Published on: 7月 31, 2026

Click chemistry combines two characteristic substituents in a fast and high yielding manner under mild conditions. Its potential as tools has gathered attentions from most of the science fields using chemical entities, including pharmaceutical sciences.¹⁾

Barry Sharpless gave birth to the concept of click chemistry and it has been expanded and now is an established field of chemical research.^2),3) Here we would like to discuss the reaction rates of click chemistry according to this paper.⁴⁾ It’s necessary information to select the appropriate reaction and to design the structures for click chemistry.

Nuclear medicine is the most relevant field where click chemistry is practically brought into application.⁵⁾ Targeted nuclear medicine requires short-lived nuclides like ¹⁸F and click chemistry in a general term is essential for the very late stage in the synthesis. Radiopharmaceuticals have also been developed, [¹⁸F]F-RGD-K5 as the first-in-human evaluation in 2011.⁶⁾ Fast click chemistry is enabling us for a broad range of applications.

The reaction rate of famous click chemistry under typical conditions are summarized below.

 

	Reaction rates (M-1s-1)	Subtrate note	Solvent
CuAAC	10~104	–	DMSO/H2O 4:1
SPAAC	2.4 x 10-3	Cyclooctyne	CD3CN
	3.1 x 10-1	DIBAC	MeOH
	9.6 x 10-1	BARAC	CD3CN
	7 x 10-2	BCN	CD3CN
IEDDA	2.2 x 104	Norbornene	MeOH
	4.48 x 10	BCN	MeOH
	1.45	BCN	PBS (pH7.4)
	8.20 x 102	TCO	PBS (pH7.4)
DA	1.22 x 10	Cyclopentadienone/BCN	DMSO/PBS (pH7.4) 10:1

 

CuAAC (Cu(I)-catalyzed Azide-Alkyne Cycloaddition) is the most traditional but still effective click chemistry. In vitro and in vivo application is limited due to the toxicity of Cu(I). In flask, it is the second fastest reaction and easily applicable for medicinal chemistry, synthesis of tool compounds for biological studies and radioisotope labeling. CuAAC has the smallest structure as the joint and wide applications have been conducted for long.

SPAAC (Strain-promoted Azide-Alkyne Cycloaddition) utilizes the reactivity of strained alkyne to promote the azide-alkyne [3+2] click chemistry in the absence of copper. Cyclooctynes, dibenzoazacyclooctynes (DIBACs), biarylazacyclooctynones (BARACs) and bicyclo[6.1.0]non-4-ynes are the widely-used strained alkynes. Reaction rates of SPAAC are slower than CuAAC in two to seven orders, but it is compatible with cells and most of the assay conditions.

IEDDA (Inverse Electron Demand [4+2] Diels-Alder reaction) of tetrazines and strained alkenes and alkynes are the fastest class of click chemistry. DA (Diels-Alder reaction) in an inverse- electron demand fashion is faster with alkenes than alkynes. Norbornenes and trans-cyclooctenes (TCOs) are useful dienophiles of the electron-deficient azadiene. Even with BCN, the reaction is 20~200 times faster than SPAAC. It is desirable for in vitro and in vivo experiments that require instantaneous click chemistry.

DA of strained molecules are relatively fast but in general it is not fast enough at room temperature and necessary to heat up and incompatible for click chemistry.

Click chemistry in general sense includes versatile reactions. You may call it as click reaction so long as it’s fast, selective and high yielding. Representative examples are shown below.

 

	Reaction rates (M-1s-1)	Subtrate note
Nucleophilic opening of a strained ring	10-4	Azirizines and oxiranes
Non-aldol carbonyl reactions	10-3	Hydrazones and oximes
Michael reactions	10-5~102	Thiol-ene and maleimide
Radical Michael reactions	104	Thiol-ene
Staudinger ligation	10-3	Azide and phosphine

 

Obviously, the reaction rates are not compatible with the conventional ones except for radical reactions and Michael reaction to highly reactive electrophile like maleimides. Those click-like chemistry works very well in flask but it is necessary to rethink of utilizing them when you need a speed of click reaction.

Click reaction rate is beneficial in many cases. But some slow click reactions generate stable products and are useful for long-time assays and tolerate harsh conditions in imaging. Faster the better. This is always the same in click chemistry but the stability of the product is necessary to be taken into consideration.

The concept of click chemistry has gathered recognition of applicability of reliable intermolecular reaction. They are useful tools for expanding science in a molecular level. We would love to utilize novel click chemistry for easier construction of library for drug discovery. Let us have time for discussion to seek the possibility of merging basic science and technology.

 

1. https://doi.org/10.1002/1521-3773(20010601)40:11%3C2004::aid-anie2004%3E3.0.co;2-5
2. https://doi.org/10.1016/j.apsb.2022.10.015
3. https://doi.org/10.1021/acs.bioconjchem.4c00084
4. https://doi.org/10.1038%2Fs41596-023-00825-8
5. https://doi.org/10.1038/s41596-023-00825-8
6. https://doi.org/10.2967/jnumed.111.088955