The authors thank the Fonds der Chemischen Industrie for a Liebig fellowship and the Hertha and Helmut Schmauser foundation for financial support. Support by K. Meyer is gratefully acknowledged.

CAUTION: Carry out all syntheses in a well-ventilated fume hood. Wear appropriate personal protective equipment (PPE) including a lab coat and safety goggles.
NOTE: The starting materials were synthesized according to the literature: 1-(2,6-diisopropylphenyl)-2,2,4,4-tetramethyl-3,4-dihydro-2H-pyrrol-1-ium tetrafluoroborate (1prot) (For the synthesis of CAACs, see:18,30,31,64,65) and 1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium iodide (2prot)65. We suggest drying these salts at 120 &#176;C in vacuo overnight in order to ensure the absence of water or halogenated solvents. Silver triflate and potassium hexamethyldisilazide (KHMDS) were obtained by commercial vendor and used as is without further purification. All manipulations were performed using Schlenk techniques or in a dinitrogen filled glovebox (O2 &#60; 0.1 ppm; H2O &#60; 0.1 ppm). Solvents were dried by a two-column, solid-state purification system and stored over activated molecular sieves. Tetrahydrofuran, diethylether, hexanes, pentane, benzene and toluene were deoxygenated by three freeze-pump-thaw cycles. Deuterated benzene was dried over molecular sieves, deoxygenated by three freeze-pump-thaw cycles and stored over a mirror of potassium, deuterated acetonitrile was distilled from calcium hydride and stored over molecular sieves. Glassware was oven-dried at 150 &#176;C for at least 12 h prior to use and brought hot directly into the glovebox (cycling the antechamber at least three times over the course of at least 15 min). Glass micro fiber filters were stored at 150 &#176;C; cannulas were either oven-dried or thoroughly purged with air prior to use in order to ensure the absence of residual organic solvent (water, respectively).
1. Synthesis of cyclic (alkyl)(amino) carbene (Compound 1)
<ol>
	<li>Transfer a hot, oven-dried 100 mL Schlenk flask equipped with a stir bar and a rubber septum into a dinitrogen filled glovebox.</li>
	<li>Weigh out the iminium salt 1-(2,6-diisopropylphenyl)-2,2,4,4-tetramethyl-3,4-dihydro-2H-pyrrol-1-ium tetrafluoroborate (1prot) (2.00 g, 5.36 mmol, 1.0 eq.) and potassium hexamethyldisilazide (KHMDS) (1.05 g, 5.25 mmol, 0.98 eq.) and combine in the 100 mL Schlenk flask. Cap the flask with a rubber septum.</li>
	<li>Transfer the flask to the Schlenk line. Evacuate and refill all connecting hoses with dinitrogen three times in order to remove any traces of water and air.</li>
	<li>Connect a second oven-dried 100 mL Schlenk flask capped with a rubber septum to the Schlenk line. Evacuate/refill the connecting hose three times.</li>
	<li>Open the solid containing flask to dinitrogen and cool the flask using an isopropanol slush bath (-88 &#176;C) or a dry ice/acetone (-78 &#176;C) cooling bath.</li>
	<li>Add 20 mL of diethylether (dry, degassed) over the course of 3 min along the cold flask wall using a syringe. Stir the suspension for 10 min before allowing the reaction mixture to warm to room temperature.</li>
	<li>Once the mixture reaches room temperature, discontinue stirring and allow the potassium tetrafluoroborate salt to settle.</li>
	<li>Prepare a steel cannula equipped with a glass micro fiber filter, which is fitted to one end of the cannula by polytetrafluoroethylene (PTFE) tape. Wind the PTFE tape around the end of the cannula to obtain an overall diameter of about 0.6 cm (0.25 inch; Figure 3a, b). Then fit the glass micro fiber filter by winding further PTFE tape around (Figure 3c).</li>
