Protecting-Group-Free Site-Selective Reactions in a Metal-Organic Framework Reaction Vessel

Article abstract of DOI:10.1021/jacs.8b02896

Site-selective organic transformations are commonly required in the synthesis of complex molecules. By employing a bespoke metal-organic framework (MOF, 1·[Mn(CO)₃N₃]), in which coordinated azide anions are precisely positioned within 1D channels, we present a strategy for the site-selective transformation of dialkynes into alkyne-functionalized triazoles. As an illustration of this approach, 1,7-octadiyne-3,6-dione stoichiometrically furnishes the mono- click product N-methyl-4-hex-5′-ynl-1′,4′-dione-1,2,3-triazole with only trace bis-triazole side-product. Stepwise insights into conversions of the MOF reaction vessel were obtained by X-ray crystallography, demonstrating that the reactive sites are isolated from one another. Single-crystal to single-crystal transformations of the Mn(I)-metalated material 1·[Mn(CO)₃(H₂O)]Br to the corresponding azide species 1·[Mn(CO)₃N₃] with sodium azide, followed by a series of [3+2] azide-alkyne cycloaddition reactions, are reported. The final liberation of the click products from the porous material is achieved by N-alkylation with MeBr, which regenerates starting MOF 1·[Mn(CO)₃(H₂O)]Br and releases the organic products, as characterized by NMR spectroscopy and mass spectrometry. Once the dialkyne length exceeds the azide separation, site selectivity is lost, confirming the critical importance of isolated azide moieties for this strategy. We postulate that carefully designed MOFs can act as physical protecting groups to facilitate other site-selective and chemoselective transformations.

Full text of DOI:10.1021/jacs.8b02896

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Protecting-Group-Free Site-Selective Reactions
in a Metal–Organic Framework Reaction Vessel
Michael T. Huxley, Alexandre Burgun, Hanieh Ghodrati, Campbell J. Coghlan, Anthony
Lemieux, Neil R. Champness, David M. Huang, Christian J Doonan, and Christopher J. Sumby
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02896 • Publication Date (Web): 26 Apr 2018
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Protecting-Group-Free Site-Selective Reactions in a Metal–Organic
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Michael. T. Huxley,a Alexandre Burgun,a Hanieh Ghodrati,a,b Campbell J. Coghlan,a Anthony
Lemieux,a Neil R. Champness,c David M. Huang,a Christian J. Doonan*a and Christopher J. Sumby*a
a
Department of Chemistry and Centre for Advanced Nanomaterials, The University of Adelaide, Adelaide, South Australia
5005, Australia; E-mail: christopher.sumby@adelaide.edu.au; E-mail: christian.doonan@adelaide.edu.au
b
Present address: School of Mechanical Engineering, University of Adelaide, Adelaide, South Australia 5005, Australia
c
Department of Chemistry, University of Nottingham, Nottingham, UK
KEYWORDS. Metal-Organic Frameworks, Azide-alkyne cycloaddition, Site-selective chemistry, single-crystal to single-crys-
tal transformations
ABSTRACT: Site-selective organic transformations are commonly required in the synthesis of complex molecules. By employing
a bespoke metal-organic framework (MOF, 1·[Mn(CO)3N3]), in which coordinated azide anions are precisely positioned within 1D
channels, we present a strategy for the site-selective transformation of dialkynes into alkyne-functionalized triazoles. As an illustra-
tion of this approach, 1,7-octadiyne-3,6-dione stoichiometrically furnishes the mono-“click” product N-methyl-4-hex-5’-ynl-1’,4’-
dione-1,2,3-triazole with only trace bis-triazole side-product. Stepwise insights into conversions of the MOF reaction vessel were
obtained by X-ray crystallography, demonstrating that the reactive sites are “isolated” from one another. Single-crystal to single-
crystal transformations of the Mn(I)-metalated material 1·[Mn(CO)3(H2O)]Br to the corresponding azide species 1·[Mn(CO)3N3] with
sodium azide, followed by a series of [3+2] azide-alkyne cycloaddition reactions, are reported. The final liberation of the “click”
products from the porous material is achieved by N-alkylation with MeBr, regenerating starting MOF 1·[Mn(CO)3(H2O)]Br, and the
organic products characterized by NMR spectroscopy and mass spectrometry. Once the dialkyne length exceeds the azide separation,
site selectivity is lost, confirming the critical importance of isolated azide moieties for this strategy. We postulate that carefully
designed MOFs can act as physical protecting groups to facilitate other site-selective and chemoselective transformations.
A key feature of 1 is that it is composed of regularly spaced
Introduction
vacant bis-pyrazolyl groups that are accessible to post-synthetic
metalation (PSM)20, 28 reactions via ca. 13 Å diameter pores.
Metal–organic frameworks (MOFs) are a class of porous
materials that are synthesized via a ‘building-block’ approach
from organic links and metal-based nodes.1-2 In recent years,
they have been intensely studied for their potential application
to catalysis,1-8 gas storage/separation,9-12 biotechnology13-14 and
microelectronics.15-16 A key feature of MOFs is that they can
be grown as single crystals, which allows their structures to be
elucidated via single-crystal X-ray diffraction (SCXRD). This
technique has proved crucial to the development of MOF chem-
istry by providing molecular-level insight into the nature of gas
adsorption,17-19 chemical reactions within pore networks,20-25 ca-
talysis,26-27 and the structure of guest molecules.8 We recently
showed that crystals of the Mn(II)-based MOF 1 (1=
[Mn3(L)2(L′)], where H2L= bis(4-(4-carboxyphenyl)-1H-3,5-
dimethylpyrazolyl)methane and L′ possesses a non-coordinated
bis(3,5-dimethylpyrazol-1-yl)methane moiety) can be em-
ployed to structurally characterize the intermediates of a cata-
lytic reaction cycle carried out within the framework pores.20, 27
Typically, PSM chemistry is employed to enhance the per-
formance characteristics of a given framework; however, we
hypothesized that the spatial isolation of reactive metal centers
could be employed to carry out chemoselective reactions within
MOF pores without the need for a traditional protecting group.
To realize this concept, we incorporated an azide functionality
into the pores of 1 via a two-step process: PSM of 1 with
[Mn(CO)5Br] followed by halide exchange with sodium azide
to afford 1·[Mn(CO)3N3], which is primed for further reaction.
