Free-Radical Reactions

Free Radicals

A free radical is a species containing one or more

unpaired electrons. Free radicals are electron-
deficient species, but they are usually uncharged,
so their chemistry is very different from the
chemistry of even-electron electron-deficient
species such as carbocations and carbenes.

The word radical comes from the Latin word for root (as in radish). The term radical
was originally used to denote a fragment of a molecule that remained unchanged
throughout a series of reactions. The term free radical was later coined to refer to a
fragment of a molecule that wasnt bonded to anything. Today, radical and free radical
are used interchangeably, although radical still retains its original meaning in certain
contexts (e.g., in the use of R in organic structures).
Stability

Most of the chemistry that is discussed in this chapter involves alkyl radicals
(CR3). The alkyl radical is a seven-electron, electron-deficient species. The
geometry of the alkyl radical is considered to be a shallow pyramid, somewhere
between sp2 and sp3 hybridization, and the energy required to invert the
pyramid is very small. In practice, one can usually think of alkyl radicals as if they
were sp2-hybridized.

Both alkyl radicals and carbocations are electron-deficient species, and the
structural features that stabilize carbocations also stabilize radicals. Alkyl radicals
are stabilized by adjacent lone-pair-bearing heteroatoms and bonds, just
as carbocations are, and the order of stability of alkyl radicals is 3 2 1.
However, there are two major differences between the energy trends in carbocations
and alkyl radicals.
A C atom surrounded by seven electrons is not as electron-deficient as a C atom
surrounded by six electrons, so alkyl radicals are generally not as high in energy as the
corresponding carbocations. Thus, the very unstable aryl and 1 alkyl carbocations are
almost never seen, whereas aryl and 1 alkyl radicals are reasonably common.
The amount of extra stabilization that adjacent lone pairs, bonds, and bonds provide to
radicals is not as great as that which they provide to carbocations. The reason is that the
interaction of a filled AO or MO with an empty AO (as in carbocations) puts two
electrons in an MO of reduced energy, whereas the interaction of a filled AO or MO with
a half-filled AO (free radicals) puts two electrons in an MO of reduced energy and one
electron in an MO of increased energy.
Free radicals are stabilized both by electron-rich bonds, like CC bonds, and by electron-
poor bonds, like CO bonds. The additional resonance provided by the carbonyl group
offsets the destabilization of localizing a radical on O and making O electron-deficient.
However, an electronrich bond is more stabilizing than one that is electron-poor. When a
radical is substituted by both an electron-donating and an electron-withdrawing group, the
total stabilization is greater than the sum of the parts in a phenomenon called the
captodative effect.

The nitroxyls (a.k.a. nitroxides) are remarkably stable free radicals. Nitroxyls have two major
resonance structures, one N-centered and one O centered; the lone electron may also be
considered to be in the * orbital of an NO bond. TEMPO (2,2,6,6- tetramethylpiperidin-1-
oxyl), a commercially available nitroxyl, is further stabilized by steric shielding.
Free radicals can also be stabilized kinetically by steric shielding of the radical centers. Such
free radicals are called persistent. Examples of persistent free radicals include
perchlorotrityl, galvinoxyl, and the radical derived from BHT (butylated hydroxytoluene, 2,6-
di-tert-butyl-4-methylphenol), an antioxidant that is used as a food preservative.
Generation from Closed-Shell Species
Most free radicals are not kinetically stablethey tend to react with one another to give
electron-sufficient speciesso free radicals that are to be used in reactions must usually be
generated from closed-shell species in situ. Free radicals can be generated from closed-shell
species in four ways: sigma-bond homolysis, photochemical excitation of a Pi bond, one-
electron reduction or oxidation, and cycloaromatization.

Sigma-bond homolysis is a very common way to generate free radicals. The bond is
usually a heteroatomheteroatom bond such as NO or BrBr, but even bonds such
as CC or CN that are normally very strong can homolyze if a very stable fragment is
formed or if the bond is very strained. Light is sometimes used to induce -bond
homolysis by promoting one of the electrons in the sigma orbital to the sigma*
orbital, but if the bond is sufficiently weak and the product radicals are sufficiently
low in energy, heat may suffice to break it.
Benzoyl peroxide and AIBN are two of the compounds most widely used to generate free
radicals in a reaction mixture. The OO bond in benzoyl peroxide and the CN bonds in
AIBN (Azobisisobutyronitrile ) homolyze under thermal or photochemical conditions.
When light of the appropriate wavelength is allowed to shine on a compound containing a
bond, an electron from the orbital is promoted to the * orbital. The product can be
considered to be a 1,2-diradical, and it undergoes reactions typical of free radicals. The C
O, CS, and CC bonds can all be photoexcited in this manner. The weaker the bond,
the easier it is to photoexcite.

