Facial Selectivities

1
Facial Selectivities Tandem Reaction Ionic
Reactions 1,3-Dipolar Cycloadditions Secondary
Orbital Interactions
2

• After completing PART 4 of this course you should
  have an understanding of, and be able to
  demonstrate, the following terms, ideas and
  methods.
• (vi) Cycloaddition reactions can be
  regioselective. The regioselectivity cannot be
  predicted from the simple treatment given to
  frontier molecular orbitals in this course.
  However, generalisations can be made from looking
  at classes of substituents (C, Z, X) which are in
  conjugation with the ?-systems, which allow us to
  predict the regioselectivity in an empirical
  manner (CHM2I3).
• (vii) Tandem cycloaddition reactions are useful
  synthetic reactions for the construction of fused
  cyclic systems, however, one has to consider the
  implications of kinetic and thermodynamic
  control, in many cases.
• (viii) 1,3-Dipolar cycloadditions are an
  important class of cycloaddition reactions, as
  they are a versatile route to highly
  functionalised heterocycles. They involve the
  reaction of a 1,3-dipole with a dipolarophile.
• (viii) Cycloaddition reactions can be initiated
  by photoexcitation. This allows many reactions
  that are not thermally allowed to occur.
  However, it is not clear in some cases whether
  the mechanism is truly concerted in nature, or
  has some component of radical generation and a
  step-wise reaction.