The azide groups of 1·[Mn(CO)3N3] are located 13 Å apart and
thus uniquely poised to selectively carry out an azide-alkyne
[3+2] cycloaddition reaction on one of the alkyne moieties of a
symmetrical dialkyne (Figure 1). Synthetic approaches towards
the preparation of compounds that
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Figure 1. (a) A representation of the spatially isolated azide sites along the 1-D c-axis pores of 1 (C, dark grey; N, blue; O, red; Mn,
beige; H atoms omitted for clarity). The insert reveals the coordination chemistry about the PSM added Mn(I) center in the MOF, showing
the loaded azide reagent in the axial site. (b) A graphical depiction of the site-isolation strategy using a dialkyne substrate, showing the
introduction of the dialkyne, its “click” conversion (the Mn(I) sites are periodically separated by ca. 13Å), and then liberation by alkylation
with MeBr to produce the desired N-methyl alkynyl triazole.
possess both triazole and alkyne functional groups generally
proceed via chemical protection of one alkyne or the addition
of the alkyne fragment to a pre-formed halogenated triazole de-
rivative via Sonogashira coupling.29-30 Direct synthesis of al-
kyne-substituted triazoles from the corresponding azide and
polyalkyne reagents are less common. Tykwinski et. al., how-
ever, reported the preparation of triazoles bearing poly-alkyne
substituents from non-symmetric poly-alkynes and benzyl az-
ide.31 Other studies have reported the synthesis of 5-alkynyl tri-
azoles from poly-alkynes featuring phenyl32 or trimethyl-silyl30,
exemplifies how the inherent crystallinity of MOFs can be ex-
ploited to gain a fundamental understanding of chemical reac-
tivity within their pores. Additionally, it develops the concept
of how the modular approach to MOF synthesis can lead to the
precise spatial isolation of reactive sites that are poised to bind
substrates34 and facilitate site-selective reactions.
Results and Discussion
Azide “loading” of the MOF
33
We previously showed that the functionality of MOF 1 can
be tailored via quantitative metalation of the bis-pyrazole moi-
eties lining its pore network.20, 27 The flexible organic linker
allows the MOF structure to respond dynamically to the chang-
ing coordination environment of the PSM added metal without
compromising the integrity of the single crystals. The post-syn-
thetically introduced reactive sites are uniformly distributed
within the MOF (ca. 13 Å apart), and so we envisaged that they
may be employed to carry out site-selective chemical transfor-
mations (Figure 1). For example, based on collision theory, a
homogeneous [3+2] cycloaddition reaction between an inor-
ganic azide and dialkyne would conventionally yield a mixture
of triazole products. However, the equivalent reaction employ-
ing a derivative of 1 bearing site-isolated inorganic azides
should selectively yield the alkyne-functionalized triazolate
complex, owing to the physical separation of the adjacent az-
ides. Accordingly, to explore the potential of MOFs as reaction
vessels for site-selective chemistry, we sought to perform selec-
tive [3+2] cycloaddition reactions using an azide-functionalized
version of 1.
terminal groups. However, direct “click”-type synthesis of
triazoles bearing unhindered terminal alkyne substituents have
not been reported.
Herein we employ SCXRD to demonstrate that reactive-site
isolation in a MOF scaffold facilitates site-selective reactions.
Single-crystal to single-crystal (SC-SC) transformations of
1·[Mn(CO)3(H2O)]Br to the corresponding azide species
1·[Mn(CO)3N3] with sodium azide, followed by a series of
[3+2] azide-alkyne cycloaddition reactions, and final liberation
of the “click” products from the porous material by N-alkyla-
tion with MeBr to regenerate 1·[Mn(CO)3(H2O)]Br, were ex-
amined by SCXRD and IR spectroscopy to reveal the postulated
reaction cycle. Five alkynes, namely dimethyl-acetylene dicar-
boxylate (DMAD), ethyl-propiolate (EPOP), 1,7-octadiyne-
3,6-dione (DA1), 1,9-decadiyne-3,8-dione (DA2), and 1,11-do-
decadiyne-3,10-dione (DA3) were investigated to test the site
isolation hypothesis. For all alkyne substrates, the reactions
yield the desired triazoles, and reveal an unexpected N1 binding
mode of the triazole in the MOF. In particular, we demonstrate
the site-selective conversion of dialkynes into alkyne-substi-
tuted triazoles when the structure metrics of the dialkyne are
smaller than the azide group spacing in the MOF. This study
An azide-functionalized derivative of 1 was prepared by a
sequential metalation and anion-exchange strategy. Initially
MOF 1 was treated with [Mn(CO)5Br] in ethanol at
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Figure 2. Representations of the metalated N,N-chelation site in the pore space of 1 at key steps in the "click" chemistry reaction scheme,
with a perspective view of each complex shown below. (a) 1·[Mn(CO)3(H2O)]Br, displaying the facial isomer of the [Mn(CO)3(H2O)] moiety
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following post-synthetic metalation, (b) 1·[Mn(CO)3N3], following facile exchange of Br- for N3 , and (c) 1·[Mn(CO)3(ET)] (where ET =
-
ethyl-4-carboxy-1,2,3-triazolate), the triazolate complex following reaction of the azide with ethyl-propiolate, including side and top views
of the Fobs electron density map associated with the triazolate. The parent MOF framework is represented by a translucent, blue van der
Waal’s surface (C, dark grey; N, blue; O, red; Mn, beige; Br, yellow; H atoms omitted for clarity).
data. These experiments elucidated the presence of an azide an-
50˚C. The crystalline product was characterized by synchrotron
SCXRD, which elucidated that the N,N-chelation site of 1 was
ion bound to the axial site of the octahedral Mn(I) complex and
retention of the facially coordinated CºO ligands. The crystal
structure of 1·[Mn(CO)3N3] obtained using synchrotron radia-
tion also confirmed that the azide anions are site-isolated (ca.
13 Å apart), well ordered and accessible to guest molecules ren-
dering this MOF an ideal candidate for site-selective ‘‘click’’
chemistry.
occupied by
a
manganese tricarbonyl moiety, fac-
1·[Mn(CO)3(H2O)]Br, with a non-coordinated Br– counterion.
