301718y | J. Org. Chem. 2012, 77, 8879−8887

The Journal of Organic Chemistry
Featured Article
estimated, which is 55 Å for 19F-81 and 85 Å for 19F-243. For
each dendron, the maximum distance between the fluorine
atoms in the head and the benzyl group in the tail can be
estimated by multiplying the number of bonds between them,
which is 28 for 19F-81 and 47 for 19F-243, and the average bond
length, which is ∼1.7 Å. The resulting values are ∼50 Å for 19F-
81 and ∼80 Å for 19F-243, which are in good agreement with
dmax obtained from SAXS measurement. Such agreement
suggests 19F-81 and 19F-243 exist as monomers in TFE,
attesting that TFE (F% = 57%), even though relatively polar
with a dielectric constant of 28, is a good solvent for 19F-81 (F
% = 52%) and 19F-243 (F% = 51%). The values of the radius of
gyration, Rg, derived from the above P(r) functions are 17.9 and
24.8 Å for 19F-81 and 19F-243, respectively. For both 19F-81 and
19F-243, Rg is markedly smaller than dmax/2 (22.5 and 42.5 Å,
respectively, for 19F-81 and 19F-243). This indicates that the
center of the scattering electron “mass” in both molecules is
moved toward the electron-rich fluorocarbon head of each
molecule, as one would expect.
compactness and flexibility in solution. The apolar fluorocarbon
chains are likely to cluster in the relatively polar TFE, leading to
smaller than expected scattering volume. The polar oxyethylene
tail, (−OCH2CH2−)4−OBn, is likely to be flexible in TFE,
leading to larger than expected scattering volume.
CONCLUSION
■
Proportionate branching is proposed to avoid steric congestion
in dendrimer growth. The effectiveness of this strategy is
demonstrated through the synthesis of four generations of
fluorinated dendrons, containing up to 243 chemically identical
fluorine atoms per dendron. The SAXS investigation indicates
that generations 3 and 4 dendrons both have a dumbbell shape
with spherical symmetry for the fluorine part, as designed.
Proportionate branching will be particularly useful in making
dendrimers with high branch multiplicity and bulky periphery
groups. Emulating the structure of living organisms might be a
general strategy for making defect-free functional macro-
molecules. The key is to translate biological observations into
principles amenable to chemical synthesis.
To restore low-resolution 3D shapes of 19F-81 and 19F-243,
we used the ab initio program DAMMIN.26 More than 20
possible structures generated by DAMMIN for each 19F-81 and
19F-243 were superimposed using the best-matching alignment
program SUPCOMB.27 The normalized structural discrepancy
parameter (NSD), which characterizes structural similarity of
DAMMIN results, was ∼0.3 for both substances (NSD = 0 for
ideal similarity, and NSD > 1 for systemically different
structures). The restored low-resolution 3D shapes of 19F-81
and 19F-243 in TFE solution are both dumbbells (Figure
3C,D), though much less pronounced in the case of 19F-81.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise stated, all chemicals were
obtained from commercial sources and used without further
purification. Analytical thin layer chromatography (TLC) was
performed on precoated silica gel 60 F254 plates with visualization
by ultraviolet (UV) irradiation at λ = 254 nm or staining with KMnO4.
1
Purifications were performed by silica gel chromatography. The H,
19F, and 13C NMR spectra were carried out on a 500 MHz
1
spectrometer. The H, 19F, and 13C NMR spectra were recorded at
500, 470, and 126 MHz, respectively. 1H NMR chemical shifts (δ) are
reported in parts per million (ppm) relative to a residual proton peak
of the solvent, δ = 7.24 for CDCl3, δ = 2.80 for CD3COCD3.
Multiplicities are reported as follows: s (singlet), d (doublet), t
(triplet), q (quartet), dd (doublet of doublets), or m (multiplet).
Broad peaks are indicated by the addition of br. Coupling constants
are reported as a J value in hertz (Hz). The number of protons (n) for
a given resonance is indicated as nH and is based on spectral
integration values. 13C NMR chemical shifts (δ) are reported in ppm
relative to CDCl3 (δ = 77.3) or CD3COCD3 (δ = 206.8). For 19F
NMR, hexafluorobenzene was used as the internal standard at δ
−164.9 ppm. Molecular mass was performed on either MALDI-TOF
or on an ion trap mass spectrometer using the DirectProbe add-on
inserted into the atmospheric pressure chemical ionization (APCI)
housing. HRMS data were collected using AccuTOF. For compounds
containing 81 and 243 fluorine atoms, HRMS data could not be
obtained in spite of repeated tries. However, their LRMS data obtained
using a DirectProbe showed the correct mass.
tert-Butyl 3-(3-hydroxy-2,2-bis(hydroxymethyl)propoxy)-
propanoate (2). To DMSO (100 mL) was added pentaerythritol 1
(68 g, 0.5 mol); the heterogeneous suspension was heated to 80 °C
until the system became clear, then aqueous NaOH (4 g of NaOH in 9
mL of H2O) was added in one portion, tert-butyl acrylate (87 mL, 0.6
mol) was added to the solution dropwise, and vigorous stirring
continued overnight at 80 °C. After cooling, the solution was extracted
with EtOAc. The combined organic phase was washed with H2O and
brine, concentrated through rotary evaporation, and the residue was
subjected to silica gel chromatography using CH2Cl2/MeOH as the
Figure 3. Pairwise distance distribution functions P(r) for 19F-81 (A)
and 19F-243 (B) in TFE solution. Side, top, and bottom projections of
low-resolution 3D structures of 19F-81 (C) and 19F-243 (D). F and H
denote, respectively, the fluorocarbon lobe and the hydrophilic lobe.
Such dumbbell shape is consistent with the chemical structures
of 19F-81 and 19F-243, with the larger lobe being the
fluorocarbon head and the smaller lobe being the oxyethylene
tail. The spherical symmetry of the fluorocarbon head of each
molecule is consistent with complete dendrimer growth for
both 19F-81 and 19F-243.
1
eluent to give 2 (54.3 g, 0.21 mol, 41% yield) as a clear oil: H NMR
(500 MHz, CDCl3) δ 3.63 (br, 3H), 3.56 (t, J = 5.5 Hz, 2H), 3.52 (s,
6H), 3.37 (s, 2H), 2.38 (t, J = 5.0 Hz, 2H), 1.37 (s, 9H); 13C NMR
(126 MHz, CDCl3) δ 171.7, 81.2, 72.1, 67.2, 63.6, 45.3, 36.1, 28.1; MS
From the chemical structures of 19F-81 and 19F-243, one
might expect much greater differences between the dimensions
of the fluorocarbon head and the oxyethylene tail. However,
what SAXS measures is not the geometric volume, but the
averaged scattering volume, which is influenced by molecular
t
(ESI) m/z 209 (M − Bu + 2H)+, 265 (M + H)+, 287 (M + Na)+;
HRMS (ESI) calcd for C12H25O6 265.1651 (M + H)+, 209.1025 [M −
tBu + 2H]+, found 265.1646, 209.1026, respectively.
tert-Butyl 3-(3-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-
propan-2-yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexa-fluoro-2-
8883
dx.doi.org/10.1021/jo301718y | J. Org. Chem. 2012, 77, 8879−8887

The Journal of Organic Chemistry
Featured Article
(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)propanoate
(4). To a stirred suspension of compound 2 (26.4 g, 100 mmol),
triphenylphosphine (118 g, 450 mmol), and 4 Å molecular sieves (15
g) in tetrahydrofuran (700 mL) at 0 °C was added dropwise
diisopropylazodicarboxylate (90 mL, 450 mmol). Afterward, the
reaction mixture was allowed to warm to room temperature and was
stirred for an additional 20 min. Then perfluoro-tert-butanol 3 (62.5
mL, 450 mmol) was added in one portion, and the resulting mixture
was stirred for 36 h at 45 °C in a sealed vessel. Water (30 mL) was
added to the reaction mixture and stirred for an additional 10 min.
