Persulfonylation of amines applied to the synthesis of higher generation dendrimers

Article abstract of DOI:10.1021/jo800179m

(Figure Presented) Systematic analysis of the persulfonylation of branched aromatic oligoamines with different arylsulfonyl chlorides allowed optimization of the repetitive steps involved in the synthesis of the sulfonimide-based dendrimers. The optimized

Full text of DOI:10.1021/jo800179m

lecular weights, but their infamous reputation for labor-intensive
and expensive syntheses often precludes their use. The large-
scale production of dendrimers is usually performed by the
divergent approach8 in which an accumulation of statistical
defects is observed at higher generations.9 Introduction of the
convergent route10 in the early 1990s enabled the preparation
of structurally pure dendrimers with high molecular weights.
However, the multiple synthetic steps along with chromato-
graphic workup procedures often take months to prepare
reasonable amounts of a structurally perfect high-generation
dendrimer. Although there were few reports on dendrimers
obtained by one-pot syntheses,11 they did not receive widespread
attention on account of the following limitations. The one-pot
synthesis of structurally pure polycarbonate-type dendrimers was
Persulfonylation of Amines Applied to the
Synthesis of Higher Generation Dendrimers
Oleg Lukin,* Dirk Schubert, Claudia Müller, Mirza Corda,
and Ramchandra Kandre
Institute of Polymers, Department of Materials, ETH Zurich,
HCI G 527, 8093 Zurich, Switzerland
oleg.lukin@mat.ethz.ch
ReceiVed NoVember 1, 2007
restricted to low molar mass (<2 kDa) species,11 whereas in
a
two other cases the prepared dendrimers were shown to suffer
from either polydispersity11 or poor chemical stability.11
b
c
Therefore, the development of straightforward methods for the
preparation of structurally perfect high molecular weight den-
drimers still remains a challenge.
Recently we reported the synthesis of “designer dendrimers”
which carry sulfonimide units at every branching point.12 By
combining the selectivity of the persulfonylation of primary
amines with the repetitive methodology we constructed a
number of selectively decorated and differently shaped sulfon-
imide dendrimers. This synthetic approach has the advantages
of a large variety of readily available, inexpensive bulding blocks
(arylsulfonyl chlorides), high chemical stability of sulfonimides,
and a convenient purification of intermediates by recrystalliza-
tion. Despite the high flexibility of these synthetic schemes there
were several obstacles restricting the synthesis to the low molar
mass (not exceeding 3 kDa) dendritic species with up to eight
peripheral groups. The major difficulty was the clean conversion
of branched intermediates with peripheral p-nitrobenzenesulfo-
nyl (p-Ns) functional groups into corresponding amines. The
second problem preventing the growth of the higher generations
was the poor solubility of dendritic sulfonimides with multiple
peripheral p-Ns units. This completely prevents the purification
of the multiply p-Ns-substituted dendrimers by means of either
Systematic analysis of the persulfonylation of branched
aromatic oligoamines with different arylsulfonyl chlorides
allowed optimization of the repetitive steps involved in the
synthesis of the sulfonimide-based dendrimers. The opti-
mized procedures afforded the fourth generation N- and
pentaphenylene-centered dendrimers with 16 and 32 periph-
eral groups, respectively. Analysis of products of incomplete
substitution showed that the amino groups in aromatic
oligoamines are persulfonylated consecutively.
Dendritic molecules,1 such as dendrimers,1,2 hyperbranched3
and dendronized4 polymers, and molecular “bottle brushes”5 are
essential building blocks for both covalent and supramolecular
assemblies and have promising technological6 and biomedical7
applications. Dendrimers are an example of useful, symmetric,
and monodisperse dendritic molecules with considerable mo-
(8) (a) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin,
S.; Roeck, J.; Ryder, J.; Smith, P. Macromolecules 1986, 19, 2466–2468. (b)
Brabander-van den Berg, E. M. M.; Meijer, E. W. Angew. Chem., Int. Ed. 1993,
32, 1308–1310. (c) Wörner, C.; Mühlhaupt, R. Angew. Chem., Int. Ed. 1993,
32, 1306–1308. (d) Newkome, G. R.; Yao, Z.; Baker, G. R.; Gupta, V. K J.