Quantitative metalation was confirmed by energy-dispersive X-
ray (EDX) analysis which yielded an Mn:Br ratio of 4:1. We
also examined 1·[Mn(CO)3(H2O)]Br by IR spectroscopy,
which revealed characteristic CºO stretches at 1951, 2040 and
‘‘Click’’ chemistry within the MOF pores
1921 cm-1.35-37
Additionally, the phase purity of
The azide functional group is known to participate in the
[3+2] cycloaddition reaction with alkyne moieties to form a tri-
azole (in the case of an organic azide) or triazolate salt (for an
inorganic azide complex).40-42 This prototypical “click” reac-
tion is applied in numerous fields of chemistry, such as den-
drimer synthesis,43-44 preparation of pharmaceuticals ,45-48 post-
synthetic modification of MOFs,49-51 and extensively in poly-
mer science.52-53 The Cu-catalyzed [3+2] cycloaddition reac-
tion between organic azides and alkynes has been studied in
various MOF frameworks54-55 and zeolites.56 However, in
1·[Mn(CO)3N3] the azide source is inorganic and, although such
transformations are colloquially termed “click’’ reactions, the
reaction described herein is formally a Huisgen cycloaddition
process. Importantly, it is expected that the reaction between
1·[Mn(CO)3N3] and an alkyne will yield a product in which the
triazolate is coordinated to the structurally isolated Mn sites.38
Thus, if a dialkyne is employed the physical separation between
the triazolate complex and adjacent azide moiety, imposed by
1·[Mn(CO)3(H2O)]Br was confirmed by PXRD analysis (SI
Figure S6.3).
Anion-exchange reactions are well known for metal-halide
complexes. Thus, we explored the direct exchange of the non-
coordinated bromide with azide to decorate the pores of the
MOF with azide moieties. Crystals of 1·[Mn(CO)3(H2O)]Br
were soaked in a methanol solution of sodium azide (NaN3) for
three days to yield 1·[Mn(CO)3N3]. The IR spectrum of
1·[Mn(CO)3N3] revealed a strong IR stretch at 2070 cm-1 that is
typical of a metal-coordinated azide;35, 37-39 furthermore, the ex-
pected n(CºO) bands were observed at 2025, 1952, and 1903
cm-1. The elemental composition of 1·[Mn(CO)3N3] was as-
sessed by EDX analysis to provide insight into the extent of Br-
substitution. Close inspection of the data showed that subse-
quent to the anion exchange protocol the Mn:Br ratio decreased
from 4:1 to 4:0.07. Throughout the anion-exchange process the
MOF retained its crystallinity allowing us to collect SCXRD
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the host framework, would prevent the remaining alkyne from reduce steric interactions between the host framework and tria-
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participating in a secondary “click’’ reaction (Figure 1). Fur-
thermore, the N-alkyl organic triazole can be easily liberated
via reaction with an alkyl halide. This chemistry facilitates a
novel synthesis strategy for alkyne-functionalized triazoles via
step-wise inorganic ‘‘click’’ chemistry and N-alkylation.
zolate. Density functional theory calculations support this hy-
pothesis. Comparison of the calculated energies of the N(1)-
and N(2)-bound complexes in 1·[Mn(CO)3(DMT)] and molec-
ular species shows that the framework stabilizes the N(1)-
bound isomer by 11 kJ/mol with respect to the N(2)-bound iso-
mer. Furthermore, significant steric interactions between the
We exposed single crystals of 1·[Mn(CO)3N3] to two elec-
tron-deficient alkynes, dimethyl-acetylene dicarboxylate
(DMAD) and ethyl-propiolate (EPOP) to afford
1·[Mn(CO)3(DMT)] and 1·[Mn(CO)3(ET)], respectively
(where DMT = dimethyl 4,5-dicarboxy-1,2,3-triazolate and ET
= ethyl 4-carboxy-1,2,3-triazolate). Each reaction was per-
formed at 50˚C in toluene to promote formation of the corre-
sponding triazolate complex and after 24h the respective sam-
ples were examined by FTIR spectroscopy. In both spectra the
characteristic azide asymmetric stretch at 2070 cm-1 of
1·[Mn(CO)3N3] was absent, indicating that quantitative conver-
sion of the azide had occurred (Figure 3a and SI Figure S7.1).
Furthermore, the simultaneous growth of a methyl or ethyl ester
carbonyl stretch at 1716 and 1711 cm-1 respectively, was ob-
served, supporting the presence of a coordinated triazolate moi-
ety.57 PXRD experiments performed on the MOF crystals after
the "click" reactions indicate that the bulk material retains a
high degree of crystallinity (Figure 3b, data shown for the
EPOP cycle).
host
framework
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Remarkably, subsequent to successive anion exchange and
‘click’ reactions the crystals of 1·[Mn(CO)3(DMT)] and
1·[Mn(CO)3(ET)] remained suitable for SCXRD. Structure so-
lution and data refinement revealed the presence of an N(1)-
bound triazolate product in both 1·[Mn(CO)3(ET)] (Figure 2c)
and 1·[Mn(CO)3(DMT)] (SI Figure S5.2.3). The structure de-
terminations were further supported by a close match of the
structural model to the Fobs electron density maps (Figure 2c).
In both instances, the triazolate resides on the mirror plane bi-
secting the Mn(I) complex and is coordinated to the axial site
formerly occupied by azide in 1·[Mn(CO)3N3]. Close exami-
nation of the data indicates preferential formation of an N(1)-
bound complex in 1·[Mn(CO)3(DMT)] (SI Figure S5.2.3). The
single ethyl ester substituent in 1·[Mn(CO)3(ET)] is appended
such that it projects into the MOF pore and, by assigning the
largest electron density peaks in the triazole ring system as ni-
trogen atoms, we also refined the triazolate complex as an N(1)-
bound isomer consistent with that observed in
1·[Mn(CO)3(DMT)].
Figure 3. (a) IR spectra of 1·[Mn(CO)3N3] and the ‘‘click’’-
chemistry product 1·[Mn(CO)3(ET)], confirming loss of the N3
stretch (2070 cm-1, indicated by α) and formation of the ethyl ester
carbonyl (stretch near 1700 cm-1, indicated by β), which supports
the formation of the observed triazolate product. The alkylation of
the triazolate is observed as a decrease in the ester stretch in
1·[Mn(CO)3(ET)], and the resulting bromide complex readily un-
dergoes azide exchange to regenerate 1·[Mn(CO)3N3]. (b) PXRD
data obtained from the material after one click cycle using EPOP
closely matches the starting material, 1·[Mn(CO)3(H2O)]Br and the
simulated pattern, indicating that the MOF retains crystallinity
throughout the cycle.