Then the mixture was transferred to a separatory funnel, and the lower
phase was collected. Removal of the perfluoro-tert-butanol under
vacuum gave the product 4 (65 g, 70.8 mmol, 71% yield) as a clear oil:
1H NMR (500 MHz, CDCl3) δ 4.08 (s, 6H), 3.66 (t, J = 6.0 Hz, 2H),
66.2, 65.8, 46.5, 30.5, 29.7, 26.0; 19F NMR (470 MHz, CDCl3) δ
−73.25 (s); MS (APCI) m/z 907 (M + H)+; HRMS (ESI) calcd for
C22H18F27O5S 907.0444 (M + H)+, 924.0709 [M + NH4]+, found
907.0430, 924.0782, respectively.
3-(3-((1,1,1,3,3,3-Hexafluoro-2-(trifluoromethyl)propan-2-
yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-
propan-2-yl)oxy)methyl)propoxy)propane-1-thiol (8). (−SH
version of 19F-27): At 0 °C, to a solution of thioester 7 (8.6 g, 9.5
mmol) in THF (90 mL) was added lithium aluminum hydride (0.90,
23.8 mmol) in one portion under nitrogen. After the starting material
was consumed completely as monitored by TLC, the reaction was
quenched with dilute HCl carefully under nitrogen, concentrated
through rotary evaporation, and subjected to silica gel chromatography
using hexane/EtOAc as the eluent to give compound 8 (8.0 g, 9.3
1
3.45 (s, 2H), 2.46 (t, J = 6.0 Hz, 2H), 1.45 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 170.6, 120.4 (q, J = 293.3 Hz), 80.8, 80.4−79.2 (m),
67.4, 66.6, 66.1, 46.4, 36.0, 28.0; 19F NMR (470 MHz, CDCl3) δ
mmol, 98% yield) as a clear oil: H NMR (500 MHz, CDCl3) δ 4.02
(s, 6H), 3.46 (t, J = 7.5 Hz, 2H), 3.36 (s, 2H), 2.53 (dd, J = 7.5, 16.0
Hz, 2H), 1.85−1.80 (m, 2H), 1.29 (t, J = 8.0 Hz, 1H); 13C NMR (126
MHz, CDCl3) δ 120.4 (q, J = 293.5 Hz), 79.9−79.4 (m), 69.8, 66.1,
66.6, 46.5, 33.9, 14.0; 19F NMR (470 MHz, CDCl3) δ −73.51 (s); MS
(APCI) m/z 865 (M + H)+, 791 (M − HSCH2CH2CH2 + 2H)+;
HRMS (ESI) calcd for C20H16F27O4S 865.0338 (M + H)+, 882.0624
[M + NH4]+, found 865.0306, 882.0582, respectively.
t
−73.50 (s); MS (APCI) m/z 863 (M − Bu + 2H)+, 791 (M −
tBuOCOCH2CH2 + 2H)+; HRMS (ESI) calcd for C24H25F27NO6
t
936.1251 (M + NH4)+, 863.0359 [M − Bu + 2H]+, found 936.1232,
863.0294, respectively.
3-(3-((1,1,1,3,3,3-Hexafluoro-2-(trifluoromethyl)propan-2-
yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-
propan-2-yl)oxy)methyl)propoxy)propan-1-ol (5). (−OH ver-
sion of 19F-27): To a suspension of lithium aluminum hydride (4.1 g,
108 mmol) in THF solution (450 mL) at 0 °C was added dropwise
compound 4 (40 g, 43.5 mmol) in THF (100 mL). Afterward, the
solution was stirred overnight at room temperature and quenched with
dilute HCl carefully, concentrated through rotary evaporation, and
subjected to silica gel chromatography using hexane/EtOAc as the
eluent to afford alcohol 5 (33.7 g, 39.7 mmol, 91% yield) as a clear oil:
1H NMR (500 MHz, CDCl3) δ 4.02 (s, 6H), 3.69 (t, J = 6.0 Hz, 2H),
3.51 (t, J = 4.5 Hz, 2H), 3.37 (s, 2H), 1.82−1.77 (m, 2H), 1.47 (s,
9H); 13C NMR (126 MHz, CDCl3) δ 120.4 (q, J = 294.7 Hz), 80.1−
79.4 (m), 69.3, 66.3, 66.7, 60.4, 46.4, 32.5; 19F NMR (470 MHz,
CDCl3) δ −73.40 (s); MS (APCI) m/z 849 (M + H)+; HRMS (ESI)
calcd for C20H16F27O5 849.0567 (M + H)+, 866.0832 [M + NH4]+,
found 849.0577, 866.0811, respectively.
3-(3-((1,1,1,3,3,3-Hexafluoro-2-(trifluoromethyl)propan-2-
yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-
propan-2-yl)oxy)methyl)propoxy)propyl methanesulfonate
(6). Triethylamine (Et3N, 9.6 mL) and methanesulfonyl chloride
(5.4 mL, 68.4 mmol) were added to a solution of compound 5 (20.2 g,
23.8 mmol) dissolved in THF (100 mL) and anhydrous CH2Cl2 (200
mL) mixed solvent at 0 °C. The reaction mixture was then stirred at rt
overnight. The reaction was quenched with water and extracted with
CH2Cl2. Evaporation through rotary evaporation followed by flash
chromatography on silica gel using hexane/EtOAc as the eluent
afforded product mesylate 6 (20.8 g, 22.5 mmol, 95% yield) as a
colorless oil: 1H NMR (500 MHz, CD3COCD3) δ 4.21 (t, J = 7.5 Hz,
2H), 4.11 (s, 6H), 3.48 (t, J = 5.0 Hz, 2H), 3.42 (s, 2H), 2.94 (s, 3H),
1.94−1.90 (m, 2H); 13C NMR (126 MHz, CD3COCD3) δ 122.9 (q, J
= 293.0 Hz), 81.2−81.0 (m), 68.6, 68.5, 67.1, 67.0, 47.7, 37.6, 30.7; 19F
NMR (470 MHz, CD3COCD3) δ −71.19 (s); MS (APCI) m/z 927
(M + H)+, 831 (M − OMs)+; HRMS (ESI) calcd for C21H18F27O7S
927.0342 (M + H)+, 944.0608 [M + NH4]+, found 927.0357,
944.0553, respectively.
