Accelerated Chemoselective Reactions to Sequence-Controlled Heterolayered Dendrimers

Article abstract of DOI:10.1021/jacs.9b11726

Chemoselective reactions are a highly desirable approach to generate well-defined functional macromolecules. Their extraordinary efficiency and selectivity enable the development of flawless structures, such as dendrimers, with unprecedented structure-to-property capacity but with typically tedious synthetic protocols. Here we demonstrate the potency of chemoselective reactions to accomplish sequence-controlled heterolayered dendrimers. An accurate accelerated design of bis-MPA monomers with orthogonally complementary moieties and a wisely selected chemical toolbox generated highly complex monodisperse dendrimers through simplified protocols. The versatility of the strategy was proved by obtaining different dendritic families with different properties after altering the order of addition of the monomers. Moreover, we evaluated the feasibility of the one-pot approach toward these heterolayered dendrimers as proof-of-concept.

Full text of DOI:10.1021/jacs.9b11726

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Article
Accelerated chemoselective reactions to
sequence-controlled heterolayered dendrimers
Sandra Garcia Gallego, Oliver C. J. Andrén, and Michael Malkoch
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11726 • Publication Date (Web): 02 Jan 2020
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Accelerated chemoselective reactions to sequence-controlled
heterolayered dendrimers.
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Sandra García-Gallego,† ‡ Oliver C. J. Andrén† and Michael Malkoch†*
† Royal Institute of Technology, School of Chemical Science and Engineering, Fiber and Polymer Technology, Teknikringen 56-58, SE-100 44 Stockholm, Sweden
ABSTRACT: Chemoselective reactions are a highly desirable approach to generate well-defined functional macromolecules.
Their extraordinary efficiency and selectivity enable the development of flawless structures, such as dendrimers, with
unprecedented structure-to-property capacity but with typically tedious synthetic protocols. Here we demonstrate the
potency of chemoselective reactions to accomplish sequence-controlled heterolayered dendrimers. An accurate accelerated
design of bis-MPA monomers with orthogonally complementary moieties and a wisely selected chemical toolbox generated
highly complex monodisperse dendrimers through simplified protocols. The versatility of the strategy was proved by
obtaining different dendritic families with different properties after altering the order of addition of the monomers.
Moreover, we evaluated the feasibility of the one-pot approach towards these heterolayered dendrimers as proof-of-
concept.
INTRODUCTION
apparent, especially for the key Passerini reaction.4b While
the MCR approach is intriguing, the synthesis of
generation (G) three or higher dendrimers, i.e. what truly
defines proper sizes, is still considered challenging.
Conclusively, simplification of the chemistry to
dendrimers is in a standstill and any future technological
breakthrough based on this singular polymeric class of
materials will depend on additional refinements of the
synthetic strategies.
The evermore demand for cutting-edge materials has
fueled polymer chemists to unlock new synthetic concepts.
In 2000´s, a clear transition was observed, from traditional
step-by-step organic reactions to chemoselective and
orthogonal reactions that generate advanced functional
polymers in an accelerated and robust fashion. In this
context, the Click Chemistry concept, proposed by
Sharpless and coworkers,1 was a game changer for the
scientific community. Today, the Click reactions are
recognized for their modular, wide in scope,
stereospecificity, high-yielding, generate inoffensive by-
products and enablers of orthogonal chemistries. As a
convincing stress-test for polymer chemists, the collective
features of the Click philosophy were successfully utilized
for the syntheses of dendrimers, the pinnacle of precision
polymers with monodisperse configuration.2 These
fascinating macromolecules are highly branched and
display a precise distribution of functional groups, batch-
to-batch consistency similar to proteins and thereof
unprecedented structure-to-property capacity. They are
only limited to the scientific community by their tedious
synthetic schemes. With the uprising of Click reactions,
chemists have further revised the synthetic landscape to
dendrimers by performing chemoselective and dual
orthogonal reactions that accelerate the synthesis of these
macromolecules.2b, 3 As a further simplification of the Click
approach, multicomponent reactions (MCR) have been
proposed to increase the structural diversity of dendritic
Similar to Nature´s approach to generate larger flawless
complex structures, the ultimate synthetic strategy to
dendrimers preparation is their one-pot synthesis. Such
approach capitalizes on a simple initiating core together
with a set of monomeric building blocks that undergo
successive chemical reactions in-situ to provide the desired
dendrimer. Whether simultaneously or consecutively –
“tandem” (TR) vs “non-tandem” reactions (NTR)-, one-pot
multi-step approaches to dendrimers require thorough
synthetic schemes where all reagents, intermediates,
catalysts and chemistries are compatible with each others.
In the dendrimer field, the one-pot strategy is highly
desired as it eliminates the need of tedious purifications
between each generation as well as making
deprotection/activation
steps
obsolete.
Overall,
accelerating the synthesis efficiency to dendrimers and
thereof increasing reaction yields. Importantly, a strict
control of the stoichiometry is required to avoid the
formation of incomplete dendrimers or by-products such
as low molecular weight dendrons. Despite the many
advantages of the one-pot strategy, the synthesis of a
perfect macromolecule via one-pot reactions is still
difficult to execute and therefore, the number of reports on
one-pot strategies to monodisperse dendrimers is scarce.