In photoexcited alkenes, there is no bond between the two radical centers, so free
rotation about the CC bond can occur. Alkenes can be isomerized from the cis to the
trans form photochemically. The reaction does not usually proceed in the reverse
direction, because the photoexcited cis alkene and the photoexcited trans alkene are in
equilibrium, and the equilibrium favors the less sterically encumbered trans isomer.
A compound with an electron in a high-energy orbital may transfer the electron to a
compound that has a lower energy orbital. Most often, the electron donor
is a metal or reduced metal salt such as Li, Na, or SmI2, but the donor may also be
a lone-pair-bearing compound such as an amine or phosphine, especially if it is
photoexcited. (Photoexcitation promotes an electron from a nonbonding orbital into a
higher energy orbital, whence it is more likely to participate in electron transfer.)
 Typical Reactions
Free radicals undergo eight typical reactions:

Addition to a bond
Fragmentation
Atom abstraction (reaction with a bond)
Radicalradical combination
Disproportionation
Electron transfer
Addition of a nucleophile
Loss of a leaving group.

The first three are by far the most important. Atom abstraction and addition reactions involve
the reaction of a free radical with a closed-shell species, and fragmentation is the conversion
of a free radical to a new free radical and a closed-shell species. Addition and fragmentation
reactions are the microscopic reverse of one another.

In general, the propagation part of a chain mechanism consists exclusively of addition,

fragmentation, and atom abstraction steps.* Radicalradical combination, disproportionation
reactions, and electron transfers are found in the termination part of chain mechanisms and
in nonchain mechanisms.
A free radical can add to a bond of a closed-shell species to give a new radical. The
radical (X) adds to a YZ bond to give XYZ, in which the new XY bond is made up
of one electron from the radical and one electron from the former bond. The addition
of free radicals to bonds is mechanistically similar to the addition of bonds to
carbocations.

A free radical does not always add to a polarized bond in the same way that a nucleophile
would add. For example, the Bu3Sn radical adds to the S atom of CS bonds, not to the C
atom.
Free radicals can also add to stable carbenes such as CO and isocyanides
(RNC). The carbene C becomes a radical center in the product.

The addition of free radicals to nitrones and nitroso compounds gives very stable
nitroxyls.
 Fragmentation is the microscopic reverse of addition to a bond. A bond that is
adjacent () to a radical center homolyzes, and one of the electrons of that bond and
the former unshared electron together form a new bond at the former radical center.
The fragmentation of a radical is mechanistically similar to the fragmentation of a
carbocation.

CO can be lost from an acyl radical by a fragmentation reaction. In this case, the bond that
breaks is directly attached () to the radical center.

The combination of Et3B and O2 is widely used to initiate radical reactions. The mechanism
involves two unusual radical reactions
In an atom abstraction reaction, a radical X attacks a YZ bond to give a new closed-
shell species XY and a new radical Z. One of the electrons in the old bond goes to
form a bond to X, and the other one ends up on Z. The transferred atom, Y, is usually H
or halogen, but not always.

The tributyltin radical (Bu3Sn) is often used to abstract heavy atoms X from CX bonds.
The atom X is usually Br or I, but it may be Se or even S. The SnBr bond is strong
enough that Bu3Sn can abstract Br from aryl bromides to generate very high energy aryl
radicals. Bu3Sn can itself be generated by H abstraction from Bu3SnH.
The solvents of choice for free-radical reactions (CH3OH, H2O, benzene) share the feature
that their XH bonds have very large BDEs, so that the solvents are unlikely to participate in
the reaction. Free-radical reactions executed in ether, THF, toluene, CH2Cl2, and CHCl3 are
often complicated by atom abstraction from the solvent. Acetone is sometimes used as a
solvent for free-radical reac tions, because it can be photoexcited to act as an initiator, but it
can also complicate free-radical reactions by giving up H to another radical to afford the
relatively stable 2-oxopropyl (acetonyl) radical.
Two radicals can react with one another in one of two ways: radicalradical combination or
disproportionation. Radicalradical combination is the opposite of bond homolysis. Each of
the two radical centers contributes its lone electron to form a new bond. Radicalradical
combination is also known as homogenesis (opposite of homolysis). Radicalradical
combination reactions are usually very fast and favorable. Most free radicals are very
unstable because they undergo very rapid radicalradical combination.