(S)-(3-(3-((1,1,1,3,3,3-Hexafluoro-2-(trifluoromethyl)propan-
2-yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-
propan-2-yl)oxy)methyl)propoxy)propyl)ethanethioate (7). To
a solution of mesylate 6 (10.2 g, 11 mmol) in DMF (100 mL) was
added potassium thioacetate (3.8 g, 33 mmol). The reaction mixture
was stirred at 50 °C overnight. The mixture was then extracted with
DCM, washed successively with water and brine, concentrated through
rotary evaporation, and subjected to silica gel chromatography using
hexane/EtOAc as the eluent to afford the thioester 7 (9.3 g, 10.3
mmol, 93% yield) as a light yellow liquid: 1H NMR (500 MHz,
CDCl3) δ 3.97 (s, 6H), 3.34 (t, J = 7.0 Hz, 2H), 3.29 (s, 2H), 2.80 (t, J
= 6.5 Hz, 2H), 2.21 (s, 3H), 1.73 (t, J = 7.0 Hz, 2H); 13C NMR (126
MHz, CDCl3) δ 195.7, 120.4 (q, J = 293.2 Hz), 80.2−79.5 (m), 70.2,
((2-(3-Bromo-2,2-bis(bromomethyl)propoxy)ethoxy)-
methyl)benzene (11). To a suspension of sodium hydride (0.4 g, 10
mmol, 60% dispersion in mineral oil) in 40 mL of DMF at 0 °C was
added a solution of monoprotected ethylene glycol 10 (1.0 g, 6.6
mmol) dropwise. The resulting mixture was stirred at 0 °C for 0.5 h
and then at rt for another 1 h to give the solution of sodium
alcoholate. Pentaerythritol tetrabromide 9 (2.9 g, 7.6 mmol) was
added. Afterward, the mixture was heated at 60 °C for 24 h and then
cooled to rt. The reaction mixture was quenched with H2O and
extracted with EtOAc, concentrated through rotary evaporation and
subjected to silica gel chromatography using hexane/EtOAc as the
eluent to give compound 11 (1.18 g, 2.6 mmol, 39% yield) as a light
1
yellow liquid: H NMR (500 MHz, CDCl3) δ 7.34−7.33 (m, 4H),
7.29−7.27 (m, 1H), 4.55 (s, 2H), 3.64 (dd, J = 4.5 Hz, 19.0 Hz, 4H),
3.55 (s, 2H), 3.53 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 138.4,
128.6, 127.88, 127.85, 73.4, 71.3, 70.1, 69.6, 44.0, 35.1; MS (ESI) m/z
458 (M + H)+, 474 (M + NH4)+; HRMS (ESI) calcd for
C14H23Br3NO2 475.9258 (M + NH4)+, found 475.9236.
13-((2-(Benzyloxy)ethoxy)methyl)-1,1,1,25,25,25-hexa-
fluoro-13-(((3-(3-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-
propan-2-yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-
(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)propyl)-
thio)methyl)-5,5,21,21-tetrakis(((1,1,1,3,3,3-hexafluoro-2-
(trifluoromethyl)propan-2-yl)oxy)methyl)-2,2,24,24-tetrakis-
(trifluoromethyl)-3,7,19,23-tetraoxa-11,15-dithiapentacosane
(12). To 45 mL of 2-pentanone solution were added the sulfhydryl
compound 8 (570 mg, 0.66 mmol), Cs2CO3 (216 mg, 0.66 mmol),
and tribromide 11 (75 mg, 0.15 mmol) successively at 0 °C under
nitrogen. Then the mixture was brought to reflux at 105 °C overnight
until the starting material 11 was completely consumed as monitored
by TLC. The reaction mixture was quenched with H2O, extracted with
CH2Cl2, concentrated through rotary evaporation, and purified by
flash chromatography using hexane/EtOAc as the eluent to afford
compound 12 (270 mg, 0.096 mmol, 64% yield) as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 7.25−7.23 (m, 4H), 7.18 (br, 1H), 4.46
(s, 2H), 3.97 (s, 18H), 3.53 (s, 4H), 3.36 (s, 2H), 3.34 (s, 6H), 3.27 (s,
6H), 2.59 (s, 6H), 2.45 (t, J = 5.5 Hz, 6H), 1.75−1.69 (m, 6H); 13C
NMR (126 MHz, CDCl3) δ 138.6, 128.5, 127.74, 127.72, 120.4 (q, J =
291.8 Hz), 80.1−79.4 (m), 73.3, 72.7, 70.9, 70.2, 69.6, 66.0, 65.5, 46.4,
44.5, 36.7, 30.4, 29.8; 19F NMR (470 MHz, CDCl3) δ −73.61 (s); MS
(MALDI-TOF) m/z 2826 (M + NH4)+.
1-Phenyl-2,5,8,11-tetraoxatridecan-13-ol (14). To 800 mL of
THF were added sodium hydride (16.8 g, 0.42 mol, 60% dispersion in
mineral oil) and tetrabutylammonium bromide (11.3 g, 35 mmol)
successively at 0 °C. Then tetraethylene glycol (121 mL, 0.7 mol) was
added dropwise. Afterward, the solution was stirred at rt for 1 h and
then brought to reflux at 80 °C; benzyl bromide (42 mL, 0.35 mol)
was added dropwise to the refluxing mixture. The reaction was
quenched by H2O after 20 h and then extracted with ethyl acetate. The
8884
dx.doi.org/10.1021/jo301718y | J. Org. Chem. 2012, 77, 8879−8887

The Journal of Organic Chemistry
Featured Article
organic phase was concentrated through rotary evaporation and
subject to silica gel chromatography using hexane/EtOAc as the eluent
to afford compound 14 (71 g, 0.25 mol, 71% yield) as a clear oil: H
NMR (500 MHz, CDCl3) δ 7.27−7.24 (m, 4H), 7.21−7.19 (m, 1H),
4.49 (s, 2H), 3.63−3.56 (m, 14H), 3.51 (t, J = 5.0 Hz, 2H), 2.94 (t, J =
5.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 138.2, 128.3, 127.7,
127.5, 73.1, 72.5, 70.58, 70.57, 70.53, 70.3, 69.4, 61.6; MS (ESI) m/z
285 (M + H)+, 307 (M + Na)+, 323 (M + K)+.
(126 MHz, CDCl3) δ 138.2, 128.3, 127.6, 127.5, 73.1, 70.9, 70.7,
70.63, 70.58, 70.3, 69.7, 69.4, 43.7, 34.9; MS (ESI) m/z 566 (M +
Na)+; HRMS (ESI) calcd for C18H28Br3O4 546.9517 (M + H)+, found
546.9536.
1
25,25,25-Trifluoro-13,13-bis(((3-(3-((1,1,1,3,3,3-hexafluoro-
2-(trifluoromethyl)propan-2-yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexa-
fluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-
propyl)thio)-methyl)-21,21-bis(((1,1,1,3,3,3-hexafluoro-2-
(trifluoromethyl)propan-2-yl)oxy)methyl)-1-phenyl-24,24-bis-
(trifluoromethyl)-2,5,8,11,19,23-hexaoxa-15-thiapentacosane
(20). The procedure was the same as the synthesis of compound 12.