Org. Chem. 1985, 50, 2003–2004. (e) Launay, N.; Caminade, A.-M.; Lahana,
R.; Majoral, J.-P. Angew. Chem., Int. Ed. 1994, 33, 1589–1592. (f) Ruiz, J.;
Latuente, H.; Marcen, S.; Ornelas, C.; Lazare, S.; Cloutet, E.; Blais, J.-C.; Astruc,
D. J. Am. Chem. Soc. 2003, 125, 7250–7257. (g) Jayamurugan, G.; Jayaraman,
N. Tetrahedron 2006, 62, 9582–9588. (h) Antoni, P.; Nyström, D.; Hawker,
C. J.; Hult, A.; Malkoch, M. Chem. Commun. 2007, 2249, 2251.
(9) For example, mass spectroscopic analysis of the 5th generation POPAM
dendrimer revealed a structural purity of ca. 20%. See: Hummelen, J. C.; van
Dongen, J. L. J.; Meijer, E. W. Chem. Eur. J. 1997, 3, 1489–1493.
(10) (a) Hawker, C. J.; Fréchet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638–
7647. (b) Xu, Z.; Moore, J. S. Angew. Chem., Int. Ed. 1993, 32, 246–248. (c)
Miller, T. M.; Neenan, T. X.; Zayas, R.; Bair, H. E. J. Am. Chem. Soc. 1992,
114, 1018–1025.
(1) Vögtle, F.; Richardt, G.; Werner, N. Dendritische Moleküle. Konzepte,
Synthesen, Eigenschaften, Anwendungen; Teubner: Wiesbaden, Germany, 2007.
(2) (a) Archut, A.; Vögtle, F. Chem. Soc. ReV. 1998, 27, 233–240. (b) Smith,
D. K.; Diederich, F. Chem. Eur. J. 1998, 4, 1351–1361. (c) Bosman, A. W.;
Jansen, H. M.; Meijer, E. W. Chem. ReV. 1999, 99, 1665–1688. (d) Fischer, M.;
Vögtle, F. Angew. Chem., Int. Ed. 1999, 38, 884–905. (e) Newkome, G. R.;
Moorefield, C. N.; Vögtle F. Dendrimers and Dendrons. Concepts, Syntheses,
Applications; Wiley-VCH: Weinheim, Germany, 2001. (f) Grayson, S. M.;
Fréchet, J. M. J. Chem. ReV. 2001, 101, 3819–3868.
(3) Gao, C.; Yan, D. Prog. Polym. Sci. 2004, 29, 183–275.
(4) (a) Schlüter, A. D.; Rabe, J. P. Angew. Chem., Int. Ed. 2000, 39, 864–
883. (b) Frauenrath, H. Prog. Polym. Sci. 2005, 30, 325–384.
(5) (a) Hadjichristidis, N.; Pitsikalis, M.; Pispas, S.; Iatrou, H. Chem. ReV.
2001, 101, 3747–3792. (b) Zhang, M.; Müller, A. H. E. J. Polym. Sci., Part A:
Polym. Chem. 2005, 43, 3461–3481. (c) Hadjichristidis, N; Iatrou, H.; Pitsikalis,
M.; Mays, J. Prog. Polym. Sci. 2006, 31, 1068–1132.
(6) (a) Nierengarten, J. F. Chem. Eur. J. 2000, 6, 3667–3670. (b) Hecht, S.;
Fréchet, J. M. J. Angew. Chem., Int. Ed. 2001, 40, 74–91. (c) Haag, R. Chem.
Eur. J. 2001, 7, 327–335.
(11) (a) Rannard, S. P.; Davis, N. J. J. Am. Chem. Soc. 2000, 122, 11739–
11730. (b) Okinawa, M.; Takeuchi, K.; Asai, M.; Ueda, M. Macromolecules
2002, 35, 6232–6238. (c) Ornelas, C.; Aranzaes, J. R.; Cloutet, E.; Astruc, D.
Org. Lett. 2006, 8, 2751–2753.
