Inverse electron-demand Diels–Alder reaction
The inverse electron demand Diels–Alder reaction, or DAINV or IEDDA
DAINV reactions often involve
History
The Diels–Alder reaction was first reported in 1928 by
Mechanism
Formal mechanism
The mechanism of the DAINV reaction is controversial. While it is accepted as a formal [4+2]
The formal DAINV mechanism for the reaction of
Transition state
Like the standard DA, DAINV reactions proceed via a single boat transition state, despite not being concerted. The single boat transition state is a simplification, but DFT calculations suggest
that the time difference in bond scission and formation is minimal, and that despite potential asynchronicity, the reaction is concerted, with relevant bonds being either partially broken or partially formed at some point during the reaction.[7] The near synchronicity of the DAINV means it can be treated similarly to the standard Diels-Alder reaction.[2]
The reaction can be modeled using a closed, boat-like transition state, with all bonds being in the process of forming or breaking at some given point, and therefore must obey the
Molecular orbital theory
Standard DA reactions
In the standard Diels-Alder reaction, there are two components: the
[4+2] dimerization reactions
Dimerization reactions are neither normally or inversely accelerated, and are usually low yielding. In this case, two
Diels–Alder with inverse electron demand
In the dimerization reactions, the diene and dienophile were equally electron rich (or equally electron poor). If the diene becomes any less electron rich, or the dienophile any more so, the possible [4+2] cycloaddition reaction will then be a DAINV reaction. In the DAINV reaction, the LUMOdiene and HOMOdienophile are closer in energy than the HOMOdiene and LUMOdienophile. Thus, the LUMOdiene and HOMOdienophile are the frontier orbitals that interact the most strongly, and result in the most energetically favourable bond formation.[2][7][9]
Regiochemistry and stereochemistry of DAINV
Regiochemistry
Regiochemistry in DAINV reactions can be reliably predicted in many cases. This can be done one of two ways, either by electrostatic (charge) control, or orbital control.[2][7][9] To predict the regiochemistry via charge control, one must consider the resonance forms of the reactants. These resonance forms can be used to assign partial charges to each of the atoms. Partially negative atoms on the diene will bond to partially positive atoms on the dienophile, and vice versa.
Predicting the regiochemistry of the reaction via orbital control requires one to calculate the relative orbital coefficients on each atom of the reactants.[7] The HOMO of the dienophile reacts with the LUMO of the diene. The relative orbital size on each atom is represented by orbital coefficients in the Frontier molecular orbital theory (FMO). Orbitals will align to maximize the bonding interactions, and minimize the anti-bonding interactions.
Alder–Stein principle
The Alder–Stein principle states that the stereochemistry of the reactants is maintained in the stereochemistry of the products during a Diels–Alder reaction. This means that groups which were cis in relation to one another in the starting materials will be syn to one another in the product, and groups that were trans to one another in the starting material will be anti in the product.
It is important to note that the Alder–Stein principle has no bearing on the relative orientation of groups on the two starting materials. One cannot predict, via this principle, whether a substituent on the diene will be syn or anti to a substituent on the dienophile. The Alder–Stein principle is only consistent across the self-same starting materials. The relationship is only valid for the groups on the diene alone, or the groups on the dienophile, alone. The relative orientation of groups between the two reactants can be predicted by the endo selection rule.