	<li>Perforate a septum with a small needle (with a smaller diameter than the cannula) and subsequently push the filter cannula through the tiny hole. Swiftly exchange this septum under a gentle flow of dinitrogen with the septum on the Schlenk flask containing the crude carbene. Purge the cannula for at least 1 min with dinitrogen.</li>
	<li>Perforate the second septum capping the second empty Schlenk flask as well with a small needle and introduce the other end of the steel cannula.</li>
	<li>Additionally, insert a thin needle through the septum of the empty flask and close the Schlenk valve connecting this flask to the Schlenk line. Note that overpressure will be released through the extra needle (Figure 4).</li>
	<li>Lower the filter cannula into the overlying solution to start the filtration of the solution containing the free carbene into the second Schlenk flask using slight dinitrogen overpressure provided by the line. Eventually, also lower the filter cannula into the suspension with the settled salt at the bottom of the flask.</li>
	<li>After quantitative transfer of the carbene, reopen the valve of the second Schlenk flask to the Schlenk line for dinitrogen supply. Remove the small needle as well as the steel cannula and seal the perforated septum of the Schlenk flask with adhesive tape. 
	Alternatively, replace the perforated septum by a well-greased glass stopper.</li>
	<li>Remove the solvent in vacuo to obtain the free carbene 1 quantitatively as a colorless to slightly yellow and greasy solid (1.53 g). Quantitative removal of hexamethyldisilazane 
	[HN(SiMe3)2] requires typically a vacuum around 1 * 10-3 mbar or gentle heating. Transfer&#160;1 to a glovebox for storage.</li>
</ol>
2. Synthesis of the N-heterocyclic carbene (Compound 2)
<ol>
	<li>Transfer a hot, oven-dried 100 mL Schlenk flask, a rubber septum and a stir bar into a dinitrogen filled glovebox.</li>
	<li>Weigh out the imidazolium salt 1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium iodide 2prot 
	(2.00 g, 8.93 mmol, 1.0 eq.) and KHMDS (1.75 g, 8.75 mmol, 0.98 eq.). Combine both in the Schlenk flask, add the stir bar and seal the flask with the rubber septum.</li>
	<li>Transfer the Schlenk flask to the Schlenk line and evacuate/refill the connecting hose three times. Additionally, connect a second oven-dried 100 mL Schleck flask equipped with a septum to the Schlenk line. Evacuate/refill with dinitrogen three times.</li>
	<li>Add 10 mL of diethylether (dry, degassed) via a syringe to the 2prot / KHMDS mixture and stir for 20 min at room temperature.</li>
	<li>To separate the precipitated salt, use a steel cannula equipped with a glass micro fiber filter to one end and transfer the solution into the second Schlenk flask as described previously (steps 1.8 &#8211; 1.13).</li>
	<li>Remove the solvent in vacuo to afford the free carbene 2 as a slightly yellow oil in a yield of 390 mg (45%). Transfer 2 to a glovebox for storage and the next step.</li>
</ol>
3. Synthesis of the CAAC&#8211;NHC salt (Compound 3prot)
<ol>
	<li>Transfer a hot, oven-dried 100 mL Schlenk flask equipped with a stir bar and a rubber septum into a dinitrogen filled glovebox.</li>
	<li>Weigh out the cyclic iminium salt 1prot (1.50 g, 4.02 mmol, 1.0 eq.) and the free carbene 2 
	(409 mg, 4.22 mmol, 1.05 eq.). Combine both in the Schlenk flask and seal the flask with a rubber septum.</li>
	<li>Transfer the Schlenk flask to a Schlenk line. Evacuate/refill the connecting hoses with dinitrogen three times.</li>