From 548 mg of 19 (1 mmol), 4 g of compound 8 (4.5 mmol), and
1.5 g of Cs2CO3 (4.5 mmol) afforded 1.7 g of 20 as a clear oil (0.59
17-Bromo-16,16-bis(bromomethyl)-1-phenyl-2,5,8,11,14-
pentaoxaheptadecane (15). To a suspension of sodium hydride
(1.2 g, 30 mmol, 60% dispersion in mineral oil) in 60 mL of dry
diglyme at 0 °C in a 100 mL flask, equipped with magnetic stirrer and
a 60 mL addition funnel, was added a solution of monobenzyl
protected tetraethylene glycol 14 (7.7 g, 27 mmol) in 15 mL dry
diglyme dropwise under nitrogen atmosphere. The resulting mixture
was stirred at 0 °C for 1 h and then at rt for another 2 h to give a
solution of sodium alcoholate. This alcoholate was added dropwise to
the refluxing solution of pentaerythritol tetrabromide 9 (11.6 g, 30
mmol) in 60 mL of diglyme at 165 °C under nitrogen atmosphere.
After the addition, the mixture was heated overnight at 165 °C and
then cooled to room temperature. The mixture was quenched with
H2O. After solvent evaporation, the residue was extracted with EtOAc
and washed with H2O, concentrated through rotary evaporation, and
subjected to silica gel chromatography using hexane/EtOAc as the
eluent to afford compound 15 (9.1 g, 15.4 mmol, 57% yield) as a clear
oil: 1H NMR (500 MHz, CDCl3) δ 7.20−7.17 (m, 4H), 7.13 (br, 1H),
4.42 (s, 2H), 3.52−3.48 (m, 5H), 3.41−3.40 (m, 9H), 3.39 (s, 8H),
3.22 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 138.2, 128.2, 127.5,
127.4, 73.0, 71.8, 70.8, 70.51, 70.49, 70.46, 70.4, 70.2, 69.6, 69.3, 58.8,
43.6, 34.8; MS (ESI) m/z 606 (M + NH4)+, 611 (M + Na)+; HRMS
(ESI) calcd for C20H32Br3O5 590.9779 (M + H)+, 610.9619 (M +
Na)+, found 590.9767, 610.9990, respectively.
1
mmol, 59% yield): H NMR (500 MHz, CDCl3) δ 7.34−7.32 (m,
4H), 7.28−7.27 (m, 1H), 4.57 (s, 2H), 4.06 (s, 18H), 3.68−3.62 (m,
10H), 3.59 (d, J = 4.5 Hz, 2H), 3.46 (t, J = 6.5 Hz, 6H), 3.41 (s, 2H),
3.38 (s, 6H), 2.67 (s, 6H), 2.56 (t, J = 7.5 Hz, 6H), 1.87−1.80 (m,
6H); 13C NMR (126 MHz, CDCl3) δ 138.6, 128.6, 127.9, 127.8, 120.4
(q, J = 293.6 Hz), 80.4−79.2 (m), 73.5, 72.8, 71.0, 70.97, 70.88, 70.63,
70.61, 70.27, 70.23, 69.73, 69.71, 66.1, 65.7, 65.62, 65.60, 65.58, 46.5,
44.5, 36.7, 30.4, 29.9; 19F NMR (470 MHz, CDCl3) δ −73.27 (s); MS
(ESI) m/z 2920.8 (M + Na)+.
2-(2-(2-(Trityloxy)ethoxy)ethoxy)ethanol (21). To a CH2Cl2
(300 mL) solution of triethylene glycol (21 g, 140 mmol) was added
Et3N (20 mL, 140 mmol); then trityl chloride (19.5 g, 70 mmol) in
CH2Cl2 (100 mL) was added dropwise at 0 °C. The mixture was
stirred overnight and quenched with H2O. The organic phase was
washed with H2O and brine successively, concentrated through rotary
evaporation, and subjected to silica gel chromatography using hexane/
EtOAc as the eluent to afford compound 21 (21 g, 53.6 mmol, 77%
yield) as a clear liquid: 1H NMR (500 MHz, CDCl3) δ 7.47−7.46 (m,
6H), 7.28 (t, J = 7.0 Hz, 6H), 7.21 (t, J = 7.0 Hz, 3H), 3.68 (s, 8H),
3.60 (br, 2H), 3.25 (br, 2H), 2.57 (br, 1H); 13C NMR (126 MHz,
CDCl3) δ 144.2, 128.8, 127.9, 127.1, 86.8, 72.7, 71.0, 70.8, 70.7, 63.4,
61.9; MS (ESI) m/z 415 (M + Na)+.
14-Bromo-13,13-bis(bromomethyl)-1,1,1-triphenyl-2,5,8,11-
tetraoxatetradecane (22). The procedure was the same as synthesis
of compound 15. From 9.3 g (24 mmol) of 9, 7.84 g (20 mmol) of 21,
and 0.92 g of NaH (60% dispersion in mineral oil, 23 mmol) afforded
7.9 g of 22 (11.3 mmol, 56% yield) as a clear oil: 1H NMR (500 MHz,
CDCl3) δ 7.47−7.46 (m, 6H), 7.27 (t, J = 8.5 Hz, 6H), 7.20 (t, J = 8.0
Hz, 3H), 3.68−3.63 (m, 10H), 3.51 (s, 2H), 3.49 (s, 6H), 3.24 (t, J =
4.5 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 144.2, 128.8, 127.8,
127.0, 86.6, 71.09, 70.96, 70.82, 70.80, 70.5, 69.9, 63.5, 43.9, 35.0; MS
(ESI) m/z 719 (M + Na)+, 243 (Ph3C)+; HRMS (ESI) calcd for
C30H35Br3NaO4 720.9963 (M + Na)+, found 720.9959.
28,28,28-Trifluoro-16,16-bis(((3-(3-((1,1,1,3,3,3-hexafluoro-
2-(trifluoromethyl)propan-2-yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexa-
fluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-
propyl)thio)methyl)-24,24-bis(((1,1,1,3,3,3-hexafluoro-2-
(trifluoromethyl)propan-2-yl)oxy)methyl)-1-phenyl-27,27-bis-
(trifluoromethyl)-2,5,8,11,14,22,26-heptaoxa-18-thiaoctaco-
sane (16) (19F-81). To 10 mL of 2-pentanone were added the
sulfhydryl compound 8 (691 mg, 0.8 mmol), Cs2CO3 (261 mg, 0.8
mmol), and tribromide 15 (105 mg, 0.18 mmol) successively at 0 °C
under nitrogen. Then the mixture was brought to overnight reflux at
105 °C. The reaction mixture was quenched with H2O and extracted
with CH2Cl2, concentrated through rotary evaporation, and purified by
silica gel chromatography using hexane/EtOAc as the eluent to afford
1
compound 16 (270 mg, 0.092 mmol, 52% yield) as a clear oil: H
NMR (500 MHz, CDCl3) δ 7.25−7.23 (m, 4H), 7.19−7.18 (m, 1H),
4.48 (s, 2H), 3.97 (s, 18H), 3.59−3.51 (m, 14H), 3.49 (d, J = 4.5 Hz,
2H), 3.37 (t, J = 7.0 Hz, 6H), 3.31 (s, 2H), 3.29 (s, 6H), 2.58 (s, 6H),
2.46 (t, J = 6.0 Hz, 6H), 1.74 (t, J = 7.0 Hz, 6H); 13C NMR (126
MHz, CDCl3) δ 138.6, 128.5, 127.9, 127.8, 120.4 (q, J = 294.0 Hz),
80.4−79.1 (m), 73.5, 72.7, 70.92, 70.90, 70.88, 70.81, 70.5, 70.2, 69.7,
66.1, 65.7, 46.4, 44.5, 36.7, 30.4, 29.8; 19F NMR (470 MHz, CDCl3) δ
−73.38 (s); MS (ESI) m/z 2965 (M + Na)+, 2981 (M + K)+.
