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Inverse electron demand Diels-Alder Reaction
The Inverse electron demand Diels-Alder rection, or DAINV is an organic chemical reaction, closely related to the Diels-Alder reaction. Unlike in the Diels-Alder reaction, the DAINV is a cycloaddition between an electron-rich dienophile and an electron-poor diene.[1] During a DAINV reaction, three pi-bonds are broken, and two sigma-bonds and one new pi-bond are formed. A prototypical DAINV reaction is shown on the right.
DAINV reactions often involve heteroatoms, and can be used to form heterocyclic compounds. This makes the DAINV reaction particularly useful in natural product syntheses, where the target compounds often contain heterocycles. Recently, the DAINV reaction has been used to synthesize a drug transport system for treatment of prostate cancer cells.[2]
History[edit]
The Diels-Alder reaction was first reported in 1928 by Otto Diels and Kurt Alder; they were awarded the Nobel Prize in chemistry for their work in 1950. Since that time, the use of the Diels-Alder reaction has grown explosively; in both 2009 and 2010, a quick literature search for the term returns over 1,200 articles. Conversely, DAINV does not have a clear date of inception, and lacks the comparative notoriety of the standard Diels-Alder - a keyword search shows roughly 25 articles each year, over the last few.
Mechanism[edit]
Formal Mechanism
There is come debate on the mechanism of the DAINV reaction mechanism. While it is accepted as a formal [4+2] cycloaddition, it is not well understood whether or not the reaction is truly concerted. In general, the accepted view is that most DAINV reactions occur via an asynchronous mechanism, where the reaction proceeds via a single transition state, but not all bonds are formed or broken at the same time, as would be the case in a concerted mechanism.[1]
The formal DAINV mechanism for the reaction of acrolein and methyl vinyl ether is shown in the figure to the right. Though, as mentioned before, there is some debate on the accuracy of this description, it provides a useful model for the reaction. Note that during the course of the reaction, three pi-bonds (labelled iwth red) are broken, and three new bonds are formed (labelled in blue): two sigma-bonds and one new pi-bond. [3]
Transition State
Like the standard DA, DAINV reactions proceed via a single boat transition state, to a close approximation. In reality, 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.[4] The approximate synchronicity of the DAINV means it can be treated similarly to the standard Diels-Alder reaction.[1]
Since the reaction can be modeled using a closed, bot-like transition state, will all bonds being in the process of forming or breaking at some given point, the reaction must obey the Woodward-Hoffman general selection rules. This means that for a three component, six electron system, all component must interact in a suprafacial manner. With all components being suprafacial, the transition state cannot be a, usually more favourable, chair, as that would make the mode of interaction for all components [[antarafacial]. A three component, six electron reaction reacting in an anatarfacial mode is thermally disallowed by the Woodward-Hoffman rules.[3]
==Molecular Orbital Theory==[5]
Note: For this section, it is useful to have, at least, a light understanding of Molecular-Orbital Theory.
Standard DA Reactions
In the standard DA reaction, there are two components, the diene, which is electron rich, and the dienophile, which is electron poor. The relative electron-richness and electron deficiency of the reactants can best be described visually, in an Molecular Orbital Diagram. In the standard DA case, the electron rich diene has orbitals that are, in general, relatively high in energy; conversely, the electron poor dienophile has orbitals that are relatively low in energy. This difference in relative orbital energies means that, of the frontier molecular orbitals the HOMO of the diene and the LUMO of the dienophile are more similar in energy than the HOMOdienophile and the LUMOdiene. [1]
According to Molecular Orbital Theory, the more similar two orbitals are in energy, the more strongly they will interact. So, looking at the MO diagram for the standard DA reaction, it is visually clear why the HOMOdiene and the LUMOdienophile interact preferentially, as opposed to the HOMOdienophile and LUMOdiene; the former two being closer in energy than the latter two, and thus having greater overlap and stronger interaction.
[4+2] Dimerization Reactions
Standard Diels-Alder reactions, and inverse electron demand reactions do not share a distinct boundary with one-another. Rather, there is a subset of, often unfavourable, reactions between the two. These are [4+2] dimerization reactions. The prototypical example is the dimerization of acrolein. In this case, the diene and dienophile are identical, and no preference exists for which frontier molecular orbitals will interact, as both sets of possible HOMO-LUMO interactions are equally favourable.