Unusual “in MOF” triazolate coordination
N(1)-bound octahedral triazolate complexes, such as
57-59
1·[Mn(CO)3(DMT)] and 1·[Mn(CO)3(ET)], are rare,38,
since steric effects in octahedral complexes usually favor the
rearrangement of the complex to form the N(2)-bound isomer.35,
39
It is evident from the crystal structures that close contacts
and the methyl substituents on the DMT ligand along the path-
way that converts the moiety from an N(1)- to the N(2)-bound
complex results in a substantial calculated energy barrier for
this process of around 170 kJ/mol. This indicates that it is
highly unlikely for the N(1)-bound complex that is initially
formed in the ‘‘click’’ reaction38 to transform into the N(2)-
bound complex (see the Supporting Information for a detailed
description of the computational procedures and results).
between the coordinated triazolate and adjacent features of the
MOF pore would be substantially increased if the triazolate
were to bind via the N(2) nitrogen. To confirm that the MOF
environment, rather than the primary coordination environ-
ment, are responsible for this behavior, we synthesized the mo-
lecular counterpart, [Mn(bis(3,5-dimethyl-pyrazolyl)me-
thane)(CO)3(dimethyl
4,5-carboxy-1,2,3-triazolate)]
([Mn(bpm)(CO)3(DMT)], where bpm = bis(3,5-dimethyl-pyra-
zolyl)methane). SCXRD studies revealed an N(2)-bound tria-
zolate coordinated to a fac-Mn(I) tricarbonyl complex (SI Fig-
ure S5.1.1). Evidently, the MOF environment enforces new ste-
ric demands on the triazolate, favoring coordination motifs that
Triazole release from the MOF platform
For the MOF to act as a functional host for ‘‘click’’ chem-
istry, the organic product must be liberated and the original
framework ‘vessel’ re-generated in suitable condition to per-
form further reaction cycles. Due to the strong metal–triazolate
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bond, simple anion exchange with sodium azide is not sufficient challenging profile for selective triazole formation. The inclu-
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to release the triazolate. Fortunately, this issue is overcome by
reacting the MOF-bound triazolate complex with MeBr 57, 60-61
to release the corresponding N-alkylated triazole and regenerate
the original host framework, 1·[Mn(CO)3(H2O)]Br. We note
that this process also occurs via a SC-SC transition. To monitor
the reaction we employed NMR spectroscopy and EDX analy-
sis to assess the formation of the N-alkylated triazole and the
MOF-bound halide complex, respectively. Alkylation was per-
formed by placing crystals of 1·[Mn(CO)3(DMT)] in CDCl3 and
heating the mixture at 50˚C overnight in the presence of excess
MeBr. Following removal of the MOF crystals, the CDCl3 so-
sion of carbonyl groups adjacent to the alkyne activate them to-
ward ‘‘click’’ chemistry, as seen for DMAD and EPOP, by
withdrawing electron density from the triple bond. The
‘‘click’’ reactions were performed in toluene at 50˚C and mon-
itored via IR spectroscopy which showed a gradual loss of the
-
asymmetric N3 stretch at 2070 cm-1. PXRD analysis after the
reaction was complete confirmed that the MOF retained crys-
tallinity (SI Figure S6.3-6.5), while the IR spectrum displayed
a C=O stretch at 1690 cm-1 consistent with presence of the ke-
tone functionality.
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1
lution was analyzed via H-NMR spectroscopy and found to
contain dimethyl N1-methyl-4,5-dicarboxy-1,2,3-triazole. The
position of the methyl group on the triazole ring was confirmed
by the presence of two separate methyl ester signals in the 1H-
NMR spectrum, indicating alkylation at N(1).57 Notably,
PXRD patterns obtained after a full ‘‘click’’ chemistry cycle
demonstrated a high degree of crystallinity (Figure 3b), as evi-
denced by the excellent agreement between the patterns of
1·[Mn(CO)3(H2O)]Br and 1·[Mn(CO)3(H2O)]Br* (* indicates a
MOF that has completed one reaction cycle). Quantitative re-
generation of the Mn(I) bromide complex is supported by EDX
experiments, which indicate a 4:1 Mn:Br ratio (SI Table S1)
while the IR spectrum of 1·[Mn(CO)3(H2O)]Br* shows analo-
gous n(CºO) bands to 1·[Mn(CO)3(H2O)]Br. Furthermore, re-
action of 1·[Mn(CO)3(ET)] with MeBr successfully released
ethyl N-methyl-4-carboxy-1,2,3-triazole to regenerate the orig-
inal framework. 1H NMR spectroscopy indicated that the lib-
erated product was a mixture of two N-alkylated isomers in a
5:3 ratio. In addition, complete loss of the ester n(C=O) band
in the IR spectrum supports the quantitative expulsion of the
organic triazole from the MOF (Figure 3a). This data supports
the successful use of 1 as a platform for the complete ‘‘click’’
chemistry cycle.
Figure 4. (a) IR spectra of Mn(I) metalated forms of 1 displaying
characteristic CO stretches, which are retained throughout the
"click" chemistry cycle. The progression of the anion exchange,
‘‘click’’ reaction and N-alkylation can be monitored by the appear-
ance and loss of the azide stretch at 2070 cm-1 (δ) and concomitant
formation of the alkyne and ester stretches at 2090 and 1680cm-1
respectively (ε and ζ, respectively). The liberated triazole product
displays the same spectroscopic features.
Buoyed by these results, we subjected the material to a sec-
ond azide exchange cycle and observed a prominent azide
stretch in the IR spectrum, consistent with that observed for
1·[Mn(CO)3N3] (Figure 3a). These results confirm that the ma-
terial could serve as a platform for ‘‘click’’ chemistry over mul-
tiple cycles.
