The Versatility of Diazirines: Properties, Synthetic and Modern Applications

Abstract

Diazirines are 3-membered heterocycles containing two nitrogen atoms connected by a double bond. They are mostly known for their usage in photoaffinity labeling (PAL), due to their stability and their facile photolysis for on-demand carbene generation. Yet diazirines possess a multi-faceted reactivity that also holds great potential for organic synthesis. This is illustrated in the present review, which is meant to be a beginner's guide for new diazirine users. After briefly summarizing the main synthetic approaches to these derivatives (with a focus on recent improvements), we emphasize some of their most critical features and properties before describing the various modes of activation toward carbene generation, some of which were only uncovered in the past decade. We then review the many modern uses of diazirines, underlining their underappreciated versatility: as carbene precursors in synthesis, but also as electrophilic nitrogen donors, as NMR hyperpolarization probes, or as molecular tools in materials science.

Keywords: carbenes; diazirines; organic synthesis; photochemistry; reactivity.

Figure 1

Diazirines combine features and properties of several structurally related motifs.

Figure 2

Non‐exhaustive, general overview of synthesis pathways to diazirines.

Figure 3

Top: Structure of 3‐trifluoromethyl‐3‐aryldiazirine (TAD) and the corresponding carbene. Bottom: General mechanism for the rearrangements of alkyl carbenes.

Figure 4

The second substituent on mono‐aryl diazirines modulates the influence of the electron density of the aromatic ring.

Figure 5

Chemical shifts in ¹H, ¹³C, and ¹⁹F NMR for phenyl trifluoromethyl derivatives. n.r. = not reported; n.o. = not observed. (Tabulated values and references can be found in the Supporting Information.)

Figure 6

Photochemical activation of diazirines, including isomerization to the corresponding diazoalkane.

Figure 7

Variation in absorption wavelength for (hetero)aromatic diazirines.^{[ 36} , ⁴³ , ⁴⁴ , ⁴⁵ , ^{46 ]} λ_abs is the apex of the absorbance band of the diazirine function and does not necessarily correspond to the maximum absorbance for the compound. The top right‐hand‐side panel was adapted from Wulff et al.^{[ 36 ]} (open‐access article under CC‐BY license).

Figure 8

Model fluorene‐diazirine conjugate.^{[ 47 ]}

Figure 9

Substituents strongly influence the electronic state of diazirine‐born carbenes.

Figure 10

Top: Variation in TAD activation temperatures and energies with the Hammett parameter σ_p ⁺.^{[ 48 ]} The strong correlations and positive slopes are indicative of carbocation character in the transition state resulting from diazirine activation. Reproduced from Wulff et al.^{[ 36 ]} (open‐access article under CC‐BY license). Bottom: Selected examples of TADs^{[ 36 ]} and aryl diazirines,^{[ 50 ]} illustrating that electron‐donating aryl substituents lower their activation temperatures.

Figure 11

A) Scheme representing the electrochemical reduction of various diazirines and their downstream pathways. B) Reduction potentials of studied diazirines, indicated versus Ag/AgCl. The indicated half‐lives were measured in MeCN + 0.1 M Et₄N·ClO₄ at 10 °C in the absence of a proton donor. For clarity, the values represented on the potential axis are approximations, given the variety of reference electrodes and conditions used in the studies. An inventory of the exact, reported values and the experimental parameters can be found in the Supporting Information.

Figure 12

Top: Overview of photocatalytic activation of diazirines with blue light. Middle: Schematic representation of electron population in frontier orbitals of photocatalyst and diazirine during activation by DEnT. Bottom: iridium‐based and deazaflavin photocatalysts.

Figure 13

Concept of glycosylation with glycosylidene carbenes and alcohols, and key examples illustrating the influence of acidity and hydrogen bonding over regioselectivity.

Figure 14

Usage of diazirine 50 as a precursor of diazo for its cyclopropanation with butyl vinyl ether. The higher yields obtained in the presence of 2 mol% Rh₂(pfb)₄ support a mechanism where the diazoalkane 51 generated from the slow decomposition of diazirine 50 is trapped as a rhodium(II)‐carbene.

