点击化学 Click chemistry — 定义、原理与由来

定义Definition

点击化学是夏普莱斯（2001）提出的一种合成理念：用少数几种高效、可靠、高选择性、条件温和（常在水中）、产物易分离的反应把小模块快速拼接成分子。最典型的是铜催化叠氮–炔环加成（CuAAC），生成 1,4-二取代 1,2,3-三唑。

Click chemistry is a synthetic philosophy introduced by Sharpless (2001): join small modules quickly using a few reactions that are high-yielding, reliable, selective, run under mild (often aqueous) conditions and give easily isolated products. The archetype is the copper-catalysed azide–alkyne cycloaddition (CuAAC) giving 1,4-disubstituted 1,2,3-triazoles.

CuAACCuAAC

惠斯根热 1,3-偶极环加成需高温且得到 1,4 与 1,5 异构体混合物；2002 年梅尔达尔与夏普莱斯–福金分别发现 Cu(I) 催化后反应加速约 10⁷ 倍，室温即可、只生成 1,4-异构体。机理涉及铜炔化物与叠氮的逐步结合（含双铜中间体）。

Huisgen’s thermal 1,3-dipolar cycloaddition needs heat and gives 1,4/1,5 mixtures; in 2002 Meldal and Sharpless–Fokin independently found that Cu(I) accelerates it ~10⁷-fold at room temperature with exclusive 1,4-selectivity, via copper acetylides (involving dinuclear copper intermediates).

生物正交化学Bioorthogonal chemistry

卡罗琳·贝尔托齐发展了无铜的应变促进叠氮–炔环加成（SPAAC，用环辛炔），以及四嗪–反式环辛烯反应，可在活细胞、活体内标记糖、蛋白质而不干扰生命过程。

Carolyn Bertozzi developed copper-free strain-promoted azide–alkyne cycloaddition (SPAAC, with cyclooctynes) and tetrazine ligations, labelling glycans and proteins in living cells and organisms without disturbing biology.

意义Significance

夏普莱斯、梅尔达尔、贝尔托齐共获 2022 年诺贝尔化学奖（夏普莱斯第二次获奖）。点击化学广泛用于药物发现、抗体–药物偶联物、材料表面修饰与高分子合成；SuFEx（硫氟交换）是新一代点击反应。

Sharpless (his second Nobel), Meldal and Bertozzi shared the 2022 Nobel Prize in Chemistry. Click chemistry serves drug discovery, antibody–drug conjugates, surface modification and polymer synthesis; SuFEx (sulfur–fluoride exchange) is a newer click reaction.

反应Reactions

R–N₃ + H–C≡C–R′ Cu(I)⟶ 1,4-二取代 1,2,3-三唑R–N₃ + H–C≡C–R′ Cu(I)⟶ 1,4- 1,2,3-

CuSO₄ + 抗坏血酸钠（原位生成 Cu(I)），t-BuOH/H₂O，室温；可加 TBTA 等配体

CuSO₄ + sodium ascorbate (Cu(I) in situ) in t-BuOH/H₂O at room temperature, optionally with ligands such as TBTA

Cu(I) 与端炔生成铜炔化物。
Cu(I) forms a copper acetylide.
叠氮配位并环化成含铜六元环中间体。
The azide binds and cyclises to a copper metallacycle.
环收缩、质子化释放三唑并再生 Cu(I)。
Ring contraction and protonation release the triazole and regenerate Cu(I).

PhCH₂N₃ + HC≡CPh ⟶ 1-苄基-4-苯基-1,2,3-三唑PhCH₂N₃ + HC≡CPh ⟶ 1--4-Phenyl group-1,2,3-

标准 CuAAC 例子。

A standard CuAAC example.

年表Timeline

1963
惠斯根系统研究 1,3-偶极环加成
Huisgen studies 1,3-dipolar cycloadditions
2001
夏普莱斯提出点击化学概念
Sharpless introduces click chemistry
2002
梅尔达尔、夏普莱斯–福金发现 CuAAC
Meldal and Sharpless–Fokin discover CuAAC
2004
贝尔托齐报道应变促进无铜点击反应
Bertozzi reports strain-promoted copper-free click
2022
诺贝尔化学奖
Nobel Prize in Chemistry

点击化学Click chemistry