Radical clock

In chemistry, a radical clock is a compound that assists in the indirect methodology to determine the kinetics of radical-molecule reactions. This involves a unimolecular radical reaction with a known rate constant competing against a bimolecular radical reaction with an unknown rate constant to form unrearranged and rearranged products. With the ratio of the products, reactant concentrations and known rate constant for the clock reaction, the unknown rate constant can be determined.

Introduction

Many reactions in organic mechanisms involve intermediates that have a key role in the reaction. Understanding these intermediates and their chemical kinetics may be helpful in the predicting the outcome of the reaction prior to performing the reaction itself. [1] Among the different types of reactive intermediates that are involved in synthetic organic mechanisms such as carbocations, carbanions, and carbenes, interests in radical intermediates reactions have increased. A great deal of attention was drawn to them due to the discovery of their linkage in enzymatic pathways and in sonodynamic therapy in the treatment of cancer. [2]

Many techniques have been developed to measure the rates of radical reactions. The two possible ways to measure the reaction rates are direct and indirect approaches. Direct approaches such as the rotating sector method (only applicable to radical-chain processes) have restrictions that hinder the expansion of this method to a variety of important radical reactions. [3] , [4] This method along with other techniques including flash photolysis, pulse radiolysis, requires a sufficient amount of time and expensive equipments. With an indirect approach, one can still obtain relative or absolute rate constants in which no special instruments are required. [5] This is where radical clocks come into the scene.

Radical clock reactions involve a competition between a unimolecular radical reaction with a known rate constant and a bimolecular radical reaction with an unknown rate constant to produce unrearranged and rearranged products. The yield of the products can be determined by gas chromatography (GC) or nuclear magnetic resonance (NMR). From the concentration of the reactant, the known rate constant, and the ratio of the products, the unknown rate constant can be indirectly established. The driving force behind radical clock reactions is their ability to rearrange. [1]

Uses and examples

Radical clocks are used in reduction of alkyl halides with sodium napthalenide, reaction of enones, the Wittig rearrangement, reductive elimination reactions of dialkylmercury compounds, dioxirane dihydroxylations, and electrophilic fluorinations. [4] Some common radical clocks (shown below) are radical cyclizations, ring openings, and 1,2-migrations. [1,4]

5-hexenyl radical rearranges to produce a five-membered ring because this entropically and enthalpically more favored than a cyclohexl ring formation. [1,4]

Cyclopropylmethyl undergoes a very rapid ring opening rearrangement which would relieve the ring strain and is enthalpically favorable. [1,4]

Mechanism

The figure below shows the general mechanism of clock reactions. The unimolecular rearrangement of an unrearranged radical, U •, proceeds to form R • (clock reaction) with a known rate constant (kr) which both then compete with a trapping agent, AB, to form the unrearranged and rearranged products. [6]

The unrearranged and rearranged products can be determined by Gas Chromatography (GC) or Nuclear Magnetic Resonance (NMR) analysis. If an equilibrium exists between U • and R •, the rearranged products are dominant. [4] Because unimolecular reaction is first order and the bimolecular reaction reaction is second order (both irreversible), the unknown rate constant (kR) can be determined by kR = kr [UA] / ( [AB] [RA] ). [7]

Calibration

In order to determine absolute rate constants for radical reactions, unimolecular clock reactions need to be calibrated for each group of radicals such as primary alkyls over a range of time. [4] Through the usage of electron pairing resonance (EPR) spectroscopy, the absolute rate constants for unimolecular reactions can be measured with a variety of temperatures. [4,5] The Arrhenius equation can then be applied to calculate the rate constant for a specific temperature at which the radical clock reactions are conducted.

Adjusting radical clock rate

The rates of radical clocks can be adjusted to increase or decrease by what types of substituents are attached to the radical clock. In the figure below, the rates of the radical clocks are shown with a variety of substituents attached to the clock. [1]

Being able to control the pace of the radical clock is great, but there is a limitation on how far the rate can increase or decrease. The general range of rate change either going fast or slowing down can only change by a factor of ten. [1]

Solvent effects

In radical clock reactions, there is an assumption that the rearrangement rate of the radical clock is the same as the conditions of calibrated reactions. [8] In a study conducted by Yao Fu et al. in 2003, solvent effects on the rates of radical clock reactions were observed. The kinetics of cyclobutylmethyl and 1-hexen-6-yl radicals (shown below) was studied in a variety of solvents consisting of cyclohexane, benzene, tetrahydrofuran, methylene chloride, acetone, methanol, acetonitrile, dimethylsulfoxide, nitromethane, and water.

Results indicated that there was an insignificant effect on the rearrangement activation free energy of the cyclobutylmethyl and 1-hexen-6-yl radicals (< 1 kcal/mol). This led to the conclusion that using calibrated clocks in unclear mediums are valid since there is no significant impact on the rate of the radical clock. [8]

References

1. Johnson, C, C.; Lippard, S.J,; Liu, K.E,; Newcomb, M. "J. Am. Chem. Soc." 1993, 115, 939-947

2. Misik, V.; Riesz, P. "Annals of New York Academy of Sciences." 2000, 899, 335-348. 3. Roschek, B. Jr.; Tallman, K. A.; Rector, C.L.; Gillmore, J.G.; Pratt, D.A.; Punta, C.; Porter, N.A. "J. Org. Chem." 2006, 71, 3527-3532.

4. Griller, D.; Ingold, K.U. "Acc. Chem. Res." 1980, 13, 317-323

5. Moss, R.A.; Platz, M.; Jones, M. Reactive Intermediate Chemistry. Wiley, John & Sons, Incorporated, 2004. 127 – 128.

6. Chatgilialoglu, Chryssostomos. Organosilanes in Radical Chemistry.Wiley, John & Sons, Incorporated, 2004. 32 - 33.

7. Newcomb, M. "Tetrahedron." 1993, 49(6), 1151-1176. 8. Yao, Fu; Rui-Qiong, Li; Lei, Lui. "Res. Chem. Intermed." 2004, 30(3), 279-286.

See also

*Radical (chemistry)

External links

* [http://www.scs.uiuc.edu/chem/research/organic/seminar_extracts/2005_2006/06_Wang.pdf RADICAL CLOCKS: MOLECULAR STOPWATCHES FOR TIMING RADICAL REACTIONS]

* [http://euch6f.chem.emory.edu/radical.html Radical Clock Reactions]