The MOF crystals of 1·[Mn(CO)3(4-hex-5’-ynl-1’,4’-dione-
1,2,3-triazolate)] (1·[Mn(CO)3(HT)]) were found to be suitable
for SCXRD studies. Refinement of the structure revealed the
presence of a five-membered ring coordinated to the Mn(I) site,
which was assigned as an N(1)-bound triazolate. Furthermore,
the alkyne functionalized chain can be discerned in the electron
density map, bound to C4 of the triazole. Refinement without
crystallographic restraints was not possible, but an energy-min-
imized organic moiety could be modelled in this site and pro-
vides a reasonable match to the Fobs electron density map (SI
Figure S5.3.5). In addition, the IR spectrum of
(1·[Mn(CO)3(HT)]) showed a band at 2090 cm-1, characteristic
of an alkyne C≡C stretch along with concomitant loss of the
azide band at 2070 cm-1 (Figure 4). Consistent with our hypoth-
esis, this evidence confirms that the shortest dialkyne, DA1,
produces the site-selective ‘’click’’ product, 4-hex-5’-ynl-
1’,4’-dione-1,2,3-triazolate.
Selective ‘‘click’’ chemistry with dialkynes
Having established the viability of 1 as a host for stoichio-
metric ‘‘click’’ conversions, we turned our attention to carrying
out site-selective functionalization on a dialkyne substrate to di-
rectly produce the corresponding alkyne-functionalized N-al-
kylated triazole. We selected a series of terminal dialkynes
DA1, DA2 and DA3 with lengths of 10.7, 13.1 and 15.6 Å, re-
spectively. Since the azide separation in 1·N3 is 13.0 Å, we an-
ticipated that the shortest dialkyne would undergo site-se-
lective ‘‘click’’ chemistry while the longest species would
produce a mixture of bis- and mono-triazole products as its
length exceeds the azide separation.
We selected the symmetric dialkyne substrates since the
well-separated and unhindered terminal alkyne sites pose a
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Figure 5. (a) The shortest dialkyne, DA1, undergoes site-selective “click” chemistry to yield N-methyl 4-hex-5’-ynl-1’,4’-dione-1,2,3-
triazole (N(2) and N(3) major isomers), as indicated by consideration of the CH triazole region of the 1H NMR spectrum, which shows two
prominent triazole CH signals (note: the N(1)-methyl isomer is also present in small quantity; see SI). (b) Extension of the dialkyne substrate
results in a mixture of bis- and mono- “click” products, resulting in multiple triazole CH peaks in the 1H NMR spectrum; the lower intensity
signals are highlighted by a blue arrow. The number of triazole CH signals increases with the dialkyne length, indicating a greater proportion
of bis-triazole products and loss of site-selectivity. (c) Site-selective "click" chemistry cycle using DA1 proceeding from
1·[Mn(CO)3(H2O)]Br to 1·[Mn(CO)3N3], formation of the ‘‘click’’ triazolate complex and regeneration of the starting material
1·[Mn(CO)3(H2O)]Br via alkylation with MeBr.
tion) and 1,11-dodecadiyne-3,10-dione (length 15.6 Å > N3 sep-
Each of the DA1-, DA2- and DA3-derived triazolate com-
aration) gave rise to a greater proportion of bis-triazole product
plexes were reacted with MeBr to yield 1·[Mn(CO)3(H2O)]Br
(Figure 5b), with the longest dialkyne producing at least 8 de-
and the respective N-alkylated triazole product using the alkyl-
tectable triazole proton environments. These results confirm
ation protocol discussed earlier. In all cases the reaction was
that the spatial isolation of the azide moieties achieved in
accompanied by a color change in the crystals from red to a yel-
1·[Mn(CO)3N3] is integral to the site-selective ‘‘click’’-chem-
istry strategy, since the selectivity is compromised once the di-
alkyne length approaches that of the azide separation. In all
cases, PXRD analysis confirmed the parent framework is pre-
low-orange color consistent with re-formation of
1·[Mn(CO)3(H2O)]Br. IR spectroscopy of each MOF sample
showed the characteristic C≡O stretches, confirming the pres-
ence of the tricarbonyl moiety and the PXRD patterns obtained
served throughout the ‘‘click’’ chemistry cycle.
after the full ‘‘click’’ chemistry cycle closely matched that of
the original framework 1·[Mn(CO)3(H2O)]Br (SI Figure S6.3-
Conclusion
6.5). We characterized the respective triazole products by 1D
Herein we have demonstrated that the crystalline structure
and 2D NMR experiments and high-resolution mass spectrom-
of MOFs can facilitate the angstrom-scale ordering of reactive
etry. The NMR analysis of the product obtained from the short-
azide sites to yield a reactive ‘vessel’ that is poised to perform
est dialkyne, 1,7-octadiyne-3,8-dione (DA1), confirmed the se-
site-selective ‘‘click’’ chemistry. The high degree of crystal-
lective formation of the alkyne functionalized triazole as a mix-
linity of the MOF framework allowed us to precisely character-
ture of N(3) and N(2)-methyl isomers in a 1:0.8 ratio (a trace of
ize the precursor azide sites and ‘‘click’’ chemistry triazolate
the N(1)-methyl isomer was also observed) (Figure 5a). The
alkyne moiety was observed as a singlet in the 1H NMR (3.27
products using SCXRD, providing insight into the effect of the
confining pore environment and isolated reactive sites on chem-
ppm and 3.32 ppm for the N(2) and N(3) isomers, respectively)
ical processes within MOFs. By way of example we performed
and further supported by the IR spectroscopy of the oily prod-
uct, which displays the characteristic CH stretch at 3249 cm-1
site-selective "click" chemistry reaction cycles using a series of
and C≡C stretch at 2091 cm-1. High-resolution mass spectrom-
dialkynes of different structure metrics. These experiments
clearly showed that the degree of site selectivity observed was
etry clearly identified the [M+H]+ ion at m/z 192.0967 with only
dependent on the length of the dialkyne relative to the distance
traces of the bis-triazole product observed (SI Figure S4.1).
between the azide moieties. We anticipate that the scope for
The combination of NMR and IR spectroscopy, and mass spec-
employing MOFs as site-selective reaction vessels is vast, given
trometry overwhelmingly supports the successful site-selective
their bespoke design and chemical mutability. Indeed, this
‘‘click’’ reaction to give the desired alkyne-functionalized tria-
chemistry could be extended by precisely positioning guest
zole product.