	<li>Add 20 mL of tetrahydrofuran (dry, degassed) via a syringe according to description in steps 1.5 - 1.6. Swiftly replace the perforated septum by a well-greased glass stopper. Stir the reaction mixture for at least 12 h at room temperature.</li>
	<li>Allow the precipitate to settle. Exchange the glass stopper by a rubber septum with a steel&#160;cannula equipped with a glass micro fiber filter to one end to transfer the yellow&#160;supernatant solution into the second Schlenk flask as described previously (1.8 &#8211; 1.12)</li>
	<li>Exchange the glass stopper by a rubber septum and wash the residue with tetrahydrofuran: Add dry tetrahydrofuran (20 mL) via a syringe and stir until you obtain a fine suspension. Remove the supernatant using a filter cannula as described previously (1.8 &#8211; 1.12). If the residue is still&#160;yellow/orange repeat the washing step with additional 20 mL tetrahydrofuran. Exchange&#160;&#160;the perforated septum along with the filter cannula by a well-greased glass stopper.</li>
	<li>Dry the residue in vacuo to afford the protonated heterodimer quantitatively as an off-white powder. Transfer 3prot to a glovebox for storage and the next step.</li>
</ol>
4. Synthesis of the mixed Wanzlick CAAC&#8211;NHC dimer (Compound 3)
<ol>
	<li>Transfer a hot, oven-dried 100 mL Schlenk flask equipped with a stir bar and a rubber septum into a dinitrogen glovebox.</li>
	<li>Weigh out 3prot (1.5 g, 3.19 mmol, 1.0 eq.) and KHMDS (624 mg, 3.13 mmol, 0.98 eq.). Combine both in the Schlenk flask and cap the flask with the rubber septum.</li>
	<li>Connect this Schlenk flask and a second oven-dried empty 100 mL Schlenk flask equipped with a rubber septum to the Schlenk line. Evacuate/refill the connecting hoses with dinitrogen three times.</li>
	<li>Add 10 mL of toluene (dry, degassed) via a syringe to the mixture of 3prot and KHMDS. Stir for 12 h at room temperature, then stop stirring and allow the precipitate to settle.</li>
	<li>Transfer the supernatant solution, containing the dimer 3, into the second Schlenk flask using a filter cannula as described previously (steps 1.8 &#8211; 1.13).</li>
	<li>Remove the solvent in vacuo.</li>
	<li>Wash the residue with hexanes to remove residual HN(SiMe3)2: Add 5 mL hexanes (dry, degassed) and stir until you obtain a fine suspension. Remove the supernatant using a filter cannula as described previously (steps 1.8 &#8211; 1.13). Exchange the perforated septum along with the filter cannula by a well-greased glass stopper.</li>
	<li>Dry the residue in vacuo to obtain CAAC&#8211;NHC heterodimer 3 as a off white powder in a yield of 970 mg (80%). Transfer 3 to a glovebox for storage.</li>
</ol>
5. Synthesis of the organic radical CAAC&#8211;NHC-2 (compound 4)
<ol>
	<li>Transfer a hot, 20 mL Schlenk flask equipped with a stir bar and a rubber septum into a dinitrogen glovebox.</li>
	<li>Weigh out the silver trifluoromethanesulfonate [Ag(OTf); 134 mg, 0.52 mmol, 1.0 eq.] and compound 3 (200 mg, 0.52 mmol, 1.0 eq.). Combine both in the 20 mL Schlenk flask and cap with a rubber septum.</li>
	<li>Connect this Schlenk flask and a second oven-dried empty 20 mL Schlenk flask equipped with a stir bar and a septum to the Schlenk line. Evacuate/refill the connecting hoses with dinitrogen three times.</li>
	<li>Add 5 mL of tetrahydrofuran (dry, degassed) via syringe to receive a deep maroon mixture.</li>
	<li>Filter the solution into the second Schlenk flask using a filter cannula as described previously (steps 1.8 &#8211; 1.13).</li>
	<li>Remove the solvent in vacuo to obtain the stable radical quantitatively as a red powder. Transfer 4 to a glovebox for storage.</li>
</ol>

