an intramolecular Diels-Alder cycloaddition is a DielsAlder

reaction in which the diene and a dienophile are both part of the
same molecule. The reaction leads to the formation of one new
double bond and two new sigma bonds, but this time the ultimate
product is a fused or bridged cyclic ring.

Reaction mechanism
The reaction occurs via a single transition state, which has a
smaller volume than either the starting materials or the product. It
is an associative type of reaction, and it is sped up by very high
pressures. DielsAlder is an example of a pericyclic reaction.
Some free-radical versions of this reaction have been observed,
though these are not DielsAlder reactions since the stereochemistry
at the carbons is scrambled. These are step-wise reactions of the
free radicals which form the new bonds in at least two steps. An
example of this type of reaction is the reaction of
selenobenzophenone with a 1,3-diene (See: thioketones).
All Diels-Alder reactions have four common features:[8]

Diels-Alder reactions are thermal reaction; the reaction is

initiated by heat.

Diels-Alder reaction form new six-membered rings.

Overall, three bonds break and two new C-C bonds and one
new C-C bond are formed.

The overall reaction is concerted: All bonds break and form in

a single step.

[edit] The diene

The diene component in the DielsAlder reaction can be open-chain or
cyclic and it can have many different kinds of substituents.[9] There
is only one limitation: it must be able to exist in the s-cis
conformation. Butadiene[10] itself normally prefers the s-trans
conformation, with the two double bonds as far away from each other
as possible. If there are substituents larger than hydrogen then
steric hindrance may influence the relative stabilities of the
conformations. For simple cases, the barrier to rotation about the
central bond is small and rotation to the less favourable but
reactive s-cis conformation is rapid. Cyclic dienes that are
permanently in the s-cis conformation are exceptionally reactive in
DielsAlder reactions (cyclopentadiene is a classic example), while
cyclic dienes that are permanently in the s-trans conformation and
cannot adopt the s-cis conformation will not undergo the DielsAlder
reaction at all. An especially reactive diene is Danishefskys
diene.

Dendralenes are a new class of experimental DA dienes.

Unstable dienes, such as o-quinodimethane, can be generated in situ.
Aromatic stabilization in the product of a DA reaction using such a
diene is, in some cases, the reason behind the very high reactivity
and lack of stability of such diene. The use of such unstable dienes
is advantageous, despite the trouble, in that the products will
contain newly formed aromatic six-membered rings.
Benzenoid compounds rarely undergo DA reactions and often require
very reactive dienophiles. One example of such rare reaction is the
Wagner-Jauregg reaction

[edit] The dienophile

In a typical DielsAlder reaction, the dienophile has an electronwithdrawing group conjugated to the alkene. Though common, this
feature is not exclusive of DielsAlder dienophiles. There must be
some extra conjugation, at least a phenyl group or chlorine atom. The
dienophile can be activated by a Lewis acid such as niobium
pentachloride.[11]

Cyclopentadiene does not react with cyclohexenone in ethyl acetate

unless the Lewis acid is present. The yield improves when reaction
temperature is lowered to 78C because polymerization side reactions
are prevented. Niobium pentachloride catalysis gives only the endo
conformer. The same reaction with aluminium chloride results in an
endo and exo mixture. Many of these Lewis acids are not good
catalysts for the reaction of ,-unsaturated carbonyls, this is
because the carbonyl oxygen binds too tightly to the metal centre. A
far better catalyst for such a system is a combination of silver
perchlorate and Lawesson's reagent in cold dichloromethane.
It is well known that it is possible to use heteroatom containing
dienophiles for DielsAlder reactions, for instance Lawesson's
reagent (and diferrocenyl dithiadiphosphetane disulfide) can react
with 1,3-dienes to form six membered ring adducts. Selenoketones and
thioketones are able to react in the same way with 1,3-dienes. Imines
are reactants in the Aza DielsAlder reaction and carbonyl groups
the reactant in Oxo DielsAlder reactions. These reactions are
collectively called hetero DielsAlder reactions.
Dienophiles can be chosen to contain a "masked functionality". The
dienophile undergoes DielsAlder reaction with a diene introducing
such a functionality onto the product molecule. A series of reactions
then follow to transform the functionality into a desirable group.