molecules within the framework via specific dynamic covalent,
dative, or H-bonding interactions to facilitate highly efficient
As anticipated the NMR and mass spectrometry data reveal
chemoselective reactions. To this end, the MOF crystal could
be considered to function as a novel solid-state protecting group
and, accordingly, this strategy may be broadened to include a
a direct relationship between the length of the dialkyne, the az-
ide separation and selectivity obtained. Both longer dialkyne
substrates, 1,9-decadiyne-3,8-dione (length 13.1 Å ≈ N3 separa-
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wide variety of site-selective and chemoselective transfor-
mations that are not easily carried out using a traditional pro-
Synthetic Procedures
1
1·[Mn(CO)3(H2O)]Br. Single crystals of 1 (30 mg) were
washed with ethanol (5 × 10 ml) with 30 minutes between each
wash. The crystals of 1 were transferred to a 20 ml scintillation
vial containing ethanol (15 ml) and excess [Mn(CO)5Br] (30
mg). The mixture was heated at 50˚C for 48 h and the resulting
yellow crystals were washed with fresh ethanol (5 × 10 ml) to
give 1·[Mn(CO)3(H2O)]Br as yellow single crystals IR υmax (nu-
jol, cm-1): 1951 (s, C=O), 2040 (s, C=O), 1921 (s, C=O), 1608
(C=O), 1553, 1511, 1408, 1306, 1272.
2
3
4
5
6
7
8
9
tecting-group strategy.
Experimental
Materials and Methods
Unless otherwise stated, all preparations of the organic
compounds were performed under an Ar atmosphere using
standard Schlenk techniques with dried and degassed solvents.
All MOF synthesis reactions were carried out in air. H2L (bis(4-
(4-carboxyphenyl)-1H-3,5-dimethylpyrazolyl)methane),
1·[Mn(CO)3N3]. Single crystals of 1·[Mn(CO)3Br] (30 mg)
were washed with methanol (5 × 10 ml) with 30 minutes be-
tween each wash and transferred to a 20 ml scintillation vial
containing methanol (5 ml). A 2 ml glass vial containing NaN3
(30 mg) was placed inside the scintillation vial, and methanol
was added such that the 2 ml vial was fully submersed within
the scintillation vial. The apparatus was left to stand at room
temperature for 72 h. The methanol solution was decanted and
the MOF crystals washed thoroughly with methanol (5 × 10 ml)
to yield 1·[Mn(CO)3N3] as yellow crystals. IR: (nujol, cm-1):
2070 (s, N3), 2025 (s, CO), 1952 (s, CO), 1903 (s, CO), 1608
(s, C=O), 1555, 1510, 1408, 1303, 1272.
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bis(3,5-dimethylpyrazolyl)methane (bpm) and 1,9-decadiyne-
3,8-dione (DA2) were synthesized as previously reported.62 63-
64
All reagents were obtained from commercial vendors and
used without further purification. NMR spectra were recorded
on Varian Gemini 500 or 600 MHz spectrometers at 23°C using
a 5 mm probe. Energy-dispersive X-ray spectroscopy (EDX)
was performed with a Philips XL30 field emission scanning
electron microscope. Infrared (IR) spectra were collected on a
Perkin-Elmer Spectrum Two, with the sample distributed be-
tween two NaCl disks in Nujol. Electrospray ionization (ESI)
high-resolution mass spectra (HR-MS) were recorded on Q-
TOF mass spectrometer (Agilent 6230). For details regarding
the preparation of the dialkynes DA1 and DA3, and the molec-
ular complex [Mn(bpm)(CO)3(DMT)], please see the Supple-
mentary Information.
1·[Mn(CO)3(DMT)]. Single crystals of 1·[Mn(CO)3N3] (30
mg) were washed with toluene (5 × 10 ml) and transferred to a
Schlenk tube containing toluene (5 ml) and dimethyl acetylene
dicarboxylate (0.1 ml). The mixture was sealed and heated at
50˚C for 20 h, after-which the solvent was decanted and the
MOF crystals washed with fresh toluene (5 × 10 ml) to yield
1·[Mn(CO)3(DMT)] as pale yellow crystals. IR υmax (nujol, cm-
1): 2034 (CO), 1956 (CO), 1909 (CO), 1716 (b, ester), 1608 (s,
C=O), 1554 (C=C), 1509 (C=C), 1406, 1376, 1302, 1271, 1169
(w).
Single Crystal and Powder X-ray Diffraction Data
Single crystals were mounted in paratone-N oil on a nylon
loop. Single-crystal X-ray data for 1·[Mn(CO)3(H2O)]Br,
1·[Mn(CO)3N3], 1·[Mn(CO)3(ET)], 1·[Mn(CO)3(DMT)] and
1·[Mn(CO)3(OT)] were collected at 100 K on the MX1 or MX2
beamlines of the Australia Synchrotron using the BluIce soft-
ware interface,65 λ=0.7108 Å. Single crystal X-ray data for,
[Mn(bpm)(CO)3Br] and [Mn(bpm)(CO)3(DMT)] were col-
lected at 150(2) K on an Oxford X-Calibur single crystal dif-
fractometer (λ = 0.71073 Å). Ntot reflections were merged to N
unique (Rint quoted) after a multi-scan absorption correction
(proprietary software) and used in the full matrix least-squares
refinements on F2. Unless otherwise stated in the additional re-
finement details, anisotropic displacement parameter forms
were refined for the non-hydrogen atoms; hydrogen atoms were
treated with a riding model [weights: (σ2(Fo)2 +(aP)2 +(bP))−1;
P=(Fo2 +2Fc2)/3]. Neutral atom complex scattering factors
were used; computation used the SHELXL2014 program.66
Pertinent results are given in the manuscript, while views of the
asymmetric units, additional refinement details, and X-ray ex-
perimental and refinement data (Table S3-4) are given in the
Supporting Information. Full details of the structure determina-
tions have been deposited with the Cambridge Crystallographic
Data Centre as CCDC #s 1826673-1826679 (see Table S3-4 for
specific deposit numbers). Copies of this information may be
obtained free of charge from The Director, CCDC, 12 Union
Street, Cambridge CB2 1EZ, U.K. (fax, +44-1223-336-033; e-
mail, deposit@ccdc.cam.ac.uk).