2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethanol (18). The proce-
dure was the same as the synthesis of compound 14. From 150 g of 17
(1 mol), 16 g of sodium hydride (0.4 mol, 60% dispersion in mineral
oil), 62.2 g of benzyl bromide (0.36 mol), 23.4 g of tetrabutylammo-
nium bromide (72.8 mmol) afforded 68 g of 18 (0.28 mol, 78% yield)
25,25,25-Trifluoro-13,13-bis(((3-(3-((1,1,1,3,3,3-hexafluoro-
2-(trifluoromethyl)propan-2-yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexa-
fluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-
propyl)thio)methyl)-21,21-bis(((1,1,1,3,3,3-hexafluoro-2-
(trifluoromethyl)propan-2-yl)oxy)methyl)-1,1,1-triphenyl-
24,24-bis(trifluoromethyl)-2,5,8,11,19,23-hexaoxa-15-thiapen-
tacosane (23). The procedure was the same as synthesis of
compound 16. From 14 g (16 mmol) of 8, 3.1 g (4.4 mmol) of 22,
and 5.8 g of Cs2CO3 (17.8 mmol) afforded 12 g of 23 (3.93 mmol,
1
89% yield) as a clear oil: H NMR (500 MHz, CDCl3) δ 7.48−7.46
(m, 6H), 7.30−7.25 (m, 6H), 7.23−7.21 (m, 3H), 4.04 (s, 18H),
3.66−3.64 (m, 8H), 3.58 (s, 2H), 3.44 (s, 6H), 3.39 (s, 2H), 3.36 (s,
6H), 3.24 (s, 2H), 2.65 (s, 6H), 2.54−2.53 (m, 6H), 1.82−1.81 (m,
6H); 13C NMR (126 MHz, CDCl3) δ 144.4, 129.0, 128.0, 127.1, 120.4
(q, J = 293.8 Hz), 86.8, 80.1−79.4 (m), 72.8, 71.1, 70.96, 70.94, 70.85,
70.6, 70.3, 66.1, 65.7, 65.6, 63.6, 46.4, 44.5, 36.7, 30.4, 29.8; 19F NMR
(470 MHz, CDCl3) δ −73.61 (s); MS (ESI) m/z 3073 (M + Na)+.
Compound 24. To a solution of 23 (11.6 g, 3.8 mmol) in DCM
(400 mL) was added TFA (5.8 mL, 76 mmol) dropwise at 0 °C. After
the starting material was consumed completely as monitored by TLC,
the solvent was removed through rotary evaporation and the residue
was subjected to silica gel chromatography using hexane/EtOAc as the
eluent to afford compound 24 (9.1 g, 3.24 mmol, 85% yield) as a
viscous liquid: 1H NMR (500 MHz, CDCl3) δ 4.06 (s, 18H), 3.72 (t, J
= 4.0 Hz, 2H), 3.66−3.59 (m, 10H), 3.46 (t, J = 7.5 Hz, 6H), 3.42 (s,
1
as a clear oil: H NMR (500 MHz, CDCl3) δ 7.34−7.28 (m, 4H),
7.27−7.26 (m, 1H), 4.56 (s, 2H), 3.71−3.66 (m, 8H), 3.63−3.60 (m,
2H), 3.59 (s, 2H), 2.76 (t, J = 6.0 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 138.3, 128.5, 127.9, 127.8, 73.4, 72.7, 70.8, 70.7, 70.5, 69.5,
61.8; MS (ESI) m/z 241 (M + H)+, 263 (M + Na)+, 279 (M + K)+.
14-Bromo-13,13-bis(bromomethyl)-1-phenyl-2,5,8,11-tet-
raoxatetradecane (19). The procedure was the same as the
synthesis of compound 15. From 4.4 g of 18 (18.2 mmol), 0.84 g
of sodium hydride (21 mmol, 60% dispersion in mineral oil), and 7.74
g of 9 (20 mmol) afforded 6.1 g of 19 (11.2 mmol, 61% yield) as a
1
light yellow oil: H NMR (500 MHz, CDCl3) δ 7.32 (br, 4H), 7.26
(br, 1H), 4.55 (s, 2H), 3.67−3.62 (m, 12H), 3.51 (s, 8H); 13C NMR
8885
dx.doi.org/10.1021/jo301718y | J. Org. Chem. 2012, 77, 8879−8887

The Journal of Organic Chemistry
Featured Article
2H), 3.38 (s, 6H), 2.68 (s, 6H), 2.60 (br, 1H), 2.56 (t, J = 7.5 Hz, 6H),
1.86−1.81 (m, 6H); 13C NMR (126 MHz, CDCl3) δ 120.4 (q, J =
293.6 Hz), 80.4−79.2 (m), 72.9, 72.7, 70.87, 70.84, 70.80, 70.64, 70.3,
66.1, 65.7, 61.9, 46.4, 44.5, 36.7, 30.4, 29.9; 19F NMR (470 MHz,
CDCl3) δ −73.34 (s); MS (APCI) m/z 2808 (M + 2H)+, 2658 (M −
HOCH2CH2OCH2CH2OCH2CH2O + H)+.
anyl protected diethylene glycol 28 (3.42 g, 18 mmol) in 8 mL dry
diglyme dropwise under nitrogen atmosphere. The resulting mixture
was stirred at 0 °C for 1 h and then at rt for another 2 h to give a
solution of sodium alcoholate. This alcoholate was added dropwise to
the refluxing solution of compound 15 (2.36 g, 4 mmol) in 10 mL of
diglyme under nitrogen atmosphere at 165 °C. Afterward, the mixture
was heated at reflux overnight and then cooled to rt. The mixture was
quenched with H2O. After solvent evaporation through rotary
evaporation, the mixture was extracted with EtOAc and washed with
H2O and brine, concentrated through rotary evaporation, and
subjected to silica gel chromatography using hexane/EtOAc as the
eluent to afford compound 29 (1.9 g, 2.07 mmol, 52% yield) as a clear
oil: 1H NMR (500 MHz, CDCl3) δ 7.36−7.35 (m, 4H), 7.29 (br, 1H),
4.58 (s, 2H), 3.75 (t, J = 6.0 Hz, 6H), 3.68−3.60 (m, 16H), 3.50−3.45
(m, 14H); 13C NMR (126 MHz, CDCl3) δ 138.4, 128.5, 127.8, 127.7,
98.9, 73.2, 71.05, 70.98, 70.66, 70.63, 70.61, 70.58, 70.56, 70.50, 70.4,
70.3, 70.0, 69.4, 66.7, 62.1, 45.6, 30.6, 25.4, 19.5; MS (ESI) m/z 937
(M + NH4)+, 942 (M + Na)+, 958 (M + K)+; HRMS (ESI) calcd for
C47H86NO17 936.5896 (M + NH4)+, found 936.5895.