The end product cannot not be made in a single DA step because

equivalent dienophile is either unreactive or inaccessible. An
example of such approach is the use of -chloroacrylonitrile
(CH2=CClCN). When reacted with a diene, this dienophile will
introduce alpha-chloronitrile functionality onto the product
molecule. This is a "masked functionality" which can be then
hydrolyzed to form a ketone. -Chloroacrylonitrile dienophile is an
equivalent of ketene dienophile (CH2=C=O), which would produce same
product in one DA step. The problem is that ketene itself cannot be
used in DielsAlder reactions because it reacts with dienes in
unwanted manner (by [2+2] cycloaddition), and therefore "masked
functionality" approach has to be used.[12]
Other such functionalities are phosphonium substituents (yielding
exocyclic double bonds after Wittig reaction), various sulfoxide and
sulfonyl functionalities (both are acetylene equivalents), and nitro
groups (ketene equivalents).

[edit] Heterodienophiles
No major loss in reactivity of dienophile is seen when one, or both,
of the carbons are substituted for another variety of atom.[13]
Carbonyl groups, for example, can successfully react with dienes to
yield pyranoid rings. Generally, the endo transition state is favored
in this case.
Nitroso compounds (N=O) react to form oxazine-like compounds (cyclic
molecules with nitrogen and oxygen present in the six-membered ring).
[14]
Another group of dienophiles successfully used for DielsAlder
reactions is imines.[15] Such reactions are useful for preparation of
alkaloid and other polycyclic compounds.
Chlorosulfonyl isocyanate can be utilized as a dienophile to prepare
Vince Lactam.[16]

[edit] Stereoselectivity in DA reactions

DielsAlder reactions can lead to formation of a variety of

structural isomers and stereoisomers (enantiomers and diastereomers).
[17]
Identity of major products can usually be predicted, however.
In unsymmetrically substituted diene and dienophile, pseudo-ortho and
para orientations in products are usually favored over meta
orientation. A particular preference in location of substitutents in
the product can, in some cases, be explained in terms of frontier
orbital theory. Most commonly, diene bears an electron-releasing
group (ERG) and dienophile bears an electron-withdrawing group (EWG).
The strongest interaction takes place between HOMO of diene and LUMO
of dienophile. Carbons that have the highest coefficients in two
frontier orbitals will begin to bond; therefore these carbons will
direct the orientation of substituents and thus identity of major
product of a DA reaction.
Dealing with the actual frontier orbital coefficients can be avoided
since the preferred orientation in product can be described in terms
of partial positive and negative charges that exist in diene and
dienophile. Carbon with a partial negative charge will interact most
readily with carbon bearing a partial positive charge. Therefore
those two carbons will start coming together, thus dictating the
relative orientation of substituents. The existence of partial
positive/negative charge can always be determined by drawing
resonance contributors for diene and dienophile, taking their ERG and
EWG into consideration.
The initial potential of the reaction was utilized in the form of
insecticides, which ultimately led to the endo rule. Otto Diels and
Kurt Alders reaction allowed for the production of weapons against
agricultural pests to be fully realized in the 1930s.[18] Most of
these chemicals contained chlorine, of which two are called Dieldrin
and Aldrin after the appropriate individuals. These chemicals have
been long-since discontinued because of their toxicity to not only
invertebrates, but to higher orders of organisms as well.[19][20]
Fortunately, insecticide use may continue unabated with the recent
introduction of various safe treatments. Though insecticides like
Dieldrin and Aldrin cause a slew of cardiac and respiratory illnesses
(as well as reproductive failure), they served as an important step
towards understanding why the endo product was the major yield. The
study of the insecticides fused norcamphane rings became a highly
popular topic in the 1930s and 1940s. Oxidative degradation revealed
high specificity of the stereochemistry; after much research by Kurt
Alder and H.F. Rickert, it became clear that steric hindrance is not
as important in DielsAlder reactions as it is in other reactions.
This led to the secondary orbital explanation as well as a
satisfactory hypothesis that elucidated polymerization of certain
DielsAlder adducts.[18]

DA substituent effects

[edit] Cis principle

According to the cis principle or the AlderStein rules
formulated by Alder and Stein in 1937, the stereochemistry of
substituents in the starting material is retained in the product.
This means that if a cis-dienophile is reacted, both of the cissubstituents will end up on same side (face) of the product ring.
Trans-dienophile will yield a product where both of transsubstituents (that came originally from the dienophile) will be on
different sides of the product ring. The same principle applies to
dienes. Trans, trans or cis, cis 1,4-substituents will end up on same
side of the ring, whereas trans, cis 1,4-substituents will be
oriented towards different faces of the ring.
Besides the ortho/meta/para-forming orientations, the diene and
dienophile may arrange themselves in different ways to yield exo and
endo transition states which result in different products. To
determine which is the endo and which is the exo transition state,
the two molecules are oriented parallel to each other, such that
diene's single bond (one which connects two double bonds) is parallel
to dienophile's double or triple bond. It makes no difference whether
the dienophile is positioned above or below the diene. The single
substituent (or cis-substituents on the dienophile) is oriented to
point in the direction of diene's pi-system. This is the endo
transition state (pictured below). If these substituents are pointed
away from the diene, this would be the exo transition state.