It should be noted, though, that the thermodynamic benefit resulting from a bond forming reaction is directly related to the overlap of the two interacting orbitals, and thus inversely related to the energetic difference between the two. That is to say: the greater the difference in energy of two interacting orbitals, the less energetically favourable the reaction will be. Since the LUMO and HOMO of the reactants in a dimerization are farther apart than the HOMOdiene and LUMOdienophile in a standard Diels-Alder reaction, the energetic benefit for dimerization is less, and the reaction is, overall, less favourable from a thermodynamic standpoint.[1]
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, the the dienophile any more so, the possbile [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.[4][6] [1]
Regiochemistry and Stereochemistry of DAINV[edit]
Regiochemistry
Whenever there are two or more possible sites for a reaction to occur, regiochemistry becomes a concern. For example, in the dimerization of acrolein, the acrolein acting as the dienophile can react at two different pi-bonds, and facing one of two directions, with respect to the diene, for a total of four possible regioisomers. Despite this, only of the regioisomers is obtained as the major product. It is possbile to predict this outcome for the dimerization of acrolein; it is also possible to make the same predictions for the regiochemical outcome of most DAINV reactions. This can be done one of two ways, either by electrostatic (charge) control, or orbital control.[4][6][1]
- Charge control:
- Each of the starting materials (diene and dienophile) has a second best resonance form.
- The second best resonance form shows where the partial charges will lie.
- Partially negative atoms on the diene will bond to partially positive atoms on the dienophile, and vice versa.
- Orbital control:[4]
- 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 FMO.
- Orbitals will align the maximize the bonding interactions, and minimize the anti-bonding interactions.
Alder-Stein Principle
The DAINV reaction is a 6-electron, three-component pericyclic reaction; meaning that the mode of approach for the diene-dienophile encounter pair must be suprafacial, not antarafacial. This is a direct implication of the Woodward-Hoffman rules. What this means with regard to DAINV reaction is that the Alder-Stein Principle is true for the inverse electron demand Diels-Alder, as much as for the standard Diels-Alder reaction. In simplest terms, the Alder-Stein principle states that the stereochemistry of the reactants is maintained in the stereochemistry of the products. That is to say, groups that 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. For instance, 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, that is to say, the groups on the diene alone, or the groups on the dienophile, alone. Prediction of the relative orientation of groups between the two reactants can be predicted by the endo selection rule.
Endo selection rule
Like the standard Diels-Alder reaction, the DAINV also obeys a general endo selection rule. In the standard Diels-Alder, it is known that electron withdrawing groups on the dienophile will approach endo, with respect to the diene; conversely, in DAINV, the it is the electron donating groups that approach in an endo fashion. The easiest way to understand what this means is to look at the transition state. Since all Diels-Alder reactions proceed through a boat transition state, there is a clear "inside" and a clear "outside" of the transition state (inside and outside the "boat"). The substituents on the dienophile are considered "endo" if they are 'inside' the boat, and "exo" if they are on the outside.
Clearly, the exo pathway would be favoured by sterics, so a different explanation is needed to justify the general predominance of endo products. To explain the endo selection rule, it is best to use frontier molecular orbital theory. 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 favourable bonding interaction, stabilizing the transition state.[4] Since the energy of the transition state of a reaction is directly related to the activation energy, then, by referring to the Arrhenius equation, it is clear that the reaction pathway with a stabilized, endo transition state will proceed faster and more completely than the exo reaction pathway, without said stabilization.[4]
Common Dienes[edit]
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 groups, or B) electronegative heteroatoms. Even some aromatic compounds can react in DAINV reactions, such as triazines and tetrazines. Other common classes of dienes are oxo- and aza- butadienes. [6][7]
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. [8][9] [1][10]
| Diene | Name | HOMO Energy (eV) | LUMO Energy (eV) |
|---|---|---|---|
 |
2-cyclohexylidene-3-oxo-3-phenylpropanenitrile | -9.558 | 2.38 |
 |
Acrolein | -14.5 | 2.5 |
 |
5-cyclopentylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione | -10.346 | 1.879 |
 |
Butadiene | -10.346 | 1.879 |
 |
1-Methoxy-butadiene | -8.21 | 3.77 |
 |
2,3-dimethyl-butadiene | -8.76 | 2.18 |
Common Dienophiles[edit]
The dienophiles used in Inverse electron demand Diels-Alder reactions are, unlike in the standard DA, very electron rich, containing one or more electron releasing groups. This results in higher orbital energies, and thus more orbital overlap with the LUMO of the diene. Common classes of dieneophiles for DAINV reaction include vinyl ethers and vinyl acetals, imine, enamines, alkynes and highly strained olefins.[7][10]
Again, 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.[8][4] [1] A second table shows how electron richness in the dienophiles affects the rate of reaction with a very electron poor diene, namely hexachlorocyclopentadiene.[11]
| Dienophile | Name | HOMO Energy (eV) | LUMO Energy (eV) |
|---|---|---|---|
 |
ethyl vinyl ether | -9..006 | 5.313 |
 |
2-methylenetetrahydro-2H-pyran | -8.939 | 5.140 |
 |
1,1'-bis(cyclopentilidene) | -8.242 | 4.749 |
 |
Acrolein | -14.5 | 2.5 |
 |
Cyclohexene | -8.94 | 2.1 |
 |
Propene | -9.13 | 1.8 |
 |
Ethylene | -10.52 | 1.5 |
| Dienophile | Relative Reaction Rate with
Hexachlorocyclopentadiene |
|---|---|
| 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[edit]
DAINV reactions provide a pathway to a rich library of synthetic targets[4][7], and have been utilized to form many highly functionalized systems, including selectively protected sugars, an important contribution to the field of sugar chemistry. In addition, DAINV reactions con produce an array of different products from a single starting material. Take the below example, where the starting compound is a generic tetrazine.[9] [1]
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 synthesis the PDE-I and PDE-II sections of (-)-CC-1065, as shown below.