(7) (a) Dennig, J. Top. Curr. Chem. 2003, 228, 227–236. (b) Lee, C. C.;
MacKay, J. A.; Fréchet, J. M. J.; Szoka, F. C. Nat. Biotechnol. 2005, 23, 1517–
1526.
(12) Lukin, O.; Gramlich, V.; Kandre, R.; Zhun, I.; Felder, T.; Schalley,
C. A.; Dolgonos, G. J. Am. Chem. Soc. 2006, 128, 8964–8974.
3562 J. Org. Chem. 2008, 73, 3562–3565
10.1021/jo800179m CCC: $40.75 2008 American Chemical Society
Published on Web 03/22/2008

SCHEME 1. Reduction of p-Nitrobenzenesulfonimides with
SnCl2
SCHEME 2. Syntheses of the 2nd Generation Sulfonimide
Dendrimers
recrystallization or column chromatography. Furthermore, only
tosyl (Ts) chloride was used at the final persulfonylation steps
and it remained unclear whether other sulfonyl chlorides could
be equally suitable for decorating the dendrimer periphery.
In this contribution we describe the successful solution of
the encountered synthetic problems.
As mentioned above, the lack of a method allowing a clean
quantitative conversion of dendritic oligosulfonimides with
multiple peripheral nitroaromatic functional groups into the
corresponding amines was the major obstacle that caused
reduced yields of the second and third generation dendrimers.
Pd- and Raney-Ni-mediated hydrogenation of p-Ns-decorated
dendritic sulfonimides turned out to be not fully reproducible
causing side reactions which could not be rationalized. Ad-
ditionally, the catalytic hydrogenation caused partial hydro-
dehalogenation in dendrons bearing bromoaromatic function-
alities. The reduction of the p-Ns-decorated dendritic sulfonimides
with SnCl2 in refluxing ethanol led to the clean reduction but
followed by the splitting of p-aminobenzenesulfonyl groups
giving rise to corresponding aminosulfonamides in quantitative
yields (Scheme 1, bottom part). Although the latter process was
shown to be advantageous with regard to the selective scissoring
out of the peripheral dendrimer branches, it is of no use in the
case where a clean reduction securing the rest of the dendrimer
structure is needed. Since it was unclear in this reaction whether
the reduction precedes the sulfonimide decomposition or vice
versa, we carried out a mass-spectrometric investigation of the
intermediates of the reduction of different di-p-nitrobenzene-
sulfonimides with a general formula of the starting compound
in Scheme 1. It turned out that upon dissolution of all reaction
components in hot ethanol the reduction takes place virtually
immediately. The electrospray ionization (ESI) mass spectra of
the raw products taken right away after the reaction had started
showed pronounced peaks of the desired diamines and small
peaks of the aminosulfonamides, the decomposition products.
After 5 min of reaction time the peaks of the aminosulfonamides
were prevailing in the mass spectra. Finally, after 1 h only the
aminosulfonamide peaks were observed in the ESI mass spectra.
Therefore, as the bottom process in Scheme 1 shows, even
though the reduction precedes the decomposition it is difficult
to stop the reaction at this stage.
diamines in quantitative yields. The straightforward workup
consists of pouring the reaction mixture into deionized water
and extracting the product with dichloromethane. The amines
obtained by this method gave very clean 1H NMR and ESI-MS
spectra.
The access to multigram amounts of highly pure dendritic
sulfonimides with peripheral arylamine groups allowed us to
carry out the systematic analysis of their persulfonylation with
different arylsulfonyl chlorides to test the applicability of the
reaction to the synthesis of higher generation dendrimers.
Previously reported arylamine persulfonylation reactions12 were
restricted to the use of p-Ns and Ts chlorides giving rise to
sulfonimide dendrimers with up to eight peripheral arylsulfonyl
groups in good yields. The diamine 2 and the tetraamine 4 were
prepared on a 10 g scale by means of the mild SnCl2 reduction
of dinitro- and tetranitro-derivatives (1 and 3f), respectively.