In disproportionation, one radical X abstracts H atom from another radical HYZ to give the
two electron-sufficient species XH and YZ. The abstracted atom is almost always H, and it
is always to the radical center Z. The two radicals may be the same or different.
Disproportionation, like radicalradical combination, is a very fast and favorable process.
In chain mechanisms, radicalradical combination and disproportionation reactions
are seen only in the termination part of the mechanism. The one exception is the
combination of O2 with a free radical, one of the propagation steps in the autoxidation
chain mechanism.

Nonchain mechanisms, though, often involve radicalradical combinations and

disproportionations. Nitroxyls can be used to trap alkyl radicals that may be present in a
reaction medium by a radicalradical combination reaction, giving an electron-sufficient
species that is more easily studied than the free radical. The photochemical reactions of
carbonyl compounds often involve radicalradical combination and disproportionation
steps.
A radical can undergo one-electron transfer (oxidation or reduction) in the presence of
an oxidizing or reducing agent to give an even-electron species. In nonchain
mechanisms, a radical that undergoes electron transfer is itself usually generated by an
electron transfer. A chain mechanism can be initiated or terminated by electron transfer.
The initiation step and one of the propagation steps in the SRN1 mechanism are electron
transfers.
A radical anion can lose an anionic leaving group to give a neutral free radical, and in the
reverse direction, a neutral free radical can combine with an anionic nucleophile to give a
new radical anion. A radical cation can also combine with a nucleophile. Such steps occur
in the SRN1 mechanism, in dissolving metal reductions, and in oxidative deprotections.
These two-electron reactions have obvious counterparts in carbocation chemistry.
Analogies between free radicals and carbocations have been drawn several times, but one of
the typical reactions of carbocations, the concerted 1,2-shift, does not occur in free radicals. A
concerted 1,2-radical shift is allowed only when one of the components can react
antarafacially. The 1,2-hydrogen atom shift is geometrically impossible, and the geometric
requirements of the 1,2-alkyl radical shift are so stringent that it is not observed.

Unsaturated groups, however, can shift by a two-step additionfragmentation mechanism

via a discrete cyclopropane radical intermediate. Phenyl groups are especially good at
undergoing radical 1,2-shifts; 1,2-shifts of acyl, alkenyl, and, to a lesser extent, alkynyl and
cyano groups are also seen.
Draw a mechanism for the following radical rearrangement.
Free-Radical Reactions
Probably the best-known example of a free-radical reaction is the
Substitution halogenation of alkanes with Br2 or NBS. This chain reaction is initiated by
Reactions homolytic cleavage of Br2 induced by light. The propagation part consists of
two atom abstraction reactions.

The termination parts of free-radical chain

mechanisms are almost always the same: two
free radicals from the propagation part react
with each other either in a radicalradical
combination or disproportionation reaction.
The termination parts of chain mechanisms will
not routinely be drawn in this text.
Free-radical dehalogenations are common, too. In these reactions, a CX bond is replaced
with a CH bond. The reducing agent is most commonly Bu3SnH, although (Me3Si)3SiH or a
combination of a catalytic amount of Bu3SnCl and a stoichiometric amount of NaBH4 may be
used instead as environmentally more friendly reagents.

A catalytic amount of AIBN

or (BzO)2 is commonly used
as a free-radical initiator.
Alcohols are deoxygenated in the BartonMcCombie reaction. The alcohol is first converted
into a xanthate (ROCS2CH3) or another thiocarbonyl compound, and then the entire
functional group is removed by Bu3SnH and replaced with H. In the propagation part of the
mechanism, Bu3Sn adds to S of the SC bond, and the resulting radical fragments to give
the alkyl radical and a carbonyl compound.
The substitution of H with OOH in alkanes is called autoxidation. (Autoxidation
is a misnomer because the substrate is not oxidizing itself; O2 is doing the oxidizing!)
Autoxidation proceeds by a free-radical chain mechanism. Note that the mechanism for
oxidation includes a very rare radicalradical combination step in the propagation part. The
radicalradical combination step doesnt terminate the chain in this particular reaction
because O2 is a 1,2-diradical.
In the HofmannLoefflerFreytag reaction, an N-chloroammonium ion is converted
by a free-radical substitution reaction into a 4-chloroalkylammonium ion, which then
undergoes intramolecular SN2 substitution to give a pyrrolidine. In the free-radical
substitution mechanism, the abstraction step occurs in an intramolecular fashion.
 Addition and Fragmentation Reactions
CarbonHeteroatom Bond-Forming Reactions
The anti-Markovnikov addition of HBr to alkenes was probably the first freeradical
addition reaction to be discovered. The discovery was inadvertent; around the turn of the
twentieth century, scientists studying the regiochemistry of addition of HBr to alkenes found
that the proportion of Markovnikov to anti-Markovnikov addition products varied
inexplicably from run to run.