The authors have nothing to disclose.

Herein, we present a general and adaptable protocol for the synthesis of stable carbenes (NHC, CAAC) and their electron rich dimer. All steps can readily be upscaled to at least a 25&#160;g scale. Crucial for a successful synthesis are the strict exclusions of moisture (air, respectively) for the synthesis of the carbenes, and of oxygen (air, respectively) for the electron rich olefin. The herein applied filtration cannula technique in combination with a Schlenk line is a very convenient method to separate solutions from...

More than half a century ago, Wanzlick reported arguably the first attempts to synthesize N-heterocyclic carbenes1,2,3. However, instead of isolating the free carbenes, he succeeded only in characterizing their dimers. This observation prompted him to suggest an equilibrium between the olefin dimer and the respective free carbenes, which is now commonly referred to as &#8220;Wanzlick&#8217;s equilibrium&#8221; (Figure 1, I.)4,5,6. Later on, it was argued that the dimerization of free carbenes and of course equally the reverse reaction (i.e., the dissociation of the related olefin dimers), is catalyzed by protons7,8,9,10,11,12. It took another 30 years until the first &#8220;bottleable&#8221; carbene, which did not dimerize at room temperature, was reported by Bertrand13,14. Especially N-heterocyclic carbenes (NHCs; imidazolin-2-ylidenes) became the subject of intensive research after Arduengo had reported a stable crystalline NHC, 1,3-diadamantyl-imidazolin-2-ylidene15. The surprising stability of this carbene was first rationalized by a combination of steric effects due to the bulky adamantyl substituents as well as electronic effects associated with the aromatic N-heterocycle. However, it was shown later in an elegant study by Murphy that even &#8220;monomeric&#8221; 1,3-dimethyl-imidazolin-2-ylidene16 (i.e., the free carbene derived from N,N-dimethylimidazolium salts) with very small methyl substituents is more stable than its dimer17. Lavallo and Bertrand showed on the contrary, that also the removal of one stabilizing nitrogen atom, as reported by the isolation of a cyclic (alkyl)(amino) carbene (CAAC), can be balanced by introduction of a bulky 2,6-diisopropylphenyl (Dipp) substituent18.
NHCs and CAACs proved extraordinarily fruitful for the coordination chemistry of the d- and p-block elements, transition metal catalysis, or organocatalysis (For thematic issues and books on NHCs, see19,20,21,22,23, for reviews on CAACs, see24,25,26,27,28, for the synthesis of CAACs, see18,29,30,31). The impressive success story of cyclic carbene ligands is mainly due to two reasons32. First, both electronic and steric properties can be readily tuned to fit the requirements of a specific application. Second, the isolation of stable free carbenes offers a convenient method to synthesize metal complexes by straightforward combination with a metal precursor. Accordingly, it is important to understand the factors which control whether a free carbene is stable at or below room temperature or whether it dimerizes to form an olefin. Note that the derived electron rich olefins usually33 do not form complexes upon treatment with a metal precursor, which is at least in part due to their highly reducing character.
Not only are free carbenes key players in synthetic chemistry nowadays. In fact, their electron rich olefin dimers34,35,36 (e.g., tetraazafulvalenes in case of NHCs37 or tetrathiafulvalenes TTF38,39,40 in case of 1,3-dithiol-2-ylidenes; Figure 1, II.), have not only found broad application as reductants41,42,43, but even more so in organic electronics.
TTF is in fact called the &#8220;brick-and-mortar&#8221; of organic electronics44. This is largely due to the particular electronic properties of electron rich olefins &#8211; notably, many of those show three stable redox states upon oxidation, including the open-shell organic radical (For reviews on carbene derived organic radicals, see:45,46,47, for recent contributions in the area of carbene stabilized organic radicals, see:48,49,50,51,52,53,54). Accordingly, TTF allows for the fabrication of conductive/semiconductive material as required for magnetic materials, organic field-effect transistors (OFETs), organic light emitting diodes (OLEDs) and molecular switches or sensors55,56,57,58,59.
Herein, we present convenient protocols for the isolation of two stable carbenes with enormous impact in coordination chemistry and homogeneous catalysis (Figure 2), viz. the cyclic (alkyl)(amino) carbene 1 18, and the dimethylimidazolin-2-ylidene NHC 2 15. We will discuss why both carbenes are stable at room temperature and do not dimerize. We will then elaborate on proton catalysis related to Wanzlick&#8217;s equilibrium and the formation of the mixed CAAC&#8211;NHC heterodimer 360,61,62. The exciting electronic properties of such triaza-alkenes is connected with the impressive stability of the related organic radical 4 63.
Methodological focus lies on the Schlenk technique using filter cannulas equipped with a glass micro fiber filter for the separation of a supernatant from a precipitate under inert conditions. A dinitrogen filled glovebox is used for weighing in starting material and the storage of air sensitive compounds.