Scheme 2 summarizes the persulfonylation of 2 with different
arylsulfonyl chlorides in the presence of triethylamine in
refluxing dichloromethane and the isolated yields of the corre-
sponding second generation dendritic sulfonimides purified by
recrystallization. Inspection of the yields in Scheme 2 indicates
that reactions with para-substituted arylsulfonyl chlorides giving
rise to compounds 3a-f are usually high yielding. The excep-
tions are the moderate yield of reaction with p-bromobenzene-
sulfonyl chloride (compound 3d) and a completely unsuccessful
reaction with p-terphenylsulfonyl chloride (not shown) in which
the starting compounds were recovered. Given the equal steric
This finding also indicates that the decomposition of the di-
p-aminobenzenesulfonimides requires somewhat higher activa-
tion energy than the foregoing reduction. As illustrated in the
top part of Scheme 1, the use of a 1:1 mixture of ethanol and
dichloromethane was found to be the key for the clean reduction
of nitrobenzenesulfonimides. The reaction proceeds in a ho-
mogeneous solution at 40 °C giving rise to corresponding
J. Org. Chem. Vol. 73, No. 9, 2008 3563

SCHEME 3. Syntheses of the 3nd generation sulfonimide
dendrimers
load at the reacting sulfur atom in the para-substituted arylsul-
fonyl chlorides, the last two cases can be attributed to the
electronic effects on the arylsulfonyl chloride reactivity. Meta-
substituted sulfonyl chlorides (entries 3g and 3h) do not show
significant drops in yields, whereas the ortho-substituents result
in decreased yields (3i and 3j). The decreased yields in reactions
with ortho-substitued arylsulfonyl chlorides can also be rational-
ized by steric and electronic contributions.
The reaction with 1-naphthylsulfonyl chloride gives rise to
the dendrimer 3i in a yield of 60%, while the reaction with
structurally similar 5-dimethylamino-1-naphthylsulfonyl (dansyl)
chloride resulted in incomplete substitution (discussed below).
Therefore, the diminished reactivity of the dansyl chloride can
be ascribed to the electronic effects. The reaction of 2 with
mesitylenesulfonyl chloride results in 3j with a moderate yield,
whereas the reaction with 2,4,6-triisopropylbenzenesulfonyl
chloride (not shown) failed indicating the detrimental factor of
the steric overcrowding around the reaction center. All second
generation dendrimers except 3f are very soluble in nonpolar
aprotic solvents (solubility in CHCl3 is over 100 mg/mL) and
extremely poorly soluble in alcohols. A considerable difference
in solubilities is found for isomeric tetranitro-compounds 3f and
3g. The chloroform solubility at room temperature of the former
is less than 3 mg/mL, while that of the latter is over 150 mg/
mL. This finding nicely illustrates how the solubility can be
influenced by a small structural change that eliminates the need
to attach solubilizing alkyl or oligoethylene glycol chains as is
usually done in the case of rigid-rod polymers.
Similar to the trend observed with the second generation
dendrimers, the yields of the reactions of 4 with para-substituted
arylsulfonyl chlorides resulting in the third generation species
being high (Scheme 3), while those with meta- and ortho-
substituents are moderate. Octanitro-derivative 5d as well as
other dendrimers in Scheme 3 showed perfect solubility in apolar
aprotic solvents making their chromatographic purification
straightforward. Notably, the chromatographic purification of
sulfonimide dendrimers starts from the third generation species;
all preceding workups are done by recrystallization.
Although the octa-m-Ns-derivative 5d was isolated in a rather
moderate yield this reaction step provides ca. 3-fold molar mass
increase furnishing the product on a gram scale. The dendrimer
5d was quantitatively reduced to the corresponding octaamine
and then subjected to persulfonylation with Ts and m-Ns
3564 J. Org. Chem. Vol. 73, No. 9, 2008

chlorides giving rise to the first representatives of sulfonimide-
based dendrimers of the fourth generation 6 (44%) and 7a
(20%), respectively. The structural purity of the fourth genera-
tion species was fully confirmed by means of NMR spectros-
copy, MALDI-TOF mass spectrometry, and elemental analyses.
