Transition state in Diels-Alder reactions

Table 5 AMI Calculation of the transition states in Diels-Alder reactions between 5-X-pentamethylcyclopentadiones and maleic anhydride...

With some 1,3-dipoles, two possible stereoisomers can be formed by syn addition. These result from two differing orientations of the reacting molecules, which are analogous to the endo and exo transition states in Diels-Alder reactions. Diazoalkanes, for example, can add to unsymmetrical dipolarophiles to give two diastereomers. 

Ab initio calculations have been performed by Birney and Houk to define the transition state in Diels-Alder reactions catalyzed by boron derivatives [38]. As a model, the authors studied the reaction between butadiene and acrolein complexed with BH3. The preferred route is endo addition of the anti complex of s-cis acrolein. 

Electrostatic potential map for transition state for Diels-Alder reaction of cyclopentadiene and acrylonitrile shows negatively-charged regions (in red) and positively-charged regions (in blue). 

The chemical reactions through cyclic transition states are controlled by the symmetry of the frontier orbitals [11]. At the symmetrical (Cs) six-membered ring transition state of Diels-Alder reaction between butadiene and ethylene, the HOMO of butadiene and the LUMO of ethylene (Scheme 18) are antisymmetric with respect to the reflection in the mirror plane (Scheme 24). The symmetry allows the frontier orbitals to have the same signs of the overlap integrals between the p-or-bital components at both reaction sites. The simultaneous interactions at the both sites promotes the frontier orbital interaction more than the interaction at one site of an acyclic transition state. This is also the case with interaction between the HOMO of ethylene and the LUMO of butadiene. The Diels-Alder reactions occur through the cyclic transition states in a concerted and stereospecific manner with retention of configuration of the reactants. 

Theoretical calculations (6-31G ) have been used to compare the energies of four possible transition states for Diels-Alder reaction of the BF3 complex of methyl acrylate with 1,3-butadiene. The results are summarized in Fig. 6.4. The endo transition state with the s-trans conformation of the dienophile is preferred to the others by about 2kcal/mol.14... 

Bond distances in transition states for Diels-Alder reactions. 15-2... 

The most important stabilizing interaction of the transition states of Diels-Alder reactions with inverse electron demand is due to the second term of Equation 15.3. In this case, the denominator of the second term is substantially smaller than that of the first term. This is because the HOMO of an electron-rich dienophile is closer to the LUMO of an electron-poor diene than is the HOMO of the same diene relative to the LUMO of the same dienophile (Figure 15.24, column 4). We saw the reason for this previously acceptors lower the energies of all 7F-type MOs donors increase these energies. 

In summary, the transition states of Diels-Alder reactions with either normal or inverse electron demand are substantially stabilized because the HOMO of one reagent lies close to the LUMO of the other reagent. This stabilization of the transition states is responsible for the fast cycloadditions. 

Butadienes with alkyl substituents in the 2-position favor the formation of the so-called para-products (Figure 15.25, X = H) in their reactions with acceptor-substituted dienophiles. The so-called mefa-product is formed in smaller amounts. This regioselectivity increases if the dienophile carries two geminal acceptors (Figure 15.25, X = CN). 2-Phenyl-1,3-butadiene exhibits a higher para -selectivity in its reactions with every unsymmetrical dienophile than any 2-alkyl-1,3-butadiene does. This is even more true for 2-methoxy- 1,3-butadiene and 2-(trimethylsilyloxy)-l,3-butadiene. Equation 15.2, which describes the stabilization of the transition states of Diels-Alder reactions in terms of the frontier orbitals, also explains the para "/"meta "-orientation. The numerators of both fractions assume different values depending on the orientation, while the denominators are independent of the orientation. 

The geometry of the Diels-Alder transition state. The Diels-Alder reaction has a concerted mechanism, with all the bond making and bond breaking occurring in a single step. Three pairs of electrons move simultaneously, requiring a transition state with overlap between the end p orbitals of the diene and those of the dienophile. 

McCabe, J. R., Eckert, C. A. Role of high-pressure kinetics in studies of the transition states of Diels-Alder reactions. Acc. Chem. Res. 

The transition state of Diels-Alder reaction of diene 56 with dienophile 57 to give the adduct 58 (Scheme 5.14) is a boat-like type. The antibody 39-Al 1, generated to the bicy-clo [2.2.2 ] octane hapten 59 that mimics the transition state of the reaction, efficaciously catalyzed the cycloaddition, selectively giving 58 in buffered aqueous medium (Scheme 5.14). ° Ribozymes are RNA molecules with catalytic properties. Artificial ribozymes, isolated fi om synthetic combinatorial libraries, accelerate a broad range of reactions including the Diels-Alder cycloaddition. These ribozymes generally require that at least one of the reactants be RNA or be covalently tethered to RNA. 

Jurczak has shown that cycloaddition reactions involving furan could also be catalyzed by transfer RNA under high pressure [13]. Flence, kinetin 9 reacts with maleic anhydride and dimethyl acetylene dicarboxylate (DMAD) at lOkbar showing that tRNA is a true Diels-Alderase (Scheme 2). These products are not formed at high pressure without tRNA. It seems that a conformation of tRNA induced at high pressure meets structural requirements of a transition state of Diels-Alder reaction. It provides complementarity of size and shape of both substrates and is a driving force in molecular recognition. 

The transition states in Diels-Alder and in 1,3-dipolar cyclo-additions are isoconjugate respectively with benzene (or a substituted benzene to be precise) and cyclopentadienyl anion (or the appropriate hetero-aromatic system). Aromatic stabilization is also available for cationic transition states provided that the six electrons are delocalized over seven atomic centres. Few examples are known, but reaction (6.67) is in this category. 

In contrast with exo (top) facial selectivity in the additions to norbomene 80 [41], Diels-Alder reaction between isodicyclopentadiene 79 takes place from the bottom [40] (see Scheme 32). To solve this problem, Honk and Brown calculated the transition state of the parent Diels-Alder reaction of butadiene with ethylene [47], They pointed ont that of particular note for isodicyclopentadiene selectivity issue is the 14.9° out-of-plane bending of the hydrogens at C2 and C3 of butadiene. The bending is derived from Cl and C4 pyramidalization and rotation inwardly to achieve overlap of p-orbitals on these carbons with the ethylene termini. To keep the tr-bonding between C1-C2 and C3-C4, the p-orbitals at C2 and C3 rotate inwardly on the side of the diene nearest to ethylene. This is necessarily accompanied by C2 and C3 hydrogen movanent toward the attacking dienophile. They proposed that when norbomene is fused at C2 and C3, the tendency of endo bending of the norbomene framework will be manifested in the preference for bottom attack in Diels-Alder reactions (Schane 38). 

Overman, Hehre and coworkers also reported anti tt-facial selectivity in Diels-Alder reactions of the vinylcyclopentenes 73,74 and 4,5-dihydro-3-ethynylthiophen 5 -oxide 75. They attributed the selectivity to destabilizing electronic interaction between the allylic heteroatom and dienophile in the syn attack transition state (Scheme 43) [38],... 

An extensive review of