Oxidation-Induced "One-Pot" Click Chemistry

Abstract

Click chemistry has been established rapidly as one of the most valuable methods for the chemical transformation of complex molecules. Due to the rapid rates, clean conversions to the products, and compatibility of the reagents and reaction conditions even in complex settings, it has found applications in many molecule-oriented disciplines. From the vast landscape of click reactions, approaches have emerged in the past decade centered around oxidative processes to generate in situ highly reactive synthons from dormant functionalities. These approaches have led to some of the fastest click reactions know to date. Here, we review the various methods that can be used for such oxidation-induced "one-pot" click chemistry for the transformation of small molecules, materials, and biomolecules. A comprehensive overview is provided of oxidation conditions that induce a click reaction, and oxidation conditions are orthogonal to other click reactions so that sequential "click-oxidation-click" derivatization of molecules can be performed in one pot. Our review of the relevant literature shows that this strategy is emerging as a powerful approach for the preparation of high-performance materials and the generation of complex biomolecules. As such, we expect that oxidation-induced "one-pot" click chemistry will widen in scope substantially in the forthcoming years.

Figure 1

Schematic depiction of the changes in oxidation states of carbon atoms during various chemical transformations (formal oxidation states are indicated in red). (A) Schematic depiction of the conversion of hydrocarbons to a representative set of fine chemicals via a process of cracking and catalysis, and three representative transformations of the heteroatom-containing derivatives. (B) Oxidation ladder of ³-hybridized a carbon atom when oxidized from sp³-hybridization in an alkane and alcohol to sp²-hybridization in an aldehyde and carboxylic acid. (C) Reaction equations of two classical C–C bond-forming reactions (aldol condensation and Claisen condensation) enabled by the oxidation state of α-carbon atoms.

Figure 2

(A) Concept of oxidation of organic substrates into clickable moieties. (B) Changes in shapes of the HOMO and LUMO orbitals as a result of oxidation, based on wb97xd/6-311+G(d,p) calculations of energy-minimized structures.

Figure 3

SPAAC between an aliphatic or aromatic azide and DBCO (A; R′ = -CH₂CH₂NH₂) or BCN (B). Panel C points to a significant change of the relevant energy levels (by extension of the π-system) by oxidation and thereby to the observed increased rate of SPAAC (DMP = Dess–Martin periodinane).

Figure 4

Photoinduced preparation of benzyne 12, an in situ generated oxidized version of benzene, and its SPAAC with benzylazide.

Figure 5

Oxidative removal of a dicobalt hexacarbonyl complex from a strained alkyne to facilitate CuAAC conjugation on a distal alkyne (A) or azide (B). In blue, the one-pot oxidation-induced click reaction is shown, leading to SPAAC and CuAAC products 14 and 16.

Figure 6

Click reactions of 1,3-dipoles with unsaturated C–C bonds. (A) One-pot oxidation of oximes 17 to nitrile oxide 18 and subsequent SPANOC with olefins (to form isooxazoline 19), with terminal alkynes or internal alkynes to form isoxazoles (20 and 21). (B) SPANC of nitrone 22, which can be obtained by means of in situ oxidation, with DBCO derivative 23 to form isoxazoline 24.

Figure 7

(A) Classical synthesis of 1,2,4,5-tetrazine (Tz, 26) by means of oxidation of dihydrotetrazine (DHTz, 25). (B) One-pot in situ oxidation-induced click chemistry activates DHTz 27 by forming Tz 28, which rapidly undergoes an IEEDA cycloaddition reaction with sTCO-dye 29 to form adduct 30.

Figure 8

Strain-promoted oxidation-controlled quinone cycloaddition reactions (first example from 1979 in panel A, and more recent example from 2010 in panel B, including various strained olefins or acetylenes that have been used in recent years (C). Note: DCE = 1,2-dichloroethane, MeOH = methanol.

Figure 9

Hydrogel formation as a result of the oxidation-induced SPOCQ reaction between DHPA-functionalized (red, 40), BCN-functionalized (black, 41), and star-PEG units. The bicyclo[2,2,2]octadienenone that connects the hydrogel monomers is highlighted. The inset (right bottom) shows the hydrogel that contains a SPAAC-linked dye on the BCN-functionalized ends that remained using nonequimolar amounts of BCN-star-PEG and DHPA-star-PEG.