[edit] Endo addition rule

Endo versus exo effect

Using the 'cis principle' it is understood that cis-substituents on
dienophile, for example, will end up on same side of the molecule. It
is not obvious where the substituents on both diene and dienophile
will end up relative to each other. To predict the cis or trans
orientation of substituents that are coming from different molecules
we have to examine possible transition states. The most stable
transition state will lead to the major product. Transition states
will also dictate the relative orientation of the diene's and
dienophile's substituents on the product ring. In some cases another
rule can be applied: the endo addition rule. According to this
rule, the most stable transition state results when there is a
'maximum accumulation of double bonds'. This rule is not always
followed. It most often applies when dealing with cyclic dienes and
dienophiles. For example, the DA reaction of cyclopentadiene and
maleic anhydride yields over 95% of the endo product. It is important
to note that labels "exo" and "endo" relate to the orientation of
substituents in the transition state and not to a specific
orientation of substituents in the product molecule. In each
individual case, the transition state has to be examined to see the
most favored relative orientation of substituents. It is not true for
the endo transition state that the substituents on dienophile and
1,4-substituents on diene will always point towards the same side of
the newly formed ring. "Endo" and "exo" define specific transition
states, not orientation of substituents. In the picture below, it
just happens that the endo transition state will yield substituents
on same side of the ring. This is not always so. In the case of
maleic anhydride and cyclopentadiene the endo product will have the R
groups of the diene and dienophile oriented toward the opposite sides
of the newly formed ring.

Reaction with both exo-endo effect

The exo product can predominate, however, for some reactions. This
can happen when the resulting endo product can easily dissociate back
into the starting material. In such reactions, the exo product
predominates with extended reaction times because the exo product is
thermodynamically favored. In other cases, the endo product can
convert to what would be the exo product of the reaction. In the
example below, endo product B was the only one isolated after the
DielsAlder reaction. However, letting the reaction go for prolonged
periods of time also yielded substantial amounts of exo product A.
The authors speculated that endo product B can epimerize to exo
product A in the following way:

Epimerization in DA reaction
In summary, diastereoselectivity is based on the postulation of the
transition state. For any given DA reaction, one can imagine one
possible transition state being favored over the other due to steric,
stereoelectronic, and complexing factors. Thus, predictions can be
made on the identity of major product of a particular DA reaction by
looking at the starting material available.

[edit] Retro-DielsAlder reactions

Main article: Retro-DielsAlder reaction
DA reactions are reversible and in a retro-DielsAlder reaction the
diene and alkene are reformed. One representative reaction is the
RickertAlder reaction [21] in which, thanks to favorable
rearomatization, the oxidized cycloadduct of quinone and 1,3-

cyclohexadiene at elevated temperatures eliminates ethylene to form

anthraquinone.

[edit] Inverse electron demand Diels-Alder

reaction
Main article: Inverse electron demand Diels-Alder reaction
Unlike in the Diels-Alder reaction, the Inverse electron demand
Diels-Alder reaction is a cycloaddition between an electron-rich
dienophile and an electron-poor diene.

[edit] Asymmetric DA reactions

In asymmetric DielsAlder reactions only one of two possible
enantiomers is formed. Asymmetric catalysis by organocatalysis is
possible with catalysts based on an imidazoline skeleton (the
MacMillan catalyst[22]) for instance in the reaction of cyclohexadiene
with acrolein:[23]

DielsAlder reactions also lend themselves to chiral synthesis with

chiral auxiliaries. In one research effort,[24] the auxiliary is
derived from L-asparagine. The telescopic synthesis with
cyclopentadiene and acrylic acid yields the DA adduct with three
stereocenters as predominantly the endo conformer and with 54% ee.

Lewis acids (AlCl3, ZnCl2, and others) act as catalysts by

coordinating to the dienophile. The complexed dienophile becomes more
electrophilic and more reactive toward the diene. This increases the
rate and often the stereoselectivity of a DA reaction.