Organic Mechanisms: Radicals Chapter 2 1) Introduction 2) Formation of Radicals (a) Homolytic Bond Cleavage (b) Hydrogen Abstraction from Organic Molecules (c) Organic Radicals Derived from Functional Groups 3) Radical Chain Processes 4) Radical Inhibitors 5) Determining the Thermodynamic Feasibility of Radical Reactions 6) Addition of Radicals (a) Intermolecular (b) Intramolecular – cyclization reactions 7) Fragmentation Reactions 8) Rearrangement of Radicals 9) The SRN1 Reaction 10) Birch Reaction 11) Radical Mechanisms for Anion Rearrangements 1 1) Introduction Radicals are species that contain one or more unpaired electrons. Radical reactions involve movements of single electrons, which means single barb, fish hook arrows. Radical reactions are very important industrially, and in nature/biological systems. Single, radical electrons are usually represented by a dot, • Radical mechanisms are written in two different ways: (i) Each individual step is written without the use of arrows, depicting the order of events, and the single electron movement is implied. (ii) Half headed arrows are used to illustrate the electron movement. You need to be fluent in both types. 2 Most studies show typical radicals to be pyramidal, but with very small barriers to inversion. Radical reactions therefore tend to result in loss of stereochemistry. Radicals are normally reactive intermediates, although we shall encounter some notable exceptions. 2) Formation of Radicals Radicals are normally formed via homolytic cleavage of a single covalent bond. This can be induced thermally, photochemically or chemically. Compounds that generate radicals are called free radical initiators. 3 A) Homolytic Bond Cleavage Radicals can be generated either thermally or photochemically from chlorine and bromine. The bromine radical is less reactive, and often brominations require heat to proceed. Peroxides and azo compounds also generate radicals when heated. The weak O-O bond cleaves easily and the formation of N2 is also a significant driving force (see next slide). 4 AIBN is one of the most famous commercial free radical initiators. 5 B) Hydrogen Abstraction from Organic Molecules The C-H bond is quite strong, and so it is rare to observe direct C-H homolytic cleavage. However, it is common to have other radicals react and remove a hydrogen atom from a C-H bond, thus generating a carbon radical ( = hydrogen abstraction). E.g. •F + CH4 → HF + •CH3 The •F is very reactive, and will react (exothermically!) with almost any organic compound. 6 Rates of H Abstraction Most radicals are electron deficient (electrophilic) and therefore their stability trends resemble those of cations. An approximate radical stability order is: Ph• < CH2=CH• < RO• < RCH2• < R2CH• < R3C• < PhCH2• Bear in mind that this is also reflected in the ease of hydrogen abstraction from parent compounds to generate these radicals. i.e. PhCH3 will undergo hydrogen abstraction very rapidly. Also it is quite difficult to abstract a hydrogen from ROH. 7 C) Organic Radicals from Functional Groups Organic radicals are commonly generated from C-Hal C-Se C-Hg bonds. Halogen abstraction is a good way to generate carbon based radicals. A typical process involves: a free radical initiator tributyltin hydride and an organic halide. The sequence is: initiator generates radicals (e.g. slide 5) radicals abstract H from Bu3Sn-H Tin radical abstracts halogen 8 A similar sequence can be used to generate radicals from organoselenium compounds. Alkyl mercury salts can generate radicals when they are exposed to sodium borohydride. Recall from undergraduate organic alkene reactions: 9 3) Radical Chain Processes Most useful radical reactions are chain processes. A radical chain process is one where many moles of product are generated from every mole of radicals formed. All radical chain processes include i. Initiation (A process where radicals are generated from some starting reagent). ii. Propagation (The radical enters a series of events that result in product formation AND a new radical which starts the propagation steps over again). iii. Termination (any steps that remove radicals from the propagation steps, thus breaking the chain process). 