<table><tbody><tr><td>&lt;strong&gt;Equipment&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>Glass micro fiber filter, 691, 24 mm. Particle retention 1.6 mm</td><td>VWR</td><td>516-0859</td><td></td></tr><tr><td>magnetic stir bar</td><td>FengTecEx</td><td>various</td><td></td></tr><tr><td>PTFE tape</td><td>Sigma-Aldrich</td><td>Z148814-1PAK</td><td>PTFE tape used in this manuscript was obtained from a local supplier. Tape from Sigma Aldrich should show comparable performance.</td></tr><tr><td>rubber septum</td><td>FengTecEx</td><td>RS112440</td><td>Joint size: 24/29</td></tr><tr><td>rubber septum</td><td>FengTecEx</td><td>RS111420</td><td>Joint size: 14/23</td></tr><tr><td>rubber septum</td><td>FengTecEx</td><td>RS111922</td><td>Joint size: 19/26</td></tr><tr><td>schlenk flasks</td><td>FengTecEx</td><td>various</td><td>100 mL</td></tr><tr><td>steel cannula</td><td>FengtecEx</td><td>C702024</td><td>Attachment of a steel joint by a machine shop not required, but facilitates preparation of filter cannula</td></tr><tr><td>syringe cannula</td><td>FengtecEx</td><td>S380221</td><td></td></tr><tr><td>&lt;strong&gt;Name&lt;/strong&gt;</td><td>&lt;strong&gt;Company&lt;/strong&gt;</td><td>&lt;strong&gt;Catalog Number&lt;/strong&gt;</td><td>&lt;strong&gt;Comments&lt;/strong&gt;</td></tr><tr><td>&lt;strong&gt;Reactants&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>1-(2,6-diisopropylphenyl)-2,2,4,4-tetramethyl-3,4-dihydro-2H-pyrrol-1-ium tetrafluoroborate</td><td></td><td></td><td>Synthesized according to: Jazzar, R., Dewhurst, R. D., Bourg, J. B., Donnadieu, B., Canac, Y., Bertrand, G. Intramolecular &amp;ldquo;Hydroiminiumation&amp;rdquo; of alkenes: Application to the synthesis of conjugate acids of cyclic alkyl amino carbenes (CAACs). Angewandte Chemie International Edition 46 (16), 2899-2902, (2007).</td></tr><tr><td>1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium iodide</td><td></td><td></td><td>Synthesized according to: Benac, B. L., Burgess, E. M., Arduengo, A. J. 1,3-Dimethylimidazole-2-Thione. Organic Synthesis 64, 92, (1986).</td></tr><tr><td>potassium hexamethyldisilazide</td><td>Sigma-Aldrich</td><td>324671-100G</td><td>CAS 40949-94-8</td></tr><tr><td>silver trifluoromethanesulfonate</td><td>Sigma-Aldrich</td><td>85325-25G</td><td>CAS 2923-28-6</td></tr><tr><td>&lt;strong&gt;Name&lt;/strong&gt;</td><td>&lt;strong&gt;Company&lt;/strong&gt;</td><td>&lt;strong&gt;Catalog Number&lt;/strong&gt;</td><td>&lt;strong&gt;Comments&lt;/strong&gt;</td></tr><tr><td>&lt;strong&gt;Solvents&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>acetonitrile-D&lt;sub&gt;3&lt;/sub&gt;</td><td>Deutero</td><td>00202-10m</td><td>distilled from CaH2, stored over activated molecular sieves</td></tr><tr><td>benzene-D&lt;sub&gt;6&lt;/sub&gt;</td><td>Deutero</td><td>00303-100ml</td><td>dried over activated molecular sieves, stored over potassium</td></tr><tr><td>diethylether</td><td>-</td><td>-</td><td>dried by two-column, solid-state purification system and degassed by three freeze-pump-thaw cycles, stored over activated molecular sieves</td></tr><tr><td>hexanes</td><td>-</td><td>-</td><td>dried by two-column, solid-state purification system and degassed by three freeze-pump-thaw cycles, stored over activated molecular sieves</td></tr><tr><td>tetrahydrofuran</td><td>-</td><td>-</td><td>dried by two-column, solid-state purification system and degassed by three freeze-pump-thaw cycles, stored over activated molecular sieves</td></tr><tr><td>toluene</td><td>-</td><td>-</td><td>dried by two-column, solid-state purification system and degassed by three freeze-pump-thaw cycles, stored over activated molecular sieves</td></tr></tbody></table>

isolating free carbenes, their mixed dimers and organic radicals

Protocols for the isolation of the commonly employed cyclic (alkyl)(amino) carbene (CAAC) and N-heterocyclic carbene (NHC) are reported. Furthermore, the synthesis of their mixed CAAC&#8211;NHC &#8220;Wanzlick&#8221; dimer and the synthesis of the related stable organic &#8220;olefin&#8221; radical are presented. The main goal of this manuscript is to give a detailed and general protocol for the synthetic chemist of any skill level on how to prepare free heterocyclic carbenes by deprotonation using filter cannulas. Due to the air-sensitivity of the synthesized compounds, all experiments are performed under inert atmosphere using either Schlenk technique or a dinitrogen filled glovebox. Controlling Wanzlick&#8217;s equilibrium (i.e., the dimerization of free carbenes), is a crucial requirement for the application of free carbenes in coordination chemistry or organic synthesis. Thus, we elaborate on the specific electronic and steric requirements favoring the formation of dimers, heterodimers, or monomers. We will show how proton catalysis allows for the formation of dimers, and how the electronic structure of carbenes and their dimers affects the reactivity with either moisture or air. The structural identity of the reported compounds is discussed based on their NMR spectra.