Endo selection rule
Similarly to the standard Diels–Alder reaction, the DAINV also obeys a general endo selection rule. In the standard Diels–Alder, it is known that
The exo pathway would be favored by sterics, so a different explanation is needed to justify the general predominance of endo products. Frontier molecular orbital theory can be used to explain this outcome. When the substituents of the dienophile are exo, there is no interaction between those substituents and the diene. However, when the dienophile substituents are endo, there is considerable orbital overlap with the diene. In the case of DAINV the overlap of the orbitals of the electron withdrawing substituents with the orbitals of the diene create a favorable bonding interaction, stabilizing the transition state relative to the exo transition state.[7] The reaction with the lower activation energy will proceed at a greater rate.[7]
Common dienes
The dienes used in Inverse electron demand Diels-Alder are relatively electron-deficient species; compared to the standard Diels-Alder, where the diene is electron rich. These electron-poor species have lower molecular orbital energies than their standard DA counterparts. This lowered energy results from the inclusion of either: A) electron withdrawing group, or B) electronegative heteroatoms. Aromatic compounds can also react in DAINV reactions, such as triazines and tetrazines. Other common classes of dienes are oxo- and aza- butadienes.[9][11]
The key quality of a good DAINV diene is a significantly lowered HOMO and LUMO, as compared to standard DA dienes. Below is a table showing a few commonly used DAINV dienes, their HOMO and LUMO energies, and some standard DA dienes, along with their respective MO energies.[2][12][13][14]
Diene | Name | HOMO Energy (eV) | LUMO Energy (eV) | Reaction Pathway (DA/DAINV) |
---|---|---|---|---|
2-cyclohexylidene-3-oxo-3-phenylpropanenitrile | -9.558 | 2.38 | DAINV | |
Acrolein | -14.5 | 2.5 | DAINV | |
5-cyclopentylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione | -10.346 | 1.879 | DAINV | |
Butadiene | -10.346 | 1.879 | DA or DAINV | |
1-Methoxy-butadiene | -8.21 | 3.77 | DA | |
2,3-dimethyl-butadiene | -8.76 | 2.18 | DA |
Common dienophiles
The
The most important consideration in choice of dienophile is its relative orbital energies. Both HOMO and LUMO impact the rate and selectivity of the reaction. A table of common DAINV dienophiles, standard DA dienophiles, and their respective MO energies can be seen below.[2][7][12]
Dienophile | Name | HOMO Energy (eV) | LUMO Energy (eV) | Reaction Pathway (DA/DAINV) |
---|---|---|---|---|
ethyl vinyl ether | -9.006 | 5.313 | DAINV | |
2-methylenetetrahydro-2H-pyran | -8.939 | 5.140 | DAINV | |
1,1'-bis(cyclopentilidene) | -8.242 | 4.749 | DAINV | |
Acrolein | -14.5 | 2.5 | DA | |
Cyclohexene | -8.94 | 2.1 | DA | |
Propene | -9.13 | 1.8 | DA | |
Ethylene | -10.52 | 1.5 | DA |
A second table shows how electron richness in the dienophiles affects the rate of reaction with a very electron poor diene, namely hexachlorocyclopentadiene. The more electron rich the dienophile is, the higher the rate of the reaction will be. This is very clear when comparing the relative rates of reaction for styrene and the less electron rich p-nitrostyrene; the more electron rich styrene reactions roughly 40% faster than p-nitrostyrene.[5]
Dienophile | Relative reaction rate with |
---|---|
Cyclopentadiene | 15200 |
p-Methoxystyrene | 1580 |
Styrene | 750 |
p-Nitrostyrene | 538 |
2,3-Dihydrofuran | 333 |
Norbornene | 70.8 |
Cyclopentene | 59.0 |
Maleic anhydride | 29.1 |
Cyclohexene | 3.0 |
Scope and applications
DAINV reactions provide a pathway to a rich library of synthetic targets,[7][11] and have been utilized to form many highly functionalized systems, including selectively protected sugars, an important contribution to the field of sugar chemistry.[15] In addition, DAINV reactions can produce an array of different products from a single starting material, such as tetrazine.[2][13]
DAINV reactions have been utilized for the synthesis of several natural products, including (-)-CC-1065, a parent compound in the Duocarmycin series, which found use as an anticancer treatment. Several drug candidates in this series have progress into clinical trials. The DAINV reaction was used to synthesise the PDE-I and PDE-II sections of (-)-CC-1065. The first reaction in the sequence is a DAINV reaction between the tetrazine and vinyl acetal, followed by a retro-Diels–Alder reaction to afford a 1,2-diazine product. After several more steps, an intramolecular DAINV reaction occurs, followed again by a retro Diels-Alder in situ, to afford an indoline product. This indoline is a converted into either PDE-I or PDE-II in a few synthetic steps.
DAINV reaction between 2,3,4,5-tetrachlorothiophene-1,1-dioxide (diene) and
See also
- Diels–Alder reaction
- Cycloaddition
- Pericyclicreaction
- Molecular orbital theory
- Boger pyridine synthesis
External links
References
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