10 Initiation was discussed previously as generation of radicals. Propagation requires many product molecules to be formed from a single radical species formed in the Initiation step. This can only occur if the Propagation steps are exothermic. Common termination steps include radical – radical coupling, disproportionation and abstraction. Abstraction by a chain transfer agent removes a radical from the propagation steps, and a new radical is formed, often this leads to termination. Remember: Propagation steps of a chain process must add up to the overall equation for the reaction. The overall equation cannot contain any radical species, meaning the radical generated in the last propagation step must be the same as the radical involved in the first propagation step. 11 Even though it is very tempting to write product formation resulting from two radicals reacting together, this is rarely correct. Radicals are reactive intermediates and thus are generated in only small concentrations and for very short lifetimes. Statistically it is very unlikely that two radicals will collide and form product. E.g. Radical Chain halogenation by tButylHypochlorite Overall the process is: 12 We can break this into the various steps: Initiation step The fragile O-Cl bond can be cleaved homolytically. The tBuO• radical is the chain carrying radical, meaning this is the radical used up in the 1st propagation step, and regenerated in the last propagation step. 13 Propagation steps Here we see why one tBuO• can initiate multiple propagation cycles. Addition of steps (1) and (2) equate to the overall reaction. Incorrect propagation steps are: these do not lead to product formation. 14 Termination steps i. Disproportionation Here a radical abstracts a hydrogen atom from another radical. It leads to a pair of saturated and unsaturated products 15 Termination steps ii. Radical Coupling There are several radical coupling reactions that can occur. 16 4) Radical Inhibitors Radical reactions can be slowed or stopped by the presence of compounds called Radical Inhibitors. Often this is good experimental evidence that certain reactions operate via a radical mechanism. Common radical inhibitors include: Basically they function as radical inhibitors since they react with radicals to form new very stable (and unreactive) radical species. The extra stability is usually a function of resonance and / or steric protection. 17 E.g. 18 E.g. 19 5) Determining the Thermodynamic Feasibility of Radical reactions Bond dissociation energies (BDE) can be used to determine whether certain radical reactions are likely or not. 20 Guidelines Radical processes only give reasonable synthetic yields if every propagation step is exothermic. The number of propagation steps per initiation is called the chain length. Longer chains come from less stable (more reactive) radicals e.g. tButylHypochlorite chlorination C-H is broken +91 kcal/mol O-H is formed -103 kcal/mol then O-Cl is broken +44 kcal/mol C-Cl is formed -79 kcal/mol So overall -12 + (-35) = -47 kcal/mol which implies a highly favorable process with a long radical chain length. 21 6) Addition of Radicals Radical additions are very common and range from simple additions to π bonds to more involved cyclization processes. A) Intermolecular Radical Addition E.g. Addition of trifluoromethyl iodide. The initiation step involves homolytic cleavage of the weak C-I bond. The •CF3 radical adds to the double bond (leading to the more stable radical intermediate). This radical abstracts an iodide atom from CF3I to give the product and the chain- propagating radical. 22 23 Addition of a Radical by Reduction of a C-Hg bond Despite their toxicity, organomercury compounds are a common way to generate carbon based radicals which can undergo addition to multiple bonds. 24 B) Intramolecular radical Additions (Cyclization reactions) When a radical is generated and there is an unsaturated region in the same molecule, there is the possibility for intramolecular radical addition, which will lead to a cyclic product. This is a very common way to prepare rings. Synthetic strategies have to be planned using a knowledge of Baldwin’s Rules. These cover the formation of 3 to 7 membered rings by a variety of reaction types, and include kinetic and thermodynamic considerations. As far as radical cyclizations are concerned, exo and endo cyclizations are possible. 25 For radical cyclizations, the most important guidelines are: 1) For unsubstituted –alkenyl radicals containing up to 8 carbons, the preferred mode of cyclization is EXO. ( - omega- means the alkene is at the terminus distant to the radical. The reaction is kinetically controlled (the faster formed product = major product). 2) When the alkene is substituted the non-terminal position, reaction to form the exo product becomes sterically hindered, and the fraction of ENDO product increases. Exo and Endo Cyclizations 26 E.g. Intramolecular Cyclization of a Vinyl Radical The overall reaction is: The vinyl radical is formed via the initiator / Sn radical / carbon radical process described earlier. Cyclization occurs to yield the preferred EXO adduct (as the major product). The carbon radical abstracts a Hydrogen atom from tributyl tin to yield the product and continue the chain. 27 28 29 30 7) Fragmentation Processes Many radical reactions involve