Eventually, it was discovered that impurities such as O2 and peroxides greatly

increased the amount of anti-Markovnikov addition product. The results were
later explained by a free-radical addition mechanism.
In contrast to HBr, the acids HCl and HI do not undergo free-radical addition to
alkenes, even in the presence of peroxides or O2. Abstraction of H from HCl is too
endothermic, and addition of I to an alkene is too endothermic. However, thiols
(RSH) add to alkenes by a free-radical mechanism exactly analogous to the
addition of HBr. The initiator is usually AIBN or (BzO)2. The alkene may be
electron-rich or electron-poor. Note that the conjugate addition of thiols to
electron-poor alkenes can occur either by a free-radical mechanism or by a polar,
nucleophilic mechanism.

Draw a free-radical mechanism for the following addition reaction.

 CarbonCarbon Bond-Forming and Bond-Cleaving Reactions

The most important free-radical chain reaction conducted in industry is the freeradical
polymerization of ethylene to give polyethylene. Industrial processes usually use (t-BuO)2 as
the initiator. The t-BuO radical adds to ethylene to give the beginning of a polymer chain.
In the laboratory, free-radical addition reactions often use Bu3Sn radicals as key chain
carriers. The initiation part of such reactions usually has a radical initiator (often derived
from AIBN) abstract H from HSnBu3 to give Bu3Sn. The propagation part of the mechanism
usually involves (1) abstraction of Br, I, or SeR by Bu3Sn to give an alkyl radical, (2)
addition of an alkyl radical to a bond, and (3) abstraction of H from HSnBu3 by an alkyl
radical to give the product and regenerate SnBu3.
Free-radical cyclization reactions (i.e., the intramolecular addition of an alkyl radical to a C
C bond) have emerged as one of the most interesting and widespread applications of free-
radical chemistry to organic synthesis. Free-radical cyclizations are useful because they are so
fast.

The mechanisms of intramolecular free-

radical cyclization reactions are no different
from their intermolecular counterparts.

Azobisisobutyronitrile
(abbreviated AIBN)
A free radical can add to CO or an isocyanide (RNC) in the course of a freeradical cyclization reaction, too, to
give an acyl radical (RC=O) or an iminyl radical (RC=NR), either of which can undergo further reactions. In
the following example, an alkyl radical adds to the terminal C of t-BuNC to give an iminyl radical. The iminyl
radical then fragments to give t-Bu and an alkyl cyanide :N=CR. In a different substrate, the iminyl radical
may undergo an addition or
an abstraction reaction instead.

Catalytic amount of Bu3SnCl and a stoichiometric amount

of NaBH3CN are added to the reaction mixture. The small
amount of Bu3SnCl that is added to the reaction mixture is
reduced to Bu3SnH with a small amount of NaBH3CN.
After each catalytic cycle, the Bu3SnH is converted to
Bu3SnI, and the stoichiometric NaBH3CN reduces it back
to Bu3SnH.
Some free-radical cyclization reactions require only a catalytic amount of Bu3SnH
or Bu3SnSnBu3. Such a reaction, instead of replacing a CX bond with a CH bond,
simply relocates the X atom. These atom transfer cyclizations differ from more
conventional free-radical cyclizations in that the last step in the propagation involves
abstraction of X from a CX bond not by SnBu3 but by the cyclized starting material.
Compounds with weak CH bonds can add to alkenes by a free-radical chain Mechanism. In
the initiation part of the mechanism, an initiator radical abstracts H from the weak CH
bond to give an alkyl radical. In the propagation part of the mechanism, the alkyl radical
adds across the C=C bond, and then the new radical abstracts H from the weak CH bond
to give the product and regenerate the first alkyl radical.
The addition of a free radical to a Pi bond is sometimes followed directly by fragmentation of
the new free radical. For example, alkyl halides and selenides react with (allyl)SnBu3 in a free-
radical allylation reaction to give a product in which the halogen or selenium is replaced with
an allyl group. In the propagation part of the mechanism, Bu3Sn abstracts X from the starting
material to generate an alkyl radical, which adds to the terminal C of the allyl group of
the stannane. Fragmentation then occurs to give the product and to regenerate
SnBu3.