Free carbenes react typically readily with water66. Hence, carefully dried glassware and solvents are required67. In the procedure described above, we used cannulas fitted with a glass micro fiber filter in order to separate air sensitive solutions from a precipitate under inert conditions. We used this technique for both the extraction of solids (i.e., the desired product is dissolved) as well as the washing of solid compounds (i.e., the de...

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Isolating Free Carbenes, their Mixed Dimers and Organic Radicals

We present protocols for the isolation of stable heterocyclic carbenes. The synthesis of a cyclic (alkyl)(amino) carbene (CAAC) and an N-heterocyclic carbene (NHC) is demonstrated using filter cannulas and Schlenk technique. We furthermore present the synthesis of the related oxygen-sensitive, electron-rich mixed &#8220;Wanzlick dimer&#8221; and the reduced stable organic radical.

Protocols for the isolation of the commonly employed cyclic (alkyl)(amino) carbene (CAAC) and N-heterocyclic carbene (NHC) are reported. Furthermore, the ...

isolating-free-carbenes-their-mixed-dimers-and-organic-radicals

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10.7K Views.  Friedrich-Alexander-Universität Erlangen-Nürnberg. We present protocols for the isolation of stable heterocyclic carbenes. The synthesis of a cyclic (alkyl)(amino) carbene (CAAC) and an N-heterocyclic carbene (NHC) is demonstrated using filter cannulas and Schlenk technique. We furthermore present the synthesis of the related oxygen-sensitive, electron-rich mixed “Wanzlick dimer” and the reduced stable organic radical.

Video: Isolating Free Carbenes, their Mixed Dimers and Organic Radicals

Free Radicals in Chemical Biology: from Chemical Behavior to Biomarker Development

The involvement of free radicals in life sciences has constantly increased with time and has been connected to several physiological and pathological processes. This subject embraces diverse scientific areas, spanning from physical, biological and bioorganic chemistry to biology and medicine, with applications to the amelioration of quality of life, health and aging. Multidisciplinary skills are required for the full investigation of the many facets of radical processes in the biological environment and chemical knowledge plays a crucial role in unveiling basic processes and mechanisms. We developed a chemical biology approach able to connect free radical chemical reactivity with biological processes, providing information on the mechanistic pathways and products. The core of this approach is the design of biomimetic models to study biomolecule behavior (lipids, nucleic acids and proteins) in aqueous systems, obtaining insights of the reaction pathways as well as building up molecular libraries of the free radical reaction products. This context can be successfully used for biomarker discovery and examples are provided with two classes of compounds: mono-trans isomers of cholesteryl esters, which are synthesized and used as references for detection in human plasma, and purine 5',8-cyclo-2'-deoxyribonucleosides, prepared and used as reference in the protocol for detection of such lesions in DNA samples, after ionizing radiations or obtained from different health conditions.

Radical-based biomimetic chemistry has been applied to building-up libraries necessary for biomarker development.

The involvement of free radicals in life sciences has constantly increased with time and has been connected to several physiological and pathological ...

Radicals: Electronic Structure and Geometry

This lesson delves into the geometry of a radical, which is influenced by the electronic structure of the molecule. The principle is similar to that of a lone pair, where the unpaired electron influences the geometry at the radical center.
Accordingly, the structure of a trivalent radical lies between the geometries of carbocations and carbanions. An sp2-hybridized carbocation is trigonal planar, while an sp3-hybridized carbanion is trigonal pyramidal. Here, the difference in geometry is attributed to the difference in the number of nonbonding electrons. While the former has nil, the latter has two nonbonding electrons. Hence, a carbon radical with one nonbonding electron present in the p orbital falls between these two cases.
It is therefore reasonable to expect the radical geometry of a trivalent carbon species to lie between trigonal planar and trigonal pyramidal. As observed experimentally, the trivalent carbon-centered radicals typically possess superficially pyramidal geometry but are nearly planar. For instance, this is observed in oxygenated radicals like &#8226;CH2OH and &#8226;CMe2OH. Certain carbon-centered radicals, such as &#8226;CF3, are closer in geometry to the sp3-hybridized carbanions, which are trigonal pyramidal. In contrast, the methyl radical is fully trigonal planar like an sp2-hybridized carbocation.
The chirality of radicals is also a good indicator of the geometry. While the carbanion could be chiral given its resistance to pyramidal inversion, radicals can be achiral, since carbon-centered radicals with alkyl substituents that are superficially pyramidal readily undergo pyramidal inversion to become nearly planar.