Figure 10

Schematic representation of interfacial polymerization with a dhTz-functionalized monomer with diTz-functionalized PEG and subsequent photocatalytic modification of the fiber with cpTCO-functionalized derivative 44.

Figure 11

Conversion of a catechol-functionalized surface by means of oxidation-induced SPOCQ reaction with BCN 46 (left) and cyclopropene 47 (right).

Figure 12

Schematic depiction of the various oxidation pathways for protein-bound Tyr and its oxygenated DOPA derivative.

Figure 13

Chemical modification of Tyr85 by means of diazonium reaction, followed by a reduction–oxidation conversion to iminoquinone 53, after which a hetero-Diels–Alder cycloaddition with acrylamide resulted in product 57.

Figure 14

(A) In situ oxidation of PTAID 58 and its subsequent conjugation to Tyr residues in trastuzumab. (B) Hemin-catalyzed oxidative coupling of N-methyl phthalic hydrazide 60 to angiotensin II (top) and photocatalytic oxidation of a peptidic Tyr residue, followed by its cross-coupling to the dimethylaniline-based radical transfer reagent (RTA, 62) (bottom).

Figure 15

Enzymatic oxidation-induced click reaction of NML-derivatives to protein Tyr residues.

Figure 16

Electrochemical activation of urazole species in situ (e-Y-click). Reproduced from the Journal of the American Chemical Society. Copyright 2018 American Chemical Society.

Figure 17

(A) Schematic depiction of the protein modification by means of hGQ DNAzymes and NML derivatives, including a model of the hemin/G-quadruplex DNAzyme derived from PDB-code 6PNK. (B) Activation of the hGQ DNAzyme by means of H₂O₂ and a neighboring adenine base.

Figure 18

Two-electron oxidation of catechol 64 to its corresponding quinone, and its SPOCQ with BCN-functionalized biotin derivative 65, resulting in product 66.

Figure 19

(A) NaIO₄ oxidation-induced activation of a substrate (10 mM, 4 equiv) and its subsequent SPOCQ to a BCN-functionalized protein (20 μM). (B) SPOCQ conjugation of the BCN-protein with the oxidatively activated lissamine rhodamine B fluorophore. (C) Dimerization of the BCN-functionalized protein with bifunctional linker 75. Reproduced from Bioconjugate Chemistry. Copyright 2015 American Chemical Society.

Figure 20

Biosynthesis of L-DOPA 76 by tyrosine phenol-lyases (TPL) from catechol 77, pyruvate 78, and ammonia, followed by its genetic incorporation by means of an evolved aatRNA and aaRS pair. The DOPA-derivatized protein was subjected to a SPOCQ with Cy5.5-DBCO 79 in the presence of sodium periodate.

Figure 21

SPOCQ labeling of G₄Y-tagged laminarinase A by reaction of BCN-modified reagent 81 with in situ generated 1,2-quinone on the protein laminarinase A. Reproduced from Bioconjugate Chemistry. Copyright 2017 American Chemical Society.

Figure 22

Schematic representation of SPOCQ on protein tyrosine residues by means of Fremy’s salt 82 and DBCO-functionalized dye 83.

Figure 23

Metal-free oxidation-induced modification of Trp 84 with keto-ABNO 86.

Figure 24

Oxidation of Cys residues to its corresponding sulfenic, sulfinic, and sulfonic acids, with emphasis on the derivatization of the sulfenic acid moieties by means of nucleophilic attack or cycloaddition reactions.

Figure 25

(A and B) Strained alkyne 2 and alkene 88 reacting with sulfenic acids under formation of covalent adducts. (C) Biscyclooctyne probe 89 reacting with protein sulfenic acids to install BCN moieties on Cys-OH in the form of 90. (D) Norbornene derivatives 91 reacting with short-lived sulfenic acids to form adduct 92. (E) Two norbornene probes for cysteine sulfenic acid detection, one containing an alkyne (93) and the other a biotin (94). (F) Application of SAM-TCO probe 95 in the labeling of biological sulfenic acid derivatives via the highly reactive thiiranium ion 96.

Figure 26

Oxidative Met derivatization with oxaziridine 98 leading to functionally derivatized N-transfer product 99.

Figure 27

SPANC derivatization of proteins by attachment of a PEG unit (A) or to a nanoparticle (B).