Alder-Stein rules - wiki

Inverse electron-demand Diels–Alder reaction

Prototypical DA_INV reaction between the electron poor diene Acrolein, and the electron rich dienophile,Methyl vinyl ether.

The Inverse electron demand Diels–Alder reaction, orDA_INV or IEDDA is an organic chemical reaction, in which two new chemical bonds and a six-membered ring are formed. It is related to the Diels–Alder reaction, but unlike the Diels–Alder (or DA) reaction, the DA_INV is a cycloaddition between an electron-rich dienophile and an electron-poor diene. During a DA_INV reaction, three pi-bonds are broken, and two sigma bonds and one new pi-bond are formed. A prototypical DA_INV reaction is shown on the right.

Alder–Stein principle

Because there is a single transition state, and all modes of attack are suprafacial, stereochemistry in this reaction is retained. R³ and R⁵ are cisin the dienophile, and syn in the product. Conversely, R³ and R⁴ aretrans in the dienophile, and anti in the product. In addition, R¹ and R²share the same starting chemistry both in the diene, and the product.

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

In the endo transition state, the methoxy group is "inside" the boat; where in the exo transition state, it is "outside".

Similarly to the standard Diels–Alder reaction, the DA_INV also obeys a general endo selection rule. In the standard Diels–Alder, it is known thatelectron withdrawing groups on the dienophile will approach endo, with respect to the diene. The exact cause of this selectivity is still debated, but the most accepted view is that endo approach maximizes secondary orbital overlap. The DA_INV favors an endo orientation of electron donating substituents on the dienophile. Since all Diels–Alder reactions proceed through a boat transition state, there is an "inside" and an "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.

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 DA_INV 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. The reaction with the lower activation energy will proceed at a greater rate.