An attempt to go further with the divergent growth proved
unsuccessful. The involvement of the convergent route at this
stage was therefore undertaken. Utilizing previously reported12
stepwise bis-sulfonylation of n-octylamine with p-Ns and
4-bromobiphenylsulfonyl chlorides and then following the
improved repetitive steps we prepared the fourth generation
dendron 8 bearing 16 Ts units on the periphery and the
4-bromobiphenylsulfonyl unit at the focal point. The double
Suzuki cross-coupling reaction of the dendron 8 with 1,4-
phenylenediboronic acid readily gives the pentaphenylene-
centered dendrimer 9 in a yield of 70%. The dendrimer 9 has
a molar mass exceeding 10 kDa that makes the compound thus
far the largest representative of the branched sulfonimides.
During the systematic investigation of the persulfonylation
of amines 2 and 4, products of incomplete substitution were
isolated and characterized in a few cases. Thus, three products
of the persulfonylation of 2 with dansyl chloride were isolated
chromatographically. The first two fractions were equal amounts
of sulfonamide 10 and sulfonimide 11, while the major fraction
(ca. 50%) was the starting diamine 2. Therefore, the first and
the second sulfonylation events took place at the same nitrogen
atom despite the accessibility of free amino groups. Column
chromatography of the raw products of other persulfonylation
reactions of 2 and 4 enabled the isolation of traces of sulfonimide
12 (ca. 3%), the triply substituted derivative 13 (ca. 2%), and
the hexasulfonylated intermediate 14 (yield 14%). The isolated
byproducts 10–14 suggest the following mechanism of the
persulfonylation of aromatic amines. The first sulfonylation
event generates the aromatic sulfonamide intermediate, which
under basic conditions is more reactive than the aromatic amine.
Our previous findings12 revealed that peripheral aromatic amino
groups of some sulfonimide dendrimers with a single aliphatic
sulfonamide unit were successfully persulfonylated leaving the
sulfonamide group intact. Therefore, the reactivity of aromatic
and aliphatic sulfonamides and aromatic amines toward sulfo-
nylation under basic conditions decreases in the order ArSO2NH-
Ar′ > ArNH2 > ArSO2NH-Alk. The ability to selectively
address these functional groups without involving protective
groups might become very useful not only in dendrimer research
but also in medicinal chemistry.
Experimental Section
Representative Procedure for the Reduction of Nitroaro-
matic Intermediates. A solution of octanitro-derivative 5d (1 g,
0.4 mmol) in 50 mL of CH2Cl2 was poured into a stirred solution
of SnCl2 (8 g) and 37% HCl (2 mL) in 50 mL of EtOH. The reaction
mixture was stirred at 40 °C for 4 h then poured into 300 mL of
deionized water and extracted with CH2Cl2 (2 × 200 mL). The
combined organic layers were washed with water and saturated
NaHCO3, then dried over MgSO4. The solvent was removed under
reduced pressure and the resulting solid residue was dried in
vacuum. Yellowish solid; yield 0.86 g (95%); 1H NMR (500 MHz,
3
DMSO-d6) δ 0.78 (t, JH, H ) 6.4 Hz, 3 H, CH3), 1.14 (m, 10 H,
CH2), 1.53 (m, 2H, CH2), 3.82 (m, 2 H, CH2), 5.75 (s, 16 H, NH2),
6.83 (m, 8 H, ArH), 6.90 (m, 8 H, ArH), 7.06 (s, 8 H, ArH), 7.24 (m,
8 H, ArH), 7.34 (d, 3JH, H ) 8.5 Hz, 8 H, ArH), 7.42 (d, 3JH, H ) 8.5
Hz, 4 H, ArH), 7.85 (d, 3JH, H ) 8.5 Hz, 8 H, ArH), 8.16 (d, 3JH, H
)
8.5 Hz, 4 H, ArH) ppm; MS (MALDI-TOF, dithranol + Na-TFA)
12
14
16
32
m/z 2322.10 [M + Na]+,
C
92
1H89
N
15
O
S
23Na requires m/z
28 14
2322.20.
Acknowledgment. We thank Prof. A. D. Schlüter (ETH
Zurich) for numerous stimulating discussions and support.
Supporting Information Available: Characterization data
for all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO800179M
J. Org. Chem. Vol. 73, No. 9, 2008 3565