23-Bromo-16,16-bis((2-(2-bromoethoxy)ethoxy)methyl)-1-
phenyl-2,5,8,11,14,18,21-heptaoxatricosane (30). To a stirred
solution of compound 29 (500 mg, 0.54 mmol) in 10 mL of CH2Cl2
was added triphenylphosphine dibromide (1.03 g, 2.45 mmol) at 0 °C.
The resulting mixture was stirred at rt overnight. The mixture was
diluted with CH2Cl2 and washed with water. The CH2Cl2 layer was
separated, dried over Na2SO4, and concentrated through rotary
evaporation. The residue was purified by chromatography on silica gel
using hexane/EtOAc as the eluent to give tribromide 30 (320 mg, 0.37
mmol, 69% yield) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.32
(s, 4H), 7.26 (s, 1H), 4.54 (s, 2H), 3.79−3.77 (m, 6H), 3.64−3.59 (m,
20H), 3.55 (s, 8H), 3.44 (s, 14H); 13C NMR (126 MHz, CDCl3) δ
138.2, 128.3, 127.6, 127.5, 73.1, 71.08, 71.02, 70.96, 70.61, 70.58,
70.55, 70.52, 70.32, 70.28, 69.93, 69.87, 69.4, 45.5, 30.6; MS (ESI) m/
z 874 (M + Na)+; HRMS (ESI) calcd for C32H59Br3NO11 872.1618
(M + NH4)+, found 872.1610.
Mesylate 25. Et3N (0.59 mL, 4.2 mmol) and methanesulfonyl
chloride (0.33 mL, 4.2 mmol) were added to a solution of compound
24 (4.75 g, 1.7 mmol) dissolved in THF (40 mL) and anhydrous
CH2Cl2 (40 mL) mixed solvent at 0 °C. The reaction mixture was
then stirred at rt overnight. The reaction was quenched with water and
extracted with CH2Cl2. Evaporation of the solvent by rotary
evaporation followed by flash chromatography on silica gel using
hexane/EtOAc as the eluent afforded the product mesylate 25 (3.7 g,
1.28 mmol, 76% yield) as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 4.38 (s, 2H), 4.06 (s, 18H), 3.77 (s, 2H), 3.66−3.58 (m, 8H), 3.47
(s, 6H), 3.41 (s, 2H), 3.38 (s, 6H), 3.08 (s, 3H), 2.67 (s, 6H), 2.56−
2.55 (m, 6H), 1.84 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 120.4 (q,
J = 294.2 Hz), 80.1−79.4 (m), 72.9, 71.0, 70.9, 70.8, 70.6, 70.2, 69.4,
69.3, 66.1, 65.7, 65.6, 46.4, 44.5, 37.8, 36.7, 30.4, 29.9; 19F NMR (470
MHz, CDCl3) δ −73.45 (s); MS (APCI) m/z 2885 (M + H)+, 2821
(M − SO2 + H)+, 2657 (M − MsOCH2CH2OCH2CH2OCH2-
CH2O)+.
Thioacetate 26. To a solution of mesylate 25 (3.6 g, 1.25 mmol)
in THF (14 mL) and DMSO (14 mL) mixed solvents was added
potassium thioacetate (0.5 g, 4.38 mmol), and the reaction mixture
was stirred at 120 °C overnight. The reaction mixture was extracted
with DCM, washed with water and brine successively, concentrated
through rotary evaporation, and subjected to silica gel chromatography
using hexane/EtOAc as the eluent to afford the thioester 26 (3.12 g,
1
1.09 mmol, 87% yield) as a light yellow oil: H NMR (500 MHz,
CDCl3) δ 4.06 (s, 18H), 3.63−3.60 (m, 10H), 3.47 (t, J = 6.5 Hz, 6H),
3.42 (s, 2H), 3.39 (s, 6H), 3.11 (t, J = 7.0 Hz, 2H), 2.68 (s, 6H), 2.57
(t, J = 6.5 Hz, 6H), 2.34 (s, 3H), 1.84 (t, J = 7.0 Hz, 6H); 13C NMR
(126 MHz, CDCl3) δ 120.3 (q, J = 293.8 Hz), 80.1−79.4 (m), 72.7,
71.8, 70.7, 70.60, 70.57, 70.2, 70.0, 66.0, 65.6, 46.4, 44.4, 36.7, 30.6,
30.4, 29.8, 29.0; 19F NMR (470 MHz, CDCl3) δ −73.62 (s); MS
(MALDI-TOF) m/z 2881.1 (M + Na)+, 2904.7 (M + K)+.
Compound 31 (19F-243). To 10 mL of 2-pentanone solution were
added the sulfhydryl compound 27 (290 mg, 0.1 mmol), Cs2CO3 (49
mg, 0.15 mmol), and tribromide 30 (21 mg, 0.025 mmol) successively
at 0 °C under nitrogen. Then the mixture was brought to reflux at 105
°C overnight until the starting material 30 was completely consumed
as monitored by TLC. The reaction mixture was quenched with H2O
and extracted with CH2Cl2, concentrated through rotary evaporation,
and purified by flash silica gel chromatography using hexane/EtOAc as
the eluent to afford compound 31 (190 mg, 0.021 mmol, 82% yield) as
a clear oil: 1H NMR (500 MHz, CDCl3) δ 7.30 (br, 3H), 7.24 (s, 2H),
4.53 (s, 2H), 4.00 (s, 54H), 3.63−3.51 (m, 64H), 3.41 (s, 26H), 3.36−
3.33 (m, 24H), 2.71−2.69 (m, 12H), 2.62 (s, 18H), 2.50 (s, 18H),
1.78 (s, 18H); 13C NMR (126 MHz, CDCl3) δ 139.2, 137.2, 128.6,
127.9, 120.3 (q, J = 294.0 Hz), 72.7, 71.15, 71.12, 70.87, 70.84, 70.80,
70.73, 70.70, 70.59, 70.55, 70.50, 70.34, 70.27, 70.23, 69.65, 66.0, 65.6
46.4, 44.4, 36.7, 32.2, 32.0, 30.4, 29.9, 29.8; 19F NMR (470 MHz,
CDCl3) δ −74.16 (s); MS (MALDI-TOF) m/z 9105 (M + Na)+.