This lesson delves into the geometry of a radical, which is influenced by the electronic structure of the molecule. The principle is similar to that of a ...

Education

JoVE Core

Organic Chemistry

Unit 1

Radical Chemistry

KEY TERMS AND CONCEPTS

Radical Formation: Overview

A bond can be broken either by heterolytic bond cleavage to form&#160;ions or homolytic bond cleavage to yield&#160;radicals. A fishhook arrow is used to represent the motion of a single electron in homolytic bond cleavage. There are two main sources from which radicals can be formed:
Radicals from spin-paired molecules: 
Radicals can be obtained from spin-paired molecules either by homolysis or&#160;electron transfer. While two radicals are formed in the former, an electron is added in the latter,&#160;also known as reduction.&#160;
Radicals from other radicals:
There are three ways of radical formation from other radicals: substitution or abstraction, addition, and elimination. During substitution, a radical interacts with a compound or spin-paired molecule. It abstracts&#160;mostly a hydrogen or halogen atom to form another spin-paired molecule and a radical. In case of addition, a radical is added to a pi bond of an unsaturated compound to produce a carbon-centered radical. Elimination is the reversal of the addition process, where a new radical and an unsaturated compound are&#160;formed from a starting radical compound.

A bond can be broken either by heterolytic bond cleavage to form&#160;ions or homolytic bond cleavage to yield&#160;radicals. A fishhook arrow is used to ...

Radical Formation: Homolysis

A bond is formed between two atoms by sharing two electrons. When this bond is broken by supplying sufficient energy, either two electrons can be taken up by one atom forming ions by the cleavage called heterolysis, or the two electrons are shared by two atoms, with one each creating&#160;radicals&#160;by the cleavage&#160;called homolysis.
<img alt="Figure1" src="/files/ftp_upload/12883/PT_12883_Figure_1.svg" style="text-align: center; height: 32px;" />
For example, HCl in solution cleaves into H+ and Cl&#8722; ions, where the chlorine atom takes both bonding electrons with it, leaving a naked proton. However, at about 200 &#176;C in the gas phase, the electron pair forming the H&#8211;Cl bond is shared between the two atoms.
<img alt="Figure2" src="/files/ftp_upload/12883/PT_12883_Figure_2.svg" style="text-align: center; height: 210px;" />
Some weak bonds undergo homolysis at around room temperature. In such cases, light is the best energy source for the homolysis of bonds. Peroxides and halogens are quite readily homolysed by heat and light. Dibenzoyl peroxide and azobisisobutyronitrile (AIBN) are often used as initiators of radical reactions because they can easily homolyse to form radicals.

A bond is formed between two atoms by sharing two electrons. When this bond is broken by supplying sufficient energy, either two electrons can be taken up ...

Radical Formation: Addition

Radicals can be formed by adding a radical to a spin-paired molecule. This is typically observed with unsaturated species, where the addition of a radical across the &#960; bond leads to the production of a new radical by dissolving the &#960; bond. For example, the addition of a Br radical to an alkene yields a carbon-centered radical.
Similar to charge conservation in chemical reactions, spin conservation is implicit for radical reactions. Accordingly, the product formed must possess an unpaired electron if the reaction begins with a reactant having an unpaired electron.
The most facile category of radical formation via the addition process is reduction, where a single electron is added. The Birch reduction of organic compounds is one such example. It employs the electron generated as a metal of group 1 in the periodic table dissolves in liquid ammonia to form the corresponding stable M+1 ion.

Radicals can be formed by adding a radical to a spin-paired molecule. This is typically observed with unsaturated species, where the addition of a radical ...

Radical Formation: Elimination

Another method of radical formation is the elimination process. It is the opposite of the addition route and is driven by the instability of the radical. For example, as depicted in Figure 1, dibenzoyl peroxide yields a pair of unstable radicals upon homolysis. Given its instability, this radical spontaneously undergoes elimination via a C&#8211;C bond cleavage to form a relatively more stable phenyl radical. The mechanism involves cleavage of the bond between the &#945; and &#946; positions with respect to the radical, leading to the formation of an unsaturated molecule as the byproduct.
<img alt="Figure1" src="/files/ftp_upload/12886/12886_PT_Figure_1v2.svg" style="text-align: center; height: 80px;" />
Figure 1. The elimination reaction of dibenzoyl peroxide for the formation of radicals.

