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Preet Pal Singh Sidhu
April 11, 2008
Department of Medicinal Chemistry
School of Pharmacy, VCU.
CATALYTIC AZIDE-ALKYNE CYCLOADDITION:
REACTIVITY AND APPLICATION
Copper catalyzed alkyne-azide cycloaddition (CuAAC) is one of the most reliable click
reaction that has enabled the practical and efficient preparation of 1,4-disubstituted 1,2,3
triazoles from a wide range of substituted alkynes and azides which cannot be typically
attained by the traditional Huisgen thermal cycloaddition reaction[1]. The reaction
defined as “click reaction” requires benign reaction conditions, simple work up and
purification procedure and can still rapidly creates molecular diversity through the use of
reactive modular building blocks [2].
+
N N
-
N
R1
60-120 0C
+
R1
N1
N
N
+
Hours-days
R2
2
R
-
+
R2
N
R1
Cu catalyst
rt, mins-hours
R1
N1
R2
1,5
1,4
+
N N
R1 N N N
1
N
N
R2
1,4
Scheme I: 1, 3-Cycloaddition reaction in the presence and absence of Cu1+ catalyst.
Thermal 1, 3 cycloaddition a reaction give a mixture of region-isomers (Scheme I) and
requires the elevated temperatures and long reaction times [3]. The copper-catalyzed 1, 3
cycloaddition reaction preferably gives 1, 4 regioisomer. Copper catalysis increases the
rate of reaction up to 107 fold at room temperature [4]. Copper is present in the +1
oxidation state. The reaction can tolerate a wide variety of functional groups in both
reactants and works well in many solvents [5]. Interestinly, the reaction perform best in
aqueous system, succeeds over a fairly temperature range and is remarkably insensitive to
pH [6].
The sources of copper [I] catalyst can be copper [I] salts such as CuI etc [5]. Cu (I) can
be produced in-situ by reduction of copper [II] salts [6] or can also be obtained through
comproportionation of Cu [0] and Cu [II] salts [6]. It can also be obtained from oxidation
of Cu [0] salt [7]. Some time ligand-assisted Cu [I]-catalysis is also used in which the
ligand shields the Cu [I] ion from the interactions that can lead to degradation. This
significantly reduces the amount of catalyst necessary for the reaction. Amine triazole
was the first reported as the most efficient ligand for cycloaddition catalysis [8]. Ligands
also add enantioselectivity to ‘click chemistry’. Ligand accelerated cycloaddition appears
to facilitate bioconjugation studies.
ph
N
N
N
N
N
N
SO3Na
N
N N
SO3Na
Sulfonated Bathophenanthroline
N N
N
ph
N
N Bn
N N
ph
TBTA
3
Amine Triazole
Although CuAAC does not require heating, microwave chemistry can dramatically
reduces the reaction time from twelve hours to less than an hour. Usually there is no
additional gain in yield but it can reduce some undesirable side reactions [9]. The
reaction of sulfonyl azides with terminal alkynes is an interesting exception. Depending
on the reaction condition, it yields different products. N-sulfonyl azides are converted to
N-sulfonyl amidines in presence of amines [10]. Similarly, in presence of water, Nacylsulfonamide is major products [11]. N-sulfonyl triazole can be obtained in good yield
when reaction is performed in chloroform in presence of 2, 6-lutidine [12].
Problem: A by-product is formed due to alkynes homocoupling. This coupling is also
catalyzed by Cu [13]. Also, in case of highly electron deficient azide binding to Cuacetylene complex is less favorable and hence side product formation occurs [14]. The
yield reduces for polyalkene substrates that have the flexibility to coordinatively saturate
copper [I] [13].
Applications: ‘Click chemistry’ has been employed in synthesis of small molecule
screening libraries to derive inhibitors of fucosyl transferases [15] and HIV-I protease
inhibitor [16] as well as to design size specific ligands for mRNA hairpin loops [17]. The
other various uses are modification and biological profiling of natural products. Many
bioactive natural products have narrow therapeutic window which limits their therapeutic
potential. Therefore modification of natural products is viable approach to improve their
therapeutic index. In, reality, most chemical transformations are not compatible with a
range of functional groups present in the parent compound. The high selectivity and
fidelity of the CuAAC make it a good reaction for the last-step derivatization of complex
bioactive molecules [18].
Bioconjugation is incorporation of amino acids containing small bioorthogonal groups
into the proteome by metabolically or through site directed mutagenesis, which allow the
tracking of proteome dynamics in response to external stimuli. CuAAC is used to
selectively label the unnatural amino acids which are incorporated during synthesis of
protein [19]. CuAAC is also used in synthesis of functional dendrimers like
peptidodendrimers, unprotected glycodendrimers, redox-active dendrimers etc for
creating bioactive nanomaterial or sensor application [20].
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E. J.Yoo, M.A. Ahlquist, S.H. Kim, I. Bae, V.V. Fokin, K.B. Sharpless, S. Chang,
Copper-catalyzed synthesis of N-sulfonyl-1,2,3-triazoles: Controlling selectivity.
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