1·[Mn(CO)3(ET)]. Single crystals of 1·Mn(CO)3N3] (30
mg) were washed with toluene (5 × 10 ml) and transferred to a
Schlenk tube containing toluene (5 ml) and ethyl propiolate (0.1
ml). The mixture was sealed and heated at 50˚C for 20 h, after
which the solvent was decanted and the MOF crystals washed
with fresh toluene (5 x 10 ml) to yield 1·[Mn(CO)3(ET)] as pale
yellow crystals. IR υmax (nujol, cm-1): 2035 (CO), 1945 (CO),
1922 (CO), 1711 (ester), 1665 (C=O), 1554, 1408, 1303, 1272.
1·[Mn(CO)3(4-hex-5’-ynl-1’,4’-dione-1,2,3-triazolate)].
Single crystals of 1·[Mn(CO)3N3] (60 mg) were washed with
toluene (5 × 10 ml) and transferred to a 8 ml glass vial contain-
ing 1,7-octadiyne-3,6-dione (DA1). The mixture was sealed
and heated at 50˚C for 20 h, after-which the solvent was de-
canted and the MOF crystals washed with fresh toluene (5 × 5
ml) to yield 1·[Mn(CO)3(HT)] as pale yellow crystals. IR υmax
(nujol, cm-1): 2093 (C≡C), 2035 (CO), 1940 (CO), 1928 (CO),
1683 (ketone), 1555, 1458, 1303, 1272.
1·[Mn(CO)3(4-octa-7’-ynl-1’,6’-dione-1,2,3-triazolate)].
Single crystals of 1·[Mn(CO)3N3] (60 mg) were washed with
toluene (5 × 10 ml) and transferred to a 8 ml glass vial contain-
ing 1,9-decadiyne-3,8-dione (DA2). The mixture was sealed
and heated at 50˚C for 20 h, after-which the solvent was de-
canted and the MOF crystals washed with fresh toluene (5 × 5
ml) to yield 1·[Mn(CO)3(OT)] as pale yellow crystals. IR υmax
(nujol, cm-1): 2089 (C≡C), 2034 (CO), 1938 (CO), 1917 (CO),
1671 (ketone), 1554, 1304, 1273.
Powder X-ray diffraction data were collected on a Bruker
Advance D8 diffractometer equipped with a capillary stage us-
ing Cu Kα radiation (λ = 1.5418 Å). Simulated powder X-ray
diffraction (PXRD) patterns were produced from the single
crystal data using Mercury 3.3.
1·[Mn(CO)3(4-hex-9’-ynl-1’,8’-dione-1,2,3-triazolate)].
Single crystals of 1·[Mn(CO)3N3] (60 mg) were washed with
toluene (5 × 10 ml) and transferred to a 8 ml glass vial contain-
ing 1,11-dodecadiyne-3,10-dione (DA3). The mixture was
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Page 8 of 10
sealed and heated at 50˚C for 20 h, after-which the solvent was
decanted and the MOF crystals washed with fresh toluene (5 ×
5 ml) to yield 1·[Mn(CO)3(DT)] as pale yellow crystals. IR υmax
(nujol, cm-1): 2091 (C≡C), 2036 (CO), 1956 (CO), 1903 (CO),
1672 (ketone), 1554, 1509, 1454, 1408, 1302, 1271.
3.22 (s, C≡C-H), 2.92 (m, CH2), 2.68 (CH2), 1.77 (m, CH2); 13C
1
2
3
4
5
6
7
8
NMR (150 MHz, CDCl3): 189.81 (C=O), 186.52 (C=O),
185.57 (C=O), 137.53 (triazole), 135.16 (triazole), 133.55 (tri-
azole), 126.23 (triazole), 81.28 (C≡C), 78.72 (C≡C), 78.67
(C≡C), 78.53 (C≡C), 45.15 (CH2), 45.01 (CH2), 44.96 (CH2),
40.61 (CH2), 39.23 (CH2), 38.97 (CH2), 38.08 (CH3), 36.99
(CH3), 23.20 (CH2), 22.99 (CH2), 22.92 (CH2), 22.77 (CH2); IR
(Nujol, cm-1): 3238 (C≡C-H), 2089 (C≡C), 1678 (C=O), 1525,
1448, 1397, 1368, 1261, 1104; m/z: 220.1130 [M+H]+ (calc’d
[M+H]+ 220.1091).
Alkylation of MOF-bound triazolate (general proce-
dure) and re-formation of 1·[Mn(CO)3(H2O)]Br. Single
crystals
of
1·[Mn(CO)3(DMT)],
1·[Mn(CO)3(ET)],
1·[Mn(CO)3(HT)], 1·[Mn(CO)3(OT)], and 1·[Mn(CO)3(DT)]
(approx. 60 mg) were washed with toluene (5 × 10 ml) followed
by dichloromethane (30 ml) and CDCl3 (5 ml). The sample was
added to CDCl3 (2 ml) in an 8 ml glass vial with Teflon cap,
degassed with Ar and cooled to -10˚C in an ice-salt bath. Sim-
ultaneously, MeBr was cooled to -78˚C and an excess poured
into the vial containing the MOF under flow of Ar. The vial
was sealed and heated to 50˚C for 20 h. The sample was cooled
to room temperature, the MOF crystals were isolated via filtra-
tion and washed with CDCl3 (5 ml) to yield
1·[Mn(CO)3(H2O)]Br as yellow single crystals. IR υmax (nujol,
cm-1): 2040 (s, CO), 1951 (s, CO), 1921 (s, CO), 1606, 1553,
1510, 1493, 1408, 1305, 1272, 1182.
9
N-Methyl 4-deca-9’-ynl-1’,8’-dione-1,2,3-triazole. Mix-
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ture of 8 isomers, signals identified as corresponding to triazole
1
products are listed below. H NMR (600MHz, CDCl3): 8.16
(three singlet signals, triazole CH), 8.03 (s, triazole CH), 8.01
(three singlet signals, triazole CH), 4.31 (s, CH3), 4,25 (s, CH3),
4.15 (s, CH3), 3.21 (two singlets, C≡C-H), 3.20 (s, C≡C-H),
3.11 (t, CH2), 2.96 (t, CH2), 2.87 (m, CH2), 2.58 (m, CH2), 1.74
(m, CH2), 1.69 (m, CH2), 1.42 (m, CH2), 1.38 (m, CH2); IR (Nu-
jol, cm-1): 3249 (C≡C-H), 2089 (C≡C), 1682 (C=O), 1609
(C=O), 1408, 1306; m/z: 248.1421 [M+H]+ (calc’d [M+H]+
248.1399).