17-Iodo-16,16-bis(iodomethyl)-1-phenyl-2,5,8,11,14-pen-
taoxaheptadecane (32). To an acetone solution (15 mL) of
compound 15 (1.18 g, 2 mmol) was added sodium iodide (4.5 g, 30
mmol), then the solution was brought to reflux at 65 °C for 3 days
The solvent was removed through rotary evaporation, and the residue
was purified by silica gel chromatography using hexane/EtOAc as the
Free Thiol Compound 27. The procedure was the same as the
synthesis of compound 8. From 3 g (1.05 mmol) of 26 and 0.12 g
(3.15 mmol) of LiAlH4 afforded 2.6 g of 27 (0.92 mmol, 88% yield) as
1
a clear oil: H NMR (500 MHz, CDCl3) δ 4.06 (s, 18H), 3.63−3.59
(m, 10H), 3.46 (t, J = 6.0 Hz, 6H), 3.41 (s, 2H), 3.36 (s, 6H), 2.71−
2.67 (m, 8H), 2.55 (t, J = 6.0 Hz, 6H), 1.83 (t, J = 7.0 Hz, 6H), 1.60 (t,
J = 7.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 120.4 (q, J = 297.4
Hz), 80.4−79.2 (m), 73.1, 72.8, 70.9, 70.8, 70.7, 70.6, 70.3, 66.1, 65.7,
46.4, 44.5, 36.7, 30.4, 29.9, 24.5; 19F NMR (470 MHz, CDCl3) δ
−73.59 (s); MS (APCI) m/z 2824 (M + 2H)+, 2763 (M −
HSCH2CH2 + H)+, 2657 (M − HSCH2CH2OCH2CH2OCH2-
CH2O)+.
2-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethanol (28).
To 800 mL of CH2Cl2 were added diethylene glycol (57 mL, 0.6
mol) and p-toluenesulfonic acid monohydrate (5.7 g, 30 mmol)
successively. Then tetrahydropyran (27.4 mL, 0.3 mol) was added
dropwise at 0 °C. The reaction mixture was stirred overnight and
quenched with H2O, extracted with CH2Cl2, washed with H2O and
brine successively, concentrated through rotary evaporation, and
subjected to silica gel chromatography using CH2Cl2/MeOH as the
eluent to afford compound 28 (32.5 g, 0.17 mol, 57% yield) as a clear
oil: 1H NMR (500 MHz, CDCl3) δ 4.59 (t, J = 4.0 Hz, 1H), 3.85−3.80
(m, 2H), 3.68−3.64 (m, 4H), 3.59−3.55 (m, 3H), 3.48−3.44 (m, 1H),
2.98 (br, 1H), 1.81−1.76 (m, 1H), 1.71−1.65 (m, 1H), 1.59−1.46 (m,
4H).
2,2′-((8-(15-Phenyl-2,5,8,11,14-pentaoxapentadecyl)-8-((2-
(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-ethoxy)methyl)-
3,6,10,13-tetraoxapentadecane-1,15-diyl)bis(oxy))bis-
(tetrahydro-2H-pyran) (29). To a suspension of sodium hydride
(0.72 g, 18 mmol, 60% dispersion in mineral oil) in 20 mL of dry
diglyme at 0 °C in a 100 mL flask, equipped with a magnetic stirrer
and an addition funnel, was added a solution of monotetrahydropyr-
1
eluent to afford compound 32 as a yellow oil: H NMR (500 MHz,
CDCl3) δ 7.35 (br, 4H), 7.29 (br, 1H), 4.58 (s, 2H), 3.68−3.65 (m,
16H), 3.52 (s, 2H), 3.37 (s, 6H); 13C NMR (126 MHz, CDCl3) δ
138.3, 128.4, 127.7, 127.6, 73.2, 71.6, 71.0, 70.70, 70.68, 70.66, 70.4,
69.5, 39.6, 11.8; MS (ESI) m/z 750 (M + NH4)+, 755 (M + Na)+, 771
(M + K)+; HRMS (ESI) calcd for C20H32I3O5 732.9384 (M + H)+,
749.9644 [M + NH4]+, found 732.9405, 749.9655, respectively.
2-((Tetrahydro-2H-pyran-2-yl)oxy)ethanol (33). The proce-
dure was the same as the synthesis of compound 28. From 62 g of
ethylene glycol (1 mol), 9.5 g of p-toluenesulfonic acid monohydrate
(50 mmol), and 28 g of tetrahydropyran (333 mmol) afforded 33 (30
g, 205 mmol, 62% yield) as a clear oil: 1H NMR (500 MHz, CDCl3) δ
8886
dx.doi.org/10.1021/jo301718y | J. Org. Chem. 2012, 77, 8879−8887

The Journal of Organic Chemistry
Featured Article
4.53 (d, J = 3.0 Hz, 1H), 3.87−3.84 (m, 1H), 3.75−3.61 (m, 4H),
3.49−3.47 (m, 1H), 3.15 (br, 1H), 1.82−1.79 (m, 1H), 1.78−1.68 (m,
1H), 1.55−1.46 (m, 4H); MS (ESI) m/z 169 (M + Na)+.
Notes
The authors declare no competing financial interest.
2-((1-Phenyl-16,16-bis((2-((tetrahydro-2H-pyran-2-yl)oxy)-
ethoxy)methyl)-2,5,8,11,14,18-hexaoxaicosan-20-yl)oxy)-
tetrahydro-2H-pyran (34). To a suspension of sodium hydride
(0.64 g, 16 mmol, 60% dispersion in mineral oil) in 30 mL of dry
diglyme at 0 °C in a 100 mL flask, equipped with a magnetic stirrer
and an addition funnel, was added a solution of monotetrahydropyr-
anyl protected ethylene glycol 33 (2.34 g, 16 mmol) in 8 mL of dry
diglyme dropwise under nitrogen atmosphere. The resulting mixture
was stirred at 0 °C for 1 h and then at rt for another 2 h to give a
solution of sodium alcoholate. This alcoholate was added dropwise to
the 165 °C refluxing solution of pentaerythritol tribromide 15 (2.36 g,
4 mmol) in 15 mL of diglyme under nitrogen atmosphere. Afterward,
the mixture was kept refluxing at 165 °C overnight and then cooled to
rt. The reaction mixture was quenched with H2O and, after solvent
evaporation, extracted with EtOAc and washed with H2O,
concentrated through rotary evaporation, and subjected to silica gel
chromatography using CH2Cl2/MeOH as the eluent to afford
compound 34 (0.7 g, 0.89 mmol, 22% yield) as a clear oil: 1H
NMR (500 MHz, CDCl3) δ 7.28 (br, 4H), 7.21 (br, 1H), 4.59 (s, 3H),
4.51 (s, 2H), 3.84−3.80 (m, 2H), 3.75−3.73 (m, 2H), 3.61−3.59 (m,
12H), 3.52−3.42 (m, 12H), 3.37−3.35 (m, 14H), 1.79−1.77 (m, 3H),
1.67−1.63 (m, 3H), 1.53−1.46 (m, 12H); 13C NMR (126 MHz,
CDCl3) δ 138.2, 128.2, 127.6, 127.4, 98.5, 73.1, 71.0, 70.8, 70.61,
70.58, 70.57, 70.55, 70.54, 70.3, 70.0, 69.9, 69.4, 66.3, 61.7, 45.6, 30.5,
25.4, 19.3; MS (ESI) m/z 804.5 (M + NH4)+; HRMS (ESI) calcd for
C41H74NO14 804.5109 (M + NH4)+, found 804.5112.