Another method of radical formation is the elimination process. It is the opposite of the addition route and is driven by the instability of the radical. ...

Radical Reactivity: Overview

Radicals, the highly reactive species, gain stability by undergoing three different reactions. The first reaction involves a radical-radical coupling, in which a radical combines with another radical, forming a spin&#8208;paired molecule. The second reaction is between a radical and a spin&#8208;paired molecule, generating a new radical and a new spin&#8208;paired molecule. The third reaction is radical decomposition in a unimolecular reaction, forming a new radical and a spin&#8208;paired molecule. These three possible reactions result in six different arrow-pushing patterns in radical mechanisms, such as homolysis, addition to a &#960; bond, hydrogen abstraction, halogen abstraction, elimination, and coupling. These six patterns can be categorized into three typical steps, initiation, propagation, and termination, of a radical mechanism. Typically, these radical reactions are governed by two key factors: steric hindrance and electronic stabilization.

Radicals, the highly reactive species, gain stability by undergoing three different reactions. The first reaction involves a radical-radical coupling, in ...

Radical Reactivity: Steric Effects

The presence of electron-donating, electron-withdrawing, or conjugating groups adjacent to a radical center, imparts electronic stabilization to the radicals. Examples of such electronically-stabilized radicals are triphenylmethyl, tetramethylpiperidine&#8208;N&#8208;oxide, and 2,2&#8208;diphenyl&#8208;1&#8208;picrylhydrazyl. These radicals are remarkably stable and are known as persistent radicals. Some of the persistent radicals can even be isolated and purified.
Along with electronic factors, steric factors also account for the stability of these persistent radicals. For instance, the exceptionally high stability of triphenylmethyl radical is due to the presence of three surrounding phenyl rings that are twisted out of the plane by 30&#176; in a propeller conformation. These twisted phenyl rings sterically shield the central carbon, which bears most of the radical character. As a result, the radical becomes highly stable and unavailable for molecules to react. Therefore, steric hindrance imparts stability to the radicals making them less reactive.

The presence of electron-donating, electron-withdrawing, or conjugating groups adjacent to a radical center, imparts electronic stabilization to the ...

Radical Reactivity: Electrophilic Radicals

Radicals adjacent to electron&#8208;withdrawing groups are called electrophilic radicals. These radicals readily react with nucleophilic alkenes. For example, the malonate radical, in which the radical center is flanked by two electron&#8208;withdrawing groups, reacts readily with butyl vinyl ether, which consists of an electron&#8208;donating oxygen substituent. The reaction between electrophilic malonate radical and nucleophilic vinyl ether is favored because the radical has a low&#8208;energy SOMO, which interacts best with the high&#8208;energy HOMO of the alkene.
The non&#8208;carbon&#8208;centered electrophilic radicals also exhibit similar SOMO&#8211;HOMO interactions. For instance, the non&#8208;carbon&#8208;centered chlorine radical abstracts a hydrogen atom from the terminal methyl group of propionic acid. This is because chlorine radical has a low&#8208;energy SOMO, and the C&#8211;H bond of the terminal methyl group has a high&#8208;energy HOMO. Therefore, interactions between low&#8208;energy SOMO of the chlorine radical and high&#8208;energy HOMO of the terminal C&#8211;H bond favor chlorine attack on the terminal carbon of propionic acid.

Radicals adjacent to electron&#8208;withdrawing groups are called electrophilic radicals. These radicals readily react with nucleophilic alkenes. For ...

Radical Reactivity: Nucleophilic Radicals

Radicals adjacent to electron-donating groups are called nucleophilic radicals. These radicals readily react with electrophilic alkenes. The SOMO&#8211;LUMO interactions are the driving force for the reaction, where the high-energy SOMO of the electron-rich, nucleophilic radicals interacts with the low-energy LUMO of the electron-deficient, electrophilic alkenes. Such SOMO&#8211;LUMO interactions are the basis of reactive radical traps, affecting the selectivity in radical reactions. For instance, consider the reaction between an alkyl halide and an alkene in the presence of tin hydride and AIBN. Initially, a nucleophilic alkyl radical is formed, which reacts with an electrophilic alkene, generating a new radical. This new radical can either react with the alkene or the tin hydride. Since the radical and the alkene are electrophilic, their interactions are not favored. Consequently, the radical reacts with tin hydride, abstracting hydrogen from it and forming the addition product.