Computational Methods
The filtrate containing N-methylated triazole from the
above reaction could be directly analyzed by NMR spectros-
copy and mass spectrometry and subsequently evacuated under
reduced pressure to yield the triazole compound(s) as oils for
IR spectroscopy analysis when possible.
Density functional theory (DFT) calculations were carried
out with the Gaussian 09 software package (Revision D.01)67
using the M06 functional.68 Geometry optimizations were car-
ried out in vacuo using the SDD effective core potential69 for
Mn ions and the 6-31G(d,p) basis set70 for all atoms. Single-
point energies were also calculated for the optimized geome-
tries with the 6-31+G(d,p) basis set and SMD continuum solv-
ation model71 with toluene solvent. Calculations were carried
out on a 306-atom fragment of 1·[Mn(CO)3(DMT)] as a model
for the extended MOF structure and on the corresponding mo-
lecular species [Mn(bpm)(CO)3(DMT)]. Geometry optimiza-
tions of the MOF fragments were carried out keeping all non-
hydrogen atoms in the framework fixed at their positions in the
experimental X-ray crystal structure except for the atoms in the
immediate vicinity of the Mn(I) ion. The energy barrier to in-
terconvert the N(1)- and N(2)-bound complexes in
1·[Mn(CO)3(DMT)] was estimated from the energies of struc-
tures obtained by interpolating between the optimized N(1)-
and N(2)-bound complexes and then optimizing the geometry
with the orientation of the triazolate ring fixed with respect to
the rest of the MOF. The computational procedures are de-
scribed in further detail in the Supporting Information.
Dimethyl N(1)-methyl-4,5-carboxy-1,2,3-triazole (Me-
DMT). 1H NMR (500 MHz, CDCl3): 4.28 (s, 3H, N-CH3), 4.02
(s, 3H, COOCH3), 3.99 (s, 3H, COOCH3); 13C NMR (150 MHz,
CDCl3): 163.11 (CO2, ester), 161.48 (CO2 ester), 142.81 (tria-
zole), 132.69 (triazole), 63.15 (CH3), 56.04 (CH3 ester), 55.39
(CH3 ester); IR (Nujol, cm-1): 1733cm-1 (C=O), 1555 cm-1,
1262, 1228, 1179, 1124, 1063; m/z: 199.0590 (calc’d
199.0593).
Ethyl N-methyl-4-carboxy-1,2,3-triazole (Me-ET). Iso-
mers a, b in 5:3 ratio respectively. 1H NMR (500MHz, CDCl3):
8.13 (s, 1H, triazole CH (a)), 8.04 (s, 1H, triazole (b)), 4.44 (q,
2H, ester CH2 (b)), 4.41 (q, 2H, ester CH2 (a)), 4.34 (s, 3H, CH3
(a)), 4.28 (s, 3H, CH3 (b)), 1.42 (t, 3H, ester CH3 (b)), 1.41 (t,
3H, ester CH3 (a)).
N-Methyl 4-hex-5’-ynl-1’,4’-dione-1,2,3-triazole. N2 and
N3 Isomers in a 1:0.8 ratio respectively.
N2-Methyl-4-hexa-5’-ynl-1’,4’-dione-1,2,3-triazole:
1H
NMR (600MHz, CDCl3): 8.03 (s, 1H, triazole CH), 4.27 (s, 3H,
CH3), 3.36 (t, 2H, CH2), 3.27 (s, 1H, C≡C-H), 3.08 (t, 2H,
CH2); 13C NMR (150 MHz, CDCl3): 191.53 (C=O), 185.16
(C=O), 146.26 (triazole), 135.10 (triazole CH), 81.10 (alkyne),
78.96 (alkyne), 42.25 (CH3), 38.41(CH2), 30.05 (CH2).
Associated content
Supporting information: characterization data for the MOF
samples and related molecular species, characterization of tria-
zole products, details of the SCXRD and tables of crystallo-
graphic data collection and refinement parameters, computa-
tional results, crystallographic information files (cifs).
N3-Methyl-4-hexa-5’-ynl-1’,4’-dione-1,2,3-triazole:
1H
NMR (600MHz, CDCl3): 8.23 (s, 1H, triazole CH), 4.31 (s, 3H,
CH3), 3.32 (s, 1H, C≡C-H), 3.25 (t, 2H, CH2), 3.09 (t, 2H, CH2);
13C NMR (150 MHz, CDCl3): 187.69 (C=O), 184.49 (C=O),
137.61 (triazole CH), 132.89 (triazole), 80.88 (C≡C), 79.56
(C≡C), 38.66 (CH3), 38.04 (CH2), 34.14 (CH2).
Analysis of mixture: IR (Nujol, cm-1): 3249 (C≡C-H), 2958
(C-H), 2919 (C-H), 2850 (C-H), 2091 (C≡C), 1680 (C=O),
1608, 1403, 1105; m/z: [M+H]+ 192.0967(calc’d
[M+H]+192.0773).
Acknowledgements
CJD, CJS, DMH and NRC gratefully acknowledge the Aus-
tralian Research Council for funding (DP160103234). Aspects
of this research were undertaken on the MX1 and MX2 beam-
lines at the Australian Synchrotron, part of ANSTO, and made
use of the Australian Cancer Research Foundation (ACRF) de-
tector. DMH gratefully acknowledges computational resources
provided by the Australian Government through the National
Computing Infrastructure under the National Computational
Merit Allocation Scheme and by the University of Adelaide's
Phoenix High-Performance Computing service. MTH, AL and
N-Methyl 4-octa-8’-ynl-1’,6’-dione-1,2,3-triazole. Iso-
1
mers a, b in a 1:0.8 ratio respectively. H NMR (600MHz,
CDCl3): 8.16 (s, triazole), 8.04 (s, triazole), 8.02 (s, triazole),
4.32 (s, CH3), 4.26 (s, CH3), 4.17 (s, CH3), 3.24 (s, C≡C-H),
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HG acknowledge the University of Adelaide and the Australian
Government for a Research Training Program PhD scholarship.
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