Figure 15

Top: Pd(0)‐catalyzed, microwave‐assisted cross‐couplings of aryl alkyl diazirines with aryl halides.^{[ 75 ]} Bottom: Metal‐free oxidative cross‐coupling of aryl alkyl diazirines with aryl boronic acids.^{[ 76 ] (a)} Diazo isomer was ruled out as an intermediate in the metal‐free cross‐coupling.

Figure 16

Enzymatic cyclopropanation of benzyl acrylate and styrene by Arnold et al.^{[ 77} , ^{78 ]}

Figure 17

Recent report of the formation of a copper benzylidene complex from a diazirine below room temperature.

Figure 18

Cyclopropenation of diphenylacetylide with TADs under direct photolytic activation in flow.

Figure 19

Cyclopropanation of alkenes with halodiazirines under direct photolytic activation in flow.

Figure 20

P─H insertion of halodiazirines into H‐phosphorous oxides, along with a few examples.

Figure 21

Difluoroolefination of aryl alkyl diazirines and subsequent access to tetrafluorocyclopropanes with excess difluorocarbene.

Figure 22

Examples of carbynyl cation equivalents and comparison with chlorodiazirines.

Figure 23

Formal (hetero)aryl methide insertion into aromatic C─C or N─N bonds via thermal decomposition of arylchlorodiazirines.

Figure 24

Formal (hetero)aryl methide insertion into aromatic C─C or N─N bonds via photochemical decomposition of arylchlorodiazirines. The azinium salts can easily be further derivatized.^{[ 50 ]}

Figure 25

Insertion of aryl methide into single C─C bonds via a two‐step process.^{[ 86 ]}

Figure 26

Top: The decomposition of vicinal bis‐diazirines leads to alkynes, even in strained systems. (Yield for 67 is isolated; yields for 68–70 are for the trapped species.) Bottom: Photolysis of mono‐diazirine control 71 yields the rearranged alkene, suggesting an intermediate carbene.

Figure 27

3,3‐Adamantyldiazirine 74 is used as an electrophilic nitrogen donor, where organo‐lithium and ‐magnesium reagents add across the N═N double bond to yield the corresponding metalated diaziridines and/or hydrazones. Those can be condensed in situ with 1,3‐diketones to afford N‐substituted pyrazoles or enolizable ketones to produce a variety of indoles. The by‐product adamantanone 75 is recovered and recycled.

Figure 28

Decarboxylative amination strategy using fluorinated diazirines 7 or 77 as electrophilic nitrogen donors,^{[ 95} , ⁹⁶ , ⁹⁷ , ^{98 ]} where the intermediate N‐alkylated diaziridines are converted selectively to a hydrazine or an amine. a) MsOH (or H₂SO₄ or p‐TsOH), EtOH, 90 °C, 16 hours; b) HI (or LiCl/TMSCl or HCl/I₂ or HCl/NaI), MeCN, r.t., 2 hours.

Figure 29

Regioselective hydroamination of unactivated alkenes using diazirine 7 as a nitrogen donor.^{[ 99 ]} (The obtained N‐alkylated diaziridines are converted selectively to amines, hydrazines, or N‐heterocycles. A few representative examples of products are given.) ^(a) [1.1.1]propellane reacted best with Mn(dpm)₃ as a catalyst.

Figure 30

Signal Amplification By Reversible Exchange (SABRE) in SHield Enables Alignment Transfer to Heteronuclei (‐SHEATH).

Figure 31

Rare reports of ill‐defined polymers made from diazirines.

Figure 32

Examples of diazirine conjugates used for the functionalization of surfaces and materials.

Figure 33

Modification of nanomaterials with diazirines.

Figure 34

Crosslinking polymers with bis‐diazirine via successive insertions of carbenes. ^# = thermal activation at 140 °C in cyclohexane.

Figure 35

Synthesis of TAD‐bearing polymers via radical polymerization.