See Also[edit]
References[edit]
- ^ a b c d e f g h i j Boger, Dale (1989). "Recent Applications of the Inverse Electron Demand Diels-Alder Reaction". Progress in Heterocyclic Chemsitry. Progress in Heterocyclic Chemistry. 1: 30–64. doi:10.1016/B978-0-08-037045-3.50007-5. ISBN 9780080370453.
- ^ Weissler, M (2010). "The Diels-Alder-Reaction with inverse-Electron-Demand, a very efficient versatile Click-Reaction Concept for proper Ligation of variable molecular Partners". International Journal of Medical Sciences. 7 (1): 19–28. doi:10.7150/ijms.7.19. PMC 2792734. PMID 20046231.
- ^ a b Woodward, R (1959). "The Mechanism of the Diels-Alder Reaction". Tetrahedron. 5: 70–89. doi:10.1016/0040-4020(59)80072-7.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ a b c d e f g h Rooshenas, Parham; Hof, Kira; Schreiner, Peter R.; Williams, Craig M. (1 February 2011). "1,2,4-Triazine vs. 1,3- and 1,4-Oxazinones in Normal- and Inverse-Electron-Demand Hetero-Diels-Alder Reactions: Establishing a Status Quo by Computational Analysis". European Journal of Organic Chemistry. 2011 (5): 983–992. doi:10.1002/ejoc.201001365.
- ^ Woodward, R (1968). "The Conservation of Orbital Symmetry". Acc. Chen. Res. 1: 17–22. doi:10.1021/ar50001a003.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ a b c Dang, Anh-Thu; Miller, David O.; Dawe, Louise N.; Bodwell, Graham J. (1 January 2008). "Electron-Deficient Dienes. 5. An Inverse-Electron-Demand Diels−Alder Approach to 2-Substituted 4-Methoxyxanthones and 3,4-Dimethoxyxanthones". Organic Letters. 10 (2): 233–236. doi:10.1021/ol702614b. PMID 18092790.
- ^ a b c Bodwell, Graham; Pottie, Ian; Nandaluru, Penchal (30 August 2011). "An Inverse Electron-Demand Diels-Alder-Based Total Synthesis of Urolithin M7". Synlett. 2011 (15): 2245–2247. doi:10.1055/s-0030-1261203.
- ^ a b Flemming, Ian (2010). Molecular Orbitals and Organic Chemical Reactions. Great Britain: Wiley. ISBN 978-0-470-74658-5.
- ^ a b Figeys, H. (1981). "Diels-Alder Reactions with Inverse Electron Demand II". Tetrahedron Letters. 22 (15): 1393–1396. doi:10.1016/S0040-4039(01)90330-2.
- ^ a b Palasz, A (2011). "Knoevenagel condensation of cyclic ketones with benzoylacetonitrile and N,N′-dimethylbarbituric acid. Application of sterically hindered condensation products in the synthesis of spiro and dispiropyrans by hetero-Diels–Alder reactions". Tetrahedron. 67 (7): 1422–1431. doi:10.1016/j.tet.2010.12.053.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Sauer, J (1962). "Diels-Alder-Additionen mit "inversem" Elektronenbedarf". Angewendte Chemie. 74 (10): 353. doi:10.1002/ange.19620741006.