ACKNOWLEDGMENTS
■
This work was supported in part by NIH Grant EB004416,
DOE Grant DE-FG02-08CH11527, and NSF Grant CBET
1133908. Use of the Advanced Photon Source at the Argonne
National Laboratory was supported by DOE Contract DE-
AC02-06CH11357. Beamtime was awarded through the
program of General User Proposals to GUP-24524.
REFERENCES
■
(1) Knapen, J. W. J.; van der Made, A. W.; de Wild, J. C.; van
Leeuwen, P. W. N. M.; Wijkens, P.; Grove, D. M.; van Koten, G.
Nature 1994, 372, 659−663.
(2) Cooper, A. I.; Londono, J. D.; Wignall, G.; McClain, J. B.;
Samulski, E. T.; Lin, J. S.; Dobrynin, A.; Rubinstein, M.; Burke, A. L.
C.; Frec
́
het, J. M. J.; DeSimone, J. M. Nature 1997, 389, 368−371.
(3) Percec, V.; Ahn, C.-H.; Ungar, G.; Yeardley, D. J. P.; Moller, M.;
̈
Sheiko, S. S. Nature 1998, 391, 161−164.
(4) Percec, V.; Glodde, M.; Bera, T. K.; Miura, Y.; Shiyanovskaya, I.;
Singer, K. D.; Balagurusamy, V. S. K.; Heiney, P. A.; Schnell, I.; Rapp,
A.; Spiess, H.-W.; Hudson, S. D.; Duan, H. Nature 2002, 419, 384−
387.
(5) Criscione, J. M.; Le, B. L.; Stern, E.; Brennan, M.; Rahner, C.;
Papademetris, X.; Fahmy, T. M. Biomaterials 2009, 30, 3946−3955.
(6) Sonke, S.; Tomalia, D. A. Adv. Drug Delivery Rev. 2005, 57,
2106−2129.
20-Bromo-16,16-bis((2-bromoethoxy)methyl)-1-phenyl-
2,5,8,11,14,18-hexaoxaicosane (35). To a stirred solution of
monotetrahydropyranyl protected ethylene glycol 34 (260 mg, 0.33
mmol) in 5 mL of CH2Cl2 was added triphenylphosphine dibromide
(627 mg, 1.49 mmol) at 0 °C. The resulting mixture was stirred at rt
overnight. The mixture was diluted with CH2Cl2 and washed with
water. The CH2Cl2 layer was separated, dried over Na2SO4, and
concentrated through rotary evaporation. The residue was purified by
silica gel chromatography using CH2Cl2/MeOH as the eluent to give
(7) Astruc, D.; Boisselier, E.; Ornelas, C. Chem. Rev. 2010, 110,
1857−1959.
́
(8) Frechet, J. M. J. Science 1994, 263, 1710−1715.
(9) Tomalia, D. A. J. Nanopart. Res. 2009, 11, 1251−1310.
(10) Caminade, A. M.; Turrin, C. O.; Sutra, P.; Majoral, J. P. Curr.
Opin. Colloid Interface Sci. 2003, 8, 282−295.
(11) Grayson, S. M.; Frec
3868.
́
het, J. M. J. Chem. Rev. 2001, 101, 3819−
1
(12) Bryant, L. H., Jr.; Brechbiel, M. W.; Wu, C.; Bulte, J. W. M.;
compound 35 (205 mg, 0.28 mmol, 86% yield) as a yellow oil: H
Herynek, V.; Frank, J. A. J. Magn. Reson. Imaging 1999, 9, 348−352.
NMR (500 MHz, CDCl3) δ 7.36−7.35 (m, 4H), 7.29 (br, 1H), 4.58
(s, 2H), 3.75 (t, J = 6.0 Hz, 6H), 3.68−3.60 (m, 16H), 3.50−3.45 (m,
14H); 13C NMR (126 MHz, CDCl3) δ 138.4, 128.5, 127.8, 127.7,
73.3, 71.3, 71.1, 70.81, 70.78, 70.75, 70.69, 70.5, 69.6, 69.5, 69.4, 45.9,
30.9; MS (ESI) m/z 738 (M + NH4)+, 743 (M + Na)+; HRMS (ESI)
calcd for C26H44Br3O8 723.0566 (M + H)+, 740.0831 (M + NH4)+,
found 723.0592, 740.0802, respectively.
Reaction between Compounds 35 and 27. To 6 mL of 2-
pentanone were added the sulfhydryl compound 27 (160 mg, 0.057
mmol), Cs2CO3 (23 mg, 0.07 mmol), and tribromide 35 (10 mg,
0.014 mmol) successively at 0 °C under nitrogen. Then the mixture
was brought to overnight reflux at 105 °C until the starting material 35
was completely consumed as monitored by TLC. The reaction mixture
was quenched with H2O, extracted with CH2Cl2, concentrated through
rotary evaporation, and purified by flash silica gel chromatography
using hexane/EtOAc as the eluent to afford a mixture of 59 mg as a
clear oil. 19F NMR showed a ratio 2/1 two peaks. 19F NMR (470
MHz, CDCl3) δ −73.72 (s), −74.28 (s).
́
(13) Wooley, K. L.; Hawker, C. J.; Frehet, J. M. J. J. Am. Chem. Soc.
1991, 113, 4252−4261.
(14) Kawaguchi, T.; Walker, K. L.; Wilkins, C. L.; Moore, J. S. J. Am.
Chem. Soc. 1995, 117, 2159−2165.
(15) Eloy, C. Phys. Rev. Lett. 2011, 107, 258101-1−258101-5.
(16) Jiang, Z.-X.; Liu, X.; Jeong, E.-K.; Yu, Y. B. Angew. Chem., Int. Ed.
2009, 48, 4755−4758.
(17) Newkome, G. R.; Shreiner, C. Chem. Rev. 2010, 110, 6338−
6442.
(18) Jiang, Z.-X.; Yu, Y. B. J. Org. Chem. 2010, 75, 2044−2049.
(19) Uneyam, K. Organofluorine Chemistry; Blackwell: Ames, IA,
2006.
(20) Jiang, Z.-X.; Yu, Y. B. J. Org. Chem. 2007, 72, 1464−1467.
(21) Jiang, Z.-X.; Yu, Y. B. Tetrahedron 2007, 63, 3982−3988.
́
(22) Szabο, D.; Mohl, J.; Bal
́
int, A.-M.; Bodor, A.; Rab
́
ai, J. J. Fluorine
D. J.
Chem. 2006, 127, 1496−1504.
(23) Nemes, A.; Tolgyesi, L.; Bodor, A.; Rab
Fluorine Chem. 2010, 131, 1368−1376.
(24) Xu, Z.; Moore, J. S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1354−
́
ai, J.; Szabo,
́
̈
ASSOCIATED CONTENT
1357.
■
(25) Svergun, D. I. J. Appl. Crystallogr. 1992, 25, 495−503.
(26) Svergun, D. I. Biophys. J. 1999, 76, 2879−2886.
(27) Kozin, M. B.; Svergun, D. I. J. Appl. Crystallogr. 2001, 34, 33−
41.
S
* Supporting Information
Characterization data of all new compounds and SAXS
procedure. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: byu@rx.umaryland.edu.
8887
dx.doi.org/10.1021/jo301718y | J. Org. Chem. 2012, 77, 8879−8887