3
Facial Selectivities
4
(No Transcript)
5
anti- and syn-Diels-Alder Adducts
p4s p2s
X anti-Adduct syn-Adduct
H 20 80
SMe 90 10
S(O)Me gt95 lt5
S(O)2ME gt95 lt5
iPr gt95 lt5
Et gt95 lt5
CHO gt95 lt5
CH2OH gt95 lt5
OH lt5 gt95
6
Other Dienophiles and p-Facial Diastereoselectivit
y
p4s p2s
7
Tandem Diels-Alder Reactions
8
(No Transcript)
9
Tandem Diels-Alder Reactions
KINETIC PRODUCT
THERMODYNAMIC PRODUCT
10
KINETIC PRODUCT
Thermal p4s p2s
THERMODYNAMIC PRODUCT
11
Ionic Cyclo-additions
12
(No Transcript)
13
Cationic Cycloadditions (Allyl Cation)
Thermal p2s p4s
14
Anionic Cycloadditions (Allyl Anion)
Thermal p4s p2s
15
1,3-Dipolar Cyclo-additions
16
1,3-Dipolar Cycloadditions
p4s p2s
p4s p2s
17
Linear 1,3-Dipoles
18
Bent 1,3-Dipoles
19
Desymmetrising Coefficients and Regiochemistry
K.N. Houk, J. Sims, R.E. Duke, R.W. Strozier,
J.K. GeorgeJ. Am. Chem. Soc., 1973, 95, 7287
y2 HOMO
y2 HOMO
20
1,3-Dipolar Cycloaddition Reaction Examples
Major Product
Minor Product
21
Major Product
Minor Product
22
(No Transcript)
23
Secondary Orbital Interactions
24
Secondary Orbital Interactions. 1
Secondary Orbital Interaction Control
25
The ENDO Transition State
Note that all of the p-conjugated system of
maleic anhdride needs to be considered, and not
just the monoene unit, in order that the
secondary orbital interactions can be taken into
account
p4s p2s
26
The EXO Transition State
Thermal p4s p2s
This orientation of reactants in the transition
state does not facilitate any secondary orbital
interactions.
27
Kinetic Thermodynamic Product
Endo Isomer Kinetic Product DG2lt DG1
Exo Isomer Thermodynamic Product DG1gtDG2
28
(No Transcript)
29
Secondary Orbital Interactions. 2
Thermal 10 (4n2, n2) e D-A
Thermal p4s p6s
30
(No Transcript)
31
Attack of a monoene on appropriately substituted
dienes can take place in a suprafacial/suprafacial
process on either face of the diene, leading
two diastereoisomers. It is often found that
there is some p-facial diastereoselectivity,
which can usually be explained by considering the
ease of accessibility of the monoene to the two
different faces. In many cycloaddition reactions
with the correct substitution on the two
partners, the two components are able to react to
afford regioisomers. In practice it is found
that one regioisomer is formed in preference to
the other. The reason for this is attributed to
the matching of the coefficients of the HOMO and
LUMO in the transition state. Calculation
predicts that the smallest coefficient of one
partner (HOMO) will interact with the smallest
coefficient of the second partner (LUMO), and
vice versa for the large coefficients, because
this results in the smallest energy gap and the
lowest energy transition state. In many,
instances the use of a Bronsted (H) or a Lewis
acid, increases the propensity for one
regioisomer. The reason for this is that the
coefficients at the termini of p-system are made
increasingly larger and smaller, respectively,
and as a result, the overlap with the second
reacting partner becomes even more
efficient. Cycloaddition reactions can also be
utilised to construct multiple ring systems, via
what are referred to as tandem cycloaddition
reactions. These are important reactions in
synthetic chemistry as complex fused ring systems
with high degrees of stereo and regio control can
be formed in one-pot reactions. The nature of
tandem cycloaddition reactions generally means
that the second cycloaddition has two choices,
one of which is controlled by thermodynamics (the
product stability) and the other by kinetics (the
ease of attainment of the transition state).
Thus, it is important to bear this in mind in
experimental design should the reaction be
carried out a low temperatures (favouring the
kinetic product) or high temperatures (favouring
the thermodynamic product), for example. Another
extremely important class of cycloaddition
reactions are the 1,3-dipolar cycloadditions.
This class of reactions allows the construction
of heterocycles with high degrees of stereo and
regioselectivity, and is thus very valuable in
organic synthesis. The reactions involve a
1,3-dipole (XYZ, a 4 p-electron system) and a
dipolarophile (generally an alkene, a 2 p
-electron system), reacting in a concerted
fashion via an ss transition state. Cycloaddition
reactions which were not permitted by thermal
routes because the phase overlap of the FMOs was
not appropriate, can be accomplished under
photochemical conditions. For example, monoenes
can be photodimerised. However, the product
outcomes sometimes suggest that the reaction is
not concerted (a stepwise radical mechanism may
be involved). Furthermore, the issue is
complicated by the fact that photoexcited singlet
and triplet states can be formed, which results
in different product outcomes. In appropriate
cases, the Diels-Alder reaction proceeds
kinetically with endo selectivity. The
so-called endo rule can be rationalised in terms
of favourable secondary orbital interactions.
Additionally, these so-called secondary orbital
interaction can also explain the formation of
only one diastereoisomer, by observing
antibonding secondary orbital interactions (a
point we shall return to when examining
sigmatropic rearrangements).
32
Remember the following very wise phrase
The man who says he can
and
The man who says he cant
Are both right!
Ali G!!
Good Luck with your exams
but remember they are nothing more than a
stepping stone in life.
33
(No Transcript)
34
Further Reading on Cycloaddition Reactions
J.D. Walker Tandem Diels-Alder Cycloadditions in
Organic Synthesis Chem. Rev., 1996, 96,
167. W. Adams, M. Prein p-Facial
Diastereoselectivity in the 42 Cycloaddition
of Singlet Oxygen as a Mechanistic Probe Acc.
Chem. Res., 1996, 29, 275. P.J. Parsons, C.S.
Penkett, A.J. Shell Tandem Reactions in Organic
Synthesis Novel Strategies for Natural Product
Elaboration and the Development of New Synthetic
Methodology Chem. Rev., 1996, 96, 195.
35
Exercise 1 4n2 p Cycloadditions
Identify the starting materials and propose arrow
pushing mechanisms for the formation of the
following products
45
64
23
36
Answer 1 4n2 p Cycloadditions
Identify the starting materials and propose arrow
pushing mechanisms for the formation of the
following products
37
Exercise 2 4n2 p Cycloadditions
Identify the starting materials and propose arrow
pushing mechanisms for the formation of the
following products
38
Answer 2 4n2 p Cycloadditions
Identify the starting materials and propose arrow
pushing mechanisms for the formation of the
following products
39
Exercise 3 4n2 p Cycloadditions and a bit more!
Rationalise the following reaction scheme
utilising frontier molecular orbitals and
identify reagent A.
40
Answer 3 4n2 p Cycloadditions and a bit more!
Rationalise the following reaction scheme
utilising frontier molecular orbitals and
identify reagent A.
Attacking from least hindered side p4s p2s
41
Exercise 4 4n2 p Cycloadditions
Rationalise the following reaction scheme
utilising secondary orbital interactions.
42
Answer 4 4n2 p Cycloadditions
Rationalise the following reaction scheme
utilising secondary orbital interactions.
y2 HOMO
y3 LUMO
Thermodynamic Product
Kinetic Product