The first attempt was performed in the 1990’s, resulting in
scaffolds.4 This concept capitalizes on
a
one-pot
combination of three or more reactants to yield highly
selective products that retain most of the atoms of the
reagents. However, this methodology is limited by the
surface steric hindrance and reduced efficiency was
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dendritic macromolecules with PDI values of up to 1.4.5 A
sequence control has recently become a priority in the field
1
2
3
4
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7
8
decade later, a successful synthesis of a second generation
carbonate-based dendron via one-pot strategy was
reported by Rannard et al.6 Taking advantage of the highly
selective reactivity of imidazole carboxylic esters, they
developed an efficient NTRs convergent approach on large
scale (100 g) where the dendron was obtained in 89% yield
after simple purification. Simultaneously, Majoral et al.7
described the synthesis of a G4 phosphorous dendrimer via
a divergent growth approach and a one-pot multi-step
reaction strategy. However, the monodispersity of the final
fourth generation dendrimer was compromised by an
inefficient control of stoichiometry. A one-pot divergent
approach was also visited by Astruc et al.8 describing
efficient synthesis of a G3 carbosilane dendrimer under
ambient conditions. Sequential hydrosilylation and
phenolate condensation steps led to G1 to G3 dendrimers
with low polydispersities (1.00 to 1.02) and only producing
NaCl as by-product. Click chemistry has also been utilized
as a tool for accelerated and one-pot synthesis of
dendrimers. The orthogonal combination of Copper Azide-
Alkyne Cycloaddition (CuAAC) and Diels-Alder [4+2]
cycloaddition reactions led to the synthesis of a defect-free
dendrimer with hydrophilic periphery of oligo(methylene)
segments via one-pot approach.9 An even smaller number
of reports on tandem reactions are described for dendrimer
synthesis. Monteiro et al.10 demonstrated a clear control on
the rates of orthogonal click reactions in one-pot by means
of the copper catalyst activity. Two click reactions, like
CuAAC and reversible Atom Transfer Nitroxide Radical
Coupling (ATNRC) or Single Electron Transfer-Nitroxide
Radical Coupling (SET-NRC), were modulated by choice of
solvent and ligand. Thus, the researchers directed the step-
wise reaction to obtain a G2 dendrimer in a divergent,
convergent and simultaneous fashion in one-pot, and
lately synthesized a G3 dendrimer by combining those
click reactions with thiol-ene chemistry (TEC).
of polymer synthesis, being crucial for tuning the structure,
properties and functions of synthetic materials.12 Our
strategy contributes to this rapidly developing field of
sequence-controlled polymers13 demonstrating the
potency and versatility of four different chemoselective
reactions.
RESULTS AND DISCUSSION
9
Accelerated, chemoselective and layer-by-layer growth
to bis-MPA dendrimers has earlier been proven as a
powerful synthetic strategy with high fidelity that excludes
activation steps. The synthetic scheme capitalizes on
orthogonal synthesis of the dendrimers being conjured
using two bis-MPA monomer derivatives with pairing
functionalities (AB2+CD2).3 The most recent report
combined FPE14 with TEC click chemistry towards 4th
generation bis-MPA dendrimer containing internal ester
and thio-ether linkages, prepared in 3.5 h with 65% yield in
overall four steps. To go beyond state-of-the-art, we herein
embark, for the first time, on a truly accelerated synthesis
of 4th generation sequence-controlled heterolayered
dendrimers utilizing bis-MPA as a versatile platform.
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Synthesis of complementary monomers based on
bis-MPA. In this context, four chemoselective reactions
steps were deemed necessary and thereof the synthesis of
four bis-MPA monomer derivatives displaying distinctively
different chemical groups available for orthogonal
reactions (Figure 1). These monomers, denoted as AB2,
CD2, EF2 and GH2 were synthesized either following earlier
reported procedures or by accelerated and simplified
strategies with straightforward purification protocols
(Scheme 1). Detailed synthetic protocols for the monomers
and dendrimers are described in the Supporting
Information.
Inspired by the “onion-peel approach”11 reported by Roy
et al. and our AB2+CD2 approach3 to accomplish
heterolayered dendrimers with varying orthogonal
functionalities at each generation layer of the scaffold, we
demonstrate in this study a promising synthetic strategy
via sequential and one-pot chemistries for the synthesis of
first to fourth generation polyester dendrimers capitalizing
on four chemoselectively robust reactions. To accomplish
this challenging endeavor, a chemical toolbox based on
monomers with orthogonal functionalities were
synthesized and amalgamated together in a controlled
fashion to generate monodisperse dendrimers via fluoride-
promoted esterification (FPE) with imidazolide-activated
OH
O
OH
O
HS
HO
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N3
N3
O
O
O
O
H3N
O
O
compounds,
CuAAC
click
reactions,
N-
H3N
hydroxysuccinimide mediated amidation and TEC
chemistry. 2,2-bis(hydroxymethyl)propionic acid (bis-
MPA) was chosen as a monomeric building block due to its
structural simplicity, synthetic versatility and commercial
availability. It should be noted, the presented strategy
should be considered as a guiding principle and can be
easily transferred to other chemistries and monomers with
Figure 1. Chemical toolbox comprising four bis-MPA based
monomers with complementary functionalities, to react
through Fluoride-Promoted Esterification (FPE), Copper
Azide-Alkyne
Cycloaddition
(CuAAC),
N-
hydroxysuccinimide mediated amidation and thiol-ene
chemistry (TEC).
orthogonally
complementary
moieties.
Monomer
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CDI +
HOOC N3
5
1
AB2 ( )
N3
O
O
O
O
EtOAc, 50°C, 15´
CsF
5
O
in situ, 50°C, 30´
HO
5
(i)
N3
2
O
O
O
O
NHR
CD2 ( )
70%
9
O
O
CDI + HOOC NHBoc
EtOAc, 50°C, 15´
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HO
CDI
CsF
NHR
in situ, 50°C, 2h
(iii)
2a
R = Boc
(
) 83%
(i)
TFA,DCM
r.t. 1h
2b
R = H2TFA ( ) 100%
O
OH
OH
HOOC
CDI +
HO
3
O
EF2 ( )
or BAPA
O
R
R
EtOAc, 50°C, 15´
CsF
bis-MPA
CDI
NHS
N O
in situ, 50°C, 4h
O
(i) One-pot FPE
(ii) Protection
(iii) Deprotection
(i)
3a
) 62%
) 87%
R = OCOCH2
(
3b
R =
O
(
4c
GH2 (
)
4a
(
)
4b
(
)
ME
DMP,
p-TSA
CDI
O
OH
OH
O
O
O
O
O
O
p-TSA
acetone,
r.t., 18h
(ii)
O
DCM
r.t., 1h
(i)
HO
O
MeOH
r.t., 1h
(iii)
HS
HS
80%
86%
100%
Scheme 1. Comparative synthesis for the library of bis-MPA based XY2 monomers. The chemoselective XY2 monomers
were prepared from bis-MPA using simplified one-pot esterification reactions and minimizing the use of
protection/deprotection steps. The monomers tested for dendrimer synthesis are highlighted within squared boxes.
Abbreviations: CDI, 1,1´-carbonyldiimidazole; Boc, tert-butoxycarbonyl; TFA, trifluoroacetic acid; BAPA, bis(allyl)propionic
acid; NHS, N-hydroxysuccinimide; DMP, 2,2´-dimethoxypropane; p-TSA, p-toluensulfonic acid; ME, 2-mercaptoethanol.
An in-situ protocol was developed based on the use of 1,1'-
Carbonyldiimidazole (CDI) as activating reagent. CDI is
considered a superior activation reagent in terms of
scalability, wide utility and greenness,15 releasing CO2 and
imidazole as the only by-products that can easily be
separated by washing procedures. CDI has less
environmental impact than other common alternatives
such as EDC or DCC, and according to our previous study,14
the released imidazole favors the progress of the
esterification reaction and avoids the use of toxic additives
such as pyridine. Furthermore, its combination with
(Scheme 1). The library of monomers was characterized by
1H-NMR, 13C-NMR, HSQC and HMBC experiments and
MALDI-TOF (Supplementary Figs. S1-S24 and Tables S4-
S5), confirming the purity of these molecules.
As previously mentioned, the strategy developed here is
based on bis-MPA as a readily available building block easy
to derivatize. Nevertheless, this approach can certainly be
transferred to other commercially available XY2 molecules
that display orthogonal moieties, such as 3-azido-2-
(azidomethyl)-propanoic acid (alternative AB2) and 1-
thioglycerol (alternative GH2), or they can be used as
reagents to accomplish the desired XY2 monomers, such as
bis(allyl)propionic acid or 2-allyl-4-pentenoic acid towards
alternative EF2 building-blocks, like monomer 3b.
Additionally, the choice of monomer is not limited to XY2–
types and can potentially be used for XY3 commercially
Cesium Fluoride (CsF) in
a
Fluoride-Promoted
Esterification (FPE) displayed an unprecedented efficiency
towards the synthesis of complex dendritic polyesters.14 In
brief, the one-pot FPE initiates by the reaction of a
carboxylic acid containing reagent Y-COOH with CDI (1.0
eq.) led to an imidazolide-activated system Y-COIm which
was further reacted with bis-MPA (0.5 eq.) to obtain a Y2-
(bis-MPA)-COOH molecule. This system was in-situ
activated with CDI (0.5 eq.) and subsequently reacted with
a hydroxyl-containing molecule X-OH. A final purification
step allowed us to obtain the desired XY2-type building-
blocks with high yields and short reaction times.
Additional protection/deprotection reactions were
required for the synthesis of monomers CD2 and GH2
available
monomers
such
as
3-hydroxy-2,2-
bis(hydroxymethyl)propanoic acid, which could increase
the branching of the dendritic macromolecules and thereof
number of reactive sites. The simplicity and versatility of
the proposed one-pot FPE is envisaged to go beyond
monomer synthesis and could potentially be exploited for
the expansion of orthogonally functionalized high-value
precursors including higher generation dendrons,
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nanoparticles,
polymers,
biomolecules
and
after chromatographical purification procedure, with a
faster reaction (30 min).
heterofunctional dendrimers,.2e
1
2
3
4
5
6
7
8
Synthesis of TMP-core heterolayered dendrimers
through sequential approach. As a proof of concept, the
initial strategy to a dendritic scaffold was a TMP-G4-
(OH)48 dendrimer, an analogue to traditional bis-MPA
systems, i.e. same core and peripheral groups but with
different internal linkages. This dendrimer was chosen as a
mean to correlate the success of the tetra-accelerated
strategy to the state-of-the-art in dendrimer chemistry
based on bis-MPA dendrimers, considered as the most
synthetically versatile platform, and that takes into
consideration the number of reaction steps, reaction time
and total yield (Table 1, entries 1-2). The sequential
synthesis of bis-MPA dendrimers was approached. As it
can be seen in Scheme 2 and Table 1 - entry 3, the
sequential synthesis is initiated from the TMP core using
the FPE protocol, previously described by our group.14 The
AB2 monomer 1 was activated as imidazolide by reaction
with CDI for 15 min at 50°C and subsequently reacted with
TMP core in situ in the presence of CsF as a soft inorganic
base. After 30 min reaction, the first generation dendrimer
TMP-[G1]-(N3)6 5 was obtained and isolated by flash
chromatography (92% yield). The subsequent CuAAC click
reaction to G1 dendrimer 5 was evaluated using CD2
monomer in both the protected (2a) and unprotected (2b)
versions, in a THF:H2O mixture assisted by CuSO4 and
sodium ascorbate. Both reactions proceeded efficiently in
30 min, but exhibited relevant differences in the isolation
step. While dendrimer TMP-[G2]-(NHBoc)12 6a was
obtained in high yields (87%) after a simple purification
through flash chromatography, the unprotected analogue
TMP-[G2]-(NH3TFA)12 6b could only be isolated in
Table 1. Overview of strategies towards fourth
generation bis-MPA dendrimers.
Strategy
Properties
TMP core
1.
Traditional
(FPE)14a
 8 steps
 76% total yield
 7.5 h
 Mw [482-5356] Da
 Ester bonds
9
OH
OH
OH
O
OH
OH
OH
OH
OH
OH
O
O
O
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11
12
13
14
15
16
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20
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22
23
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30
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O
O
O
O
O
O
O
O
O
O
O
O
OH
O
O
O
O
OH
OH
OH
O
O
O
O
O
O
O
O
O
OH
OH
OH
2. Di-accelerated (FPE+TEC)14a
 4 steps
 65% total yield
 3.5 h
 Mw [850-9032] Da
 Ester/thioether
bonds
HO
HO
OH
OH
O
O
S
OH
OH
O
O
O
S
O
OH
OH
OH
S
O
O
O
O
S
OH
O
O
O
O
O
O
O
O
S
O
O
O
O
O
O
O
OH
OH
S
S
O
O
O
O
O
O
S
O
O
OH
OH
O
S
O
O
O
O
S
O
O
OH
OH
3. Sequential tetra-accelerateda
 4 steps
OH
O
O
OH
OH
O
O
 34% total yield
 1 h 45´
S
O
S
O
OH
OH
S
O
O
O
O
S
O
O
HN
O
O
O
NH
O
OH
OH
O
O
O
O
O
N
O
 Mw [1317-11061]
N
S
N
O
O
O
H
S
O
O
O
O
N
O
O
O
Da
O
O
O
N
O
N
O
N
O
O
HN
O
O
S
O
 Ester/triazol/amido/
thioether bonds
TREN core
3. Sequential tetra-accelerateda
 4 steps
 55% total yield
 2 h 20´
 Mw [986-18562] Da
 Amido/thioether/
ester/triazol bonds
O
O
O
O
O
HN
O
O
N
N
N
H
O
N
N
O
N
N
O
HN
O
N
N
O
O
N
O
O
O
O
NH
O
O
O
O
O
moderate
yields
(44%)
using
size
exclusion
O
O
O
O
N
N
N
O
O
O
O
HN
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
chromatography using Sephadex LH-10 in water at pH 2.5
and further freeze-drying. This could be ascribed to the
known affinity of ammonium groups towards Cu(II) ions
as well as the relative instability of the polyester
dendrimers to nucleophilic amines. The latter was recently
described by our group detailing an exceptionally fast
degradation of the ammonium functional bis-MPA
dendrimers at physiological conditions through loss of its
peripheral β-alanines.16
S
O
O
O
O
O
O
O
O
O
O
O
O
N
N
O
S
O
N
O
O
O
NH
O
O
O
N
O
N
N
4. One-Pot tetra-accelerateda
 1 stepb
 89% total yield
 2 h 20´
aThis work. bA single step comprising sequential addition
of monomers and a final purification step.
Considering the great interest in ammonium-functional
macromolecules, with potential applications as gene
carriers or antibacterial agents,17 we pursued a high-
yielding preparation of dendrimer 6b through the
deprotection of TMP-[G2]-(NHBoc)12 6a. The reaction in a
DCM:TFA mixture for 1 h at r.t. resulted in the desired
dendrimer 6b with overall two-step 72% yield. The growth
towards the third generation dendrimer required the N-
hydroxysuccinimide promoted amidation of dendrimer 6b
with EF2 building-block, in the presence of NEt3. EF2
monomers 3a and 3b, displaying ester and ether based allyl
groups, were explored and in both cases the reaction
proceeded efficiently in less than 1 h at r.t. Third generation
allyl functional dendrimer, TMP-[G3]-(ene)24 7b based on
bis(allyl)propionic acid3 provided the highest yield of 93%
As the final step, the allyl functional dendrimer 7b was
subjected to UV-initiated TEC click chemistry with GH2
monomer 4c assisted by the photoinitiator 2,2-Dimethoxy-
2-phenylacetophenone
(DMPA),
achieving
fourth
generation dendrimer TMP-[G4]-(OH)48 8 in 15 min and
90% yield. Importantly, all utilized chemistries resulted in
complete conversion being corroborated by MALDI-TOF
MS with distinct shifts of molecular ion single peaks in
each synthetic step (Table 2, Fig. 2.a); by SEC, with shifts
of the bands to lower elution volume and quite low
polydispersities (Table 2); as well as by the appearance and
disappearance of characteristics signals in 1H- and 13C-NMR
spectroscopy (Supporting Figs. S25-S38, Tables S4 and S6).
From the information provided by the combination of
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these techniques, we could confirm the structure and
purity of the TMP-core dendrimers 5-8.
1
2
3
4
5
6
7
8
9
NH2
OH
N
OH
NH2
N3
H2N
HO
O
TREN
TMP
O
N3
O
O
N3
O
O
O
O
O
O
O
O
O
O
O
O
NH
O
H
O
O
O
TMP ROUTE
N
TREN ROUTE
N
O
O
O
HN
O
3a
1
O
O
N3
O
O
O
O
O
O
(i) CDI, EtOAc
15 min, 50 C
(ii) CsF, in situ
O
N3
9
CH2Cl2
10 min, r.t.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NH3
O
H3
N
O
5
N3
OHOH
30 min, 50 C.
O
O
O
O
O
O
amidation
NH3
O
FPE
N
N
N
S
OH
OH
O
NH3
NH3
H3
N
O
O
O
O
O
O
O
O
O
HO
HO
O
N
S
N
N
O
O
9
O
O
, 95%
5
, 92%
O
N
N
N
O
O
O
O
O
O
O
S
S
O
O
O
O
O
O
NH
O
O
H
O
O
O
N
O
O
O
N
O
O
O
HN
O
O
O
N
N
N
O
O
H3
N
O
O
O
O
4
O
O
NH3
2a,b
O
O
O
HO
HO
O
S
O
O
O
O
N
O
N
N
O
S
DMPA
UV, CH2Cl2
10 min, r.t.
O
O
CuSO4, NaAsc,
THF:H2O,
O
H3
N
OH
OH
NH3
N
N
10
O
N
30 min, r.t.
F
F
O
O
O
O
O
O
F
O
12
6b
CuAAC
TEC
O
O
OHOH
NH3
H3
N
N3
O
N3
O
6a
6b
, 87%
TFA, CH2Cl2,
1 h, r.t.
10
, 72%
direct
, 44%
N3
N3
O O
N3
O
100% indirect
O
O
O
O
O
O
O
N3
O
O
O
O
O
O
O
HN
O
NH
O
N3
O
O
O
O
N3
O
O
O
O
O
O
O
O
O
N3
1
O
O
3a,b
O
O
S
O
O
N3
O
O
O
O
NH
HN
O
O
O
O
O
O
O
O
N
O
O
O
(i) CDI, EtOAc
15 min, 50 C
O
N
O
O
NEt3, CH2Cl2
30 min, r.t.
O
O
N
O
O
O
HN
S
O
O
N
O
O
O
O
O
O
O
O
H
O
O
O
O
O
N
O
O
N
N
O
S
(ii) CsF, in situ
1 h, 50 C.
O
O
N3
O
O
O
O
N
N
N
O
NH
O
N3
N3
H
N
O
O
O
amidation
O
O
O
O
N
O
O
FPE
O
O
O
HN
O
N3
O
O
S
O
O
O
O
O
O
O
N
O
O
N
O
S
N
O
O
7a
, 32%
7b
, 93%
O
O
O
O
O
H
N
O
O
O
S
O
O
11
O
, 32%
O
O
O
N
O
O
O
O
H
O
O
O
N
O
O
O
N
O
O
O
N
N3
O
O
O
O
O
O
HN
O
O
O
N3
O
O
O
O
NH
O
O
N
N3
O
O
O
N
O
O
N
O
N3
O
O
O
O
O
O
O
O
O
O
N3
2a,b
4
O
O
O
O
O
O
7b
N3
O
O
CuSO4, NaAsc
THF:H2O,
1 h, r.t.
DMPA
UV, MeOH
15 min, r.t.
N3
NH
HN
N3
O
11
OO
O
O
O
O
N3
N3
CuAAC
TEC
H3
N
NH3H3
N
NH3
O
TFA, CH2Cl2,
1 h, r.t.
O
O
O
O
O
O
O
O
O
12a
12b
, 94%
HO
OH
NH3
O
O
H3
N
HO
OH
8
, 90%
direct
O
, 8%
O
O
O
O
O
O
O
NH3
N
N
H3
N
O
O
100% indirect
O
H3
O
N
N
N
OH
OH
HO
HO
O
O
O
N
N
S
S
NH3
O
O
O
O
OHOH
O
H3
O
N
NH3
O
O
NH3
O
O
O
O
N
N
N
O
O
O
O
OH
S
S
OH
N
O
O
NH3
O
O
N
N
O
O
N
N
N
O
OO
O
O
O
O
H3
N
O
N
O
O
HO
O
O
O
O
N
O
S
O
O
O
O
N
O
O
O
O
NH
O
O
HO
HN
O
OH
O
OH
O
O
N
NH3
O
O
NH3
S
O
O
O O O
S
O
N
N
O
O
O
O
O
HO
HO
O
N
N
O
O
S
O
N
NH3
O
N
N
O
H3
N
O
O
O
O
OH
OH
N
O
O
N
NH
O
O
O
O
N
O
O
O
O
O
S
N
O
N
O
O
O
O
O
S
O
O
HN
O
O
N
O
O
O
O
O
O
H3
N
O
O
O
N
S
O
O
NH3
O
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
H
O
O
N
O
O
S
O
N
N
O
O
O
O
O
N
O
O
NH3
O
S
O
O
O
O
O
O
H
O
O
N
O
N
O
S
O
O
H3
N
HO
HO
O
N
N
N
O
O
O
O
OH
OH
N
O
S
S
O
O
O
O
O
O
N
O
N
N
O
N
NH
O
O
H
N
O
O
O
O
NH3
NH3
O
O
O
N
H3
N
O
N
O
O
N
N
HN
O
O
HO
HO
O
O
N
O
O
O
O
O
OH
OH
O
N
O
N
N
N
O
O
O
O
O
O
O
O
O
O
S
O
S
S
O
O
O
O
H3
N
O
O
S
O
H
O
O
O
O
O
N
O
O
O
H
O
N
O
O
O
N
N
O
O
O
O
O
N
S
O
NH3
O
O
O
O
O
O
O
O
O
O
O
O
H3
N
O
O
O
O
O
O
N
O
O
O
O
HN
S
O
O
N
N
O
NH
N
O
O
O
O
O
O
NH3
N
OH
OH
O
O
O
N N
O
N
O
O
O
O
O
N
N
HO
HO
O
O
N
NH3
O
O
N
O
O
O
O
O
S
S
O
O
N
N
O
O
O
O
HO
O
N
NH3
OH
OH
N
N
N
H3
N
O O O O
O
O
O
O
O
HO
O
S
S
O
O
O
O
O
O
O
O
NH3
HN
NH
O
O
O
O
O
O
N
N
O
O
O
O
O
O
OO
NH3
O
O
O
O
N
N
N
N
O
O
N
N
O
O
H3
N
O
OH
O
N
OH
O
HO
HO
O
NH3
S
NH3
O
S
O
O
O
O
O
O
NH3
O
N
N
N
O
O
O
O
HO
HO
8
12b
O
S
OH
OH
N
S
NH3
NH3
O
O
H3
N
N
N
O
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
NH3
H3
O
F
F
O
O
O
O
OH
OH
OH
OH
F
48
NH3
H3N
NH3 NH3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 11
Scheme 2. Synthetic sequences towards two different families of bis-MPA dendrimers. The selected core, TREN or TMP,
determines the order of addition of the monomers and the synthesis of two different families of dendrimers from generation
1 to 4. a. TMP-G4-(OH)48 is achieved in 1 h 45´ reaction time with 34% overall yield. b. TREN-G4-(NHBoc)48 is achieved in
2 h 20´ reaction time with 55% overall yield.
1
2
3
4
5
6
7
8
Synthesis of TREN-core heterolayered dendrimers
through sequential approach. To showcase the
versatility of the proposed synthetic strategy, we further
synthesized a second family of bis-MPA dendrimers by
altering the order of monomer feedstock. The
chemoselective reaction sequence and thereof queued
internal bonds is dictated by the core of choice and in this
case Tris(2-aminoethyl)amine (TREN) was used. The
sequential synthesis of the TREN-core dendrimer family is
outlined in Scheme 2. In the first step, TREN was
selectively reacted with EF2 3a building block via NHS-
assisted amidation. The reaction towards TREN-[G1]-
(ene)6 9 was complete in 10 min at room temperature. In a
second step, UV-initiated TEC click reaction was
performed between dendrimer 9 and GH2 building block
4c. Again, only 10 min irradiation assisted by 2,2-
dimethoxy-2-phenylacetophenone were required to the
full conversion of the alkene bonds and the delivery of the
dendrimer TREN-[G2]-(OH)12 10. Further growth to
achieve the third generation was performed through the
FPE of the peripheral hydroxyl groups via imidazolide-
activated AB2 monomer in the presence of CsF. After 1 h
was easily isolated through flash chromatography in high
yields (94%), but TREN-[G4]-(NH3TFA)48 12b required an
additional step via deprotection of 12a to accomplish an
excellent overall two-step 97% yield. Quantitative
conversions in all reactions are shown by the appearance
and disappearance of characteristics signals in 1H- and 13C-
NMR spectroscopy (Supporting Figs. S39-S50, Tables S4
and S7); by SEC, with shifts of the bands to lower elution
volume and low polydispersities (Table 2); and by complete
shifts of molecular ion single peaks in each synthetic step
in MALDI-TOF spectrometry (Table 2, Fig. 2.a), whenever
it was possible.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Collectively, two sophisticated bis-MPA dendrimers,
TMP-[G4]-(OH)48 and TREN-[G4]-(NHBoc)48, were
synthesized for the first time in a sequential matter
utilizing four different chemoselective reactions with
satisfactory total yields (Table 1). Compared to the
traditional growth/activation synthesis to bis-MPA
dendrimers the total reaction time was reduced from 7.5 h
to less than 2 h. The obtained dendrimers possess
unprecedented sequence defined queues of heterogeneous
linkages being ester, triazol, amido and thioether bonds,
which inevitably provide chemical and physically different
behavior than their traditional counterpart. The complete
library of dendrimers was thoroughly characterized to
reaction,
dendrimer
TREN-[G3]-(N3)24
11
was
accomplished. As a final step, the fourth generation
dendrimers, in the protected (12a) and unprotected (12b)
versions, were obtained after 1 h at r.t. of CuAAC reaction
of CD2 monomers 2a or 2b with dendrimer 11, assisted by
CuSO4 and sodium ascorbate. TREN-[G4]-(NHBoc)48 12a
1
assess their structure and purity (MALDI-TOF; H-,13C-
NMR, 2D-NMR; SEC) and their thermal properties (DSC).
Table 2. Relevant properties for the library of dendrimers described.
Dendrimer
MTEO (g/mol)
m/zMALDI a)
MnSEC (g/mol)
PDISEC
TgDSC (ºC)
TMP-G4-(OH)48 (traditional)14a
TMP-G1-(N3)6 (5)
TMP-G2-(NHBoc)12 (6a)
TMP-G2-(NH3TFA)12 (6b)
TMP-G3-(ene)24 (7b)
TMP-G4-(OH)48 (8)
TREN-G1-(ene)6 (9)
TREN-G2-(OH)12 (10)
TREN-G3-(N3)24 (11)
TREN-G4-(NHBoc)48 (12a)
TREN-G4-(NH3TFA)48 (12b)
5359.4
1316.7
4236.6
3045.5
5390.1
11060.9
986.5
2150.9
6881.3
18562.3
13796.4
5390.4
1340.3
4258.6
3063.2
5510.0
1207.7
4844.1
2687.8
6085.5
12556.0
1017.8
3306.0
7708.6
14400.0
6337.4
1.07
1.06
1.02
1.43
1.01
1.01
1.04
1.03
1.01
1.13
1.50
47.2
< -60.0c)
39.5
57.0
-11.2
2.9
5393.5
b)
1010.0
2174.4
-42.5
-14.5
< -60.0c)
32.0
6895.9
b)
b)
62.0
a) Values of m/z + Na+; b) Not observed; c) Value below the DSC limit of measurement (-60°C).
Supporting Information for detailed spectra). The
molecular weight distribution of the dendrimer library was
determined by SEC (Supporting Fig. S51 and S52), showing
a low polydispersity for all four generations of dendrimers,
with PDI values ranging 1.01-1.06, except for dendrimers
6b, 12a and 12b. The ammonium-functional dendrimers 6b
and 12b displayed a higher dispersity due to the presence
of aggregates between two molecules via physical
The combination of all these techniques was essential to
obtain valuable information. An overview of the properties
is depicted in Fig. 2 and Table 2. Whenever it was possible
to measure, the MALDI-TOF spectra displayed a single
peak that confirmed the total conversion and
monodispersity of the dendrimers and provided an
accurate value for the molecular weight of each sample (see
ACS Paragon Plus Environment

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Journal of the American Chemical Society
interactions (Fig. S52). The absence of several bands and reaction deuterated solvent (CDCl3). The different
1
2
3
4
5
6
7
8
the recovery of monomodal spectra after subsequent
growth to higher generation rules out the uncontrolled
covalent attachment of the ammonium-functional
dendrimers. A similar explanation can be found for G4
dendrimer 12a, whose SEC band depicts a shoulder at
higher molar mass arising from potential aggregates (Fig.
S54). However, all theoretical and obtained values from
MALDI-TOF still correlated well, verifying the flawlessness
of the dendrimers (Table 2). The thermal behavior of the
new dendrimers covers a broad range of glass transition
temperatures (Tg) due to the complexity of their structure
(Fig. 2b). While the traditional homolayered bis-MPA
dendrimers displayed Tg values in the range -5 to 50°C, the
new families broadened this range from below -60 to 62°C.
Indeed, the results confirm the dramatic influence of i) the
molecular weight, ii) the internal bonds and iii) the end
groups on the thermal properties of the dendrimers, as
previously reported by Fréchet et al.18 For TMP-[G4]-
(OH)48 dendrimers, 44°C difference is observed between
the traditional dendrimer, with uniform ester bonds in the
scaffold, and the heterolayered, comprising also triazol,
amido and thioether bonds. The end-groups influence is
mainly related to their polarity, where the lower Tg values
are found for the non-polar azide-functional dendrimers
and the higher ones for the ammonium-functional
macromolecules capable of H-bond formation, with
around 120°C difference between them. Consequently, the
proposed accelerated strategy facilitates the accurate
design of dendrimers, by wise selection of these
parameters, that pinpoint macromolecules with desired Tg
value for a particular application.
building-blocks were sequentially added to the reaction
vessel, once the previous step was complete, and reacted
in-situ (Fig. 2c). In order to guarantee the monodispersity
of the dendrimers, a small excess of the different
monomers was used in each step ranging from 1.02 to 1.5
eq. in relation to the reactive groups (see Tables S1-S3 for
details). It becomes evident that the isolation of the
targeted dendrimers – especially the higher generations- is
thus a challenging task considering the parallel synthesis
of dendrons as byproducts, formed as due to excess of
monomers during the reaction sequence. The reactions
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
were monitored through H-NMR (Fig. 2d), together with
MALDI and SEC (Fig. 2e). In all cases, the reaction
sequence was initiated from 5 mg of TREN core and,
remarkably, delivered the targeted dendrimer after a single
purification step. Importantly, the formation of dendrons
did not interfere with the synthesis and isolation of the
dendrimers. Our efforts in the optimization of the final
purification step demonstrated the possibility of isolating
the targeted dendrimers in high yield. For the lower
generation dendrimers TREN-G1-(ene)6 (9) and TREN-G2-
(OH)12 (10), automated flash chromatography using Isolera
successfully delivered pure dendrimers both with 95%
yield. For the higher generation dendrimers TREN-G3-
(N3)24 (11) and TREN-G4-(NHBoc)48 (12a), however, a
better isolation protocol was found by means of size-
exclusion chromatography using Sephadex-LP20 in
MeOH, with around 90% yield. After isolation, the TREN-
core dendrimers prepared via one-pot route exhibited the
same structural profile – NMR, MALDI, SEC spectra- than
those prepared through the sequential route (Fig. S54),
confirming the feasibility of the strategy. Overall, the one-
pot approach reduced the total reaction time, minimized
the purification steps and delivered the targeted
dendrimers in higher yields, in comparison to the
sequential route. A fourth generation dendrimer was
isolated in ca 400 mg (89% yield) and in less than 2.5 h of
total reaction time and through a single purification step.
One-pot synthesis of TREN-core heterolayered
dendrimers as proof-of-concept. Satisfied with the
sequential chemoselective strategy to bis-MPA dendrimers
we further ventured into the simplification of the synthesis
using one-pot chemistry to bis-MPA dendrimers 9, 10, 11
and 12a through a non-tandem approach. The TREN route
was selected for an easier in-situ characterization of the
different dendrimers, due to their complete solubility in
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 11
a
1
2
b
TMP traditional
TMP heterolayered
TREN heterolayered
80
60
40
20
0
3
4
5
6
7
8
9
+
-NH3
homo
layered
TREN-[Gn](X)m
TMP-[Gn](X)m
-OH
hetero
layered
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
e
120
90
G1
G2
G3
G4
G3 (7b) 5393.5
G2 (6) 3063.2
t / min
60
-20
-40
-60
G3 (11) 6895.9
G1 (5) 1340.3
G2 (10) 2174.4
G1 (9) 1010.0
30
*
*
-N3
m/z
2500
5000
7500 10000
c
d
4
-CH2NH2
3
2
1
-CH=CH2
One-Pot
synthesis
Single
purification
-CH2OH
e
G4
(12a)
G3
(11)
G2
(10)
G1
(9)
-CH2N3
-NHBoc
.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
4,0
4,5
5,0
Elution volume
5,5
6,0
f1 (ppm)
Figure 2. The heterolayered dendrimers expanded the properties and simplified the synthetic protocol of traditional
dendrimers, including one-pot approach that delivered TREN-G4-(NHBoc)48 in less than 2.5 h reaction time with a single
purification step and 89% yield. a) MALDI-TOF MS spectra of bis-MPA dendrimers from first (G1) to third (G3) generation
with different cores and the accumulative reaction time for their synthesis. Experimental m/z values for [M+Na+] are
depicted in the figure. Theoretical m/z values for [M+]: 1316.7 (5), 3045.5 (6), 5386.7 (7b), 986.5 (9), 2150.0 (10), 6881.3 (11);
b) Tg values measured through DSC, *indicating values below the limit of detection of the instrument; c) schematic of the
one-pot non-tandem approach; d) the one-pot reaction was easily monitored through 1H-NMR spectroscopy, observing the
disappearance of the signals at 2.75 ppm (-CH2NH2, G0 to G1), 4.96-5.84 ppm (-CH=CH2, G1 to G2), 3.68-3.86 ppm (–CH2OH,
G2 to G3) and 3.25 ppm (-CH2N3, G3 to G4). e) The SEC curves for the isolated dendrimers accomplished through the one-
pot approach indicate the successful dendrimer formation at each step.
CONCLUSION
accelerated synthetic scheme to AB2-monomers that
displayed desired functional groups and their
amalgamation in four consecutive and orthogonal
chemical reactions to generate fourth generation
Chemoselective reactions are an excellent chemical
toolbox that enables the synthesis of complex
macromolecules in a simplified way. Relying on their
efficiency and selectivity, we herein showcased an
dendrimers
with
internal
sequence-controlled
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4593-4609; (d) Carlmark, A.; Malmström, E.; Malkoch, M.,
heterolayered configuration. In its simplest form, using
Dendritic architectures based on bis-MPA: functional polymeric
scaffolds for application-driven research. Chem. Soc. Rev. 2013, 42
(13), 5858-5879; (e) García-Gallego, S.; Nyström, A. M.; Malkoch,
M., Chemistry of multifunctional polymers based on bis-MPA and
their cutting-edge applications. Prog. Polym. Sci. 2015, 48, 85-110.
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bis-MPA as a model monomer, this growth concept makes
the typical usage of activation steps obsolete, introduces
heterogeneous covalent linkages across the dendritic
skeleton, allows the synthesis of different frameworks by
altering the sequence order of reactions, reduces the
reaction time from days into minutes, can potentially be
accomplished in sequence or one-pot and all while
preserving the structural perfection that is typical defining
dendrimers as the most precise polymers available. The
proposed strategy leaps the synthesis of complex
dendrimers to a new domain and in parallel minimizes
their synthetic challenges. It can be considered a guiding
strategy that can easily be transferred to generate a myriad
of monomers and thereof functional macromolecules and
materials that go beyond monodisperse dendrimers.
3. Antoni, P.; Robb, M. J.; Campos, L.; Montañez, M.; Hult, A.;
Malmström, E.; Malkoch, M.; Hawker, C. J., Pushing the limits for
Thiol−Ene and CuAAC reactions: Synthesis of a 6th generation
dendrimer in a single day. Macromolecules (Washington, DC, U.
S.) 2010, 43 (16), 6625-6631.
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4. (a) Kreye, O.; Kugele, D.; Faust, L.; Meier, M. A., Divergent
dendrimer synthesis via the Passerini three-component reaction
and olefin cross-metathesis. Macromol. Rapid Commun. 2014, 35
(3), 317-322; (b) Deng, X.-X.; Du, F.-S.; Li, Z.-C., Combination of
orthogonal ABB and ABC multicomponent reactions toward
efficient divergent synthesis of dendrimers with structural
diversity. ACS Macro Lett. 2014, 3 (7), 667-670.
ASSOCIATED CONTENT
Supporting Information.
Experimental details, structure and synthetic procedures of
monomers and dendrimers. Analytical data including 1H, 13C-
NMR, 2D-NMR, SEC traces, MALDI-TOF-MS, DSC analysis.
This material is available free of charge via the Internet at
http://pubs.acs.org.
5. Yamakawa, Y.; Ueda, M.; Takeuchi, K.; Asai, M., One-pot
synthesis of dendritic polyamide. J. Polym. Sci., Part A: Polym.
Chem. 1999, 37 (18), 3638-3645.
6. Rannard, S. P.; Davis, N. J., A Highly selective, one-pot multiple-
addition convergent synthesis of polycarbonate dendrimers. J.
Am. Chem. Soc. 2000, 122 (47), 11729-11730.
7. Brauge, L.; Magro, G.; Caminade, A.-M.; Majoral, J.-P., First
divergent strategy using two AB2 unprotected monomers for the
rapid synthesis of dendrimers. J. Am. Chem. Soc. 2001, 123 (27),
6698-6699.
AUTHOR INFORMATION
Corresponding Author
* Prof. Michael Malkoch
Royal Institute of Technology, School of Chemical Science
and Engineering, Fibre and Polymer Technology,
Teknikringen 56-58, SE-100 44 Stockholm, Sweden
E-mail: malkoch@kth.se.
8. Ornelas, C.; Aranzaes, J. R.; Cloutet, E.; Astruc, D., A one-pot
synthesis of a 243-allyl dendrimer under ambient conditions. Org.
Lett. 2006, 8 (13), 2751-2753.
9. Xiong, X. Q., One-pot synthesis of dendrimer via double click
reactions. Chin. J. Org. Chem. 2010, 2, 307-310.
Present Addresses
‡Department of Organic and Inorganic Chemistry. Faculty of
Sciences. University of Alcalá (Madrid, Spain)
10. Jia, Z.; Bell, C. A.; Monteiro, M. J., Directing the pathway of
orthogonal 'click' reactions by modulating copper-catalytic
activity. Chem. Commun. (Cambridge, U. K.) 2011, 47 (14), 4165-
4167.
ACKNOWLEDGMENT
This work was generously supported by the Swedish Research
Council VR (2011-5358, 2010-435 and 2015-04779) and Knut and
Alice Wallenberg Foundation KAW (2012-0196). This project
has received funding for Sandra García-Gallego from the
European Union's Horizon 2020 research and innovation
programme under the Marie Skłodowska-Curie Grant
Agreement No. 655649. The authors also acknowledge the
experimental support from Kim Öberg and Marco Massa.
11. (a) Sharma, R.; Naresh, K.; Chabre, Y. M.; Rej, R.; Saadeh, N. K.;
Roy, R., "Onion peel" dendrimers: a straightforward synthetic
approach towards highly diversified architectures. Polym. Chem.
2014, 5 (14), 4321-4331; (b) Sharma, R.; Kottari, N.; Chabre, Y. M.;
Abbassi, L.; Shiao, T. C.; Roy, R.,
A highly versatile
convergent/divergent "onion peel" synthetic strategy toward
potent multivalent glycodendrimers. Chem. Commun.
(Cambridge, U. K.) 2014, 50 (87), 13300-13303; (c) Sharma, R.;
Zhang, I.; Abbassi, L.; Rej, R.; Maysinger, D.; Roy, R., A fast track
strategy toward highly functionalized dendrimers with different
structural layers: an "onion peel approach". Polym. Chem. 2015, 6
(9), 1436-1444.
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Single
purification
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O
2
O
O
O
O
O
HN
O
N
N
N
H
O
N
N
O
N
N
O
HN
O
N
N
O
O
N
O
O
O
NH
O
O
O
O
O
O
1
O
O
O
N
N
O
N
O
O
O
O
HN
O
O
Sequential
or one-pot
synthesis
O
O
O
O
O
O
O
O
O
N
N
N
O
S
O
O
O
O
O
O
O
O
O
O
O
O
N
S
O
N
N
O
NH
O
O
O
O
O
O
N
O
N
N
Heterolayered
dendrimers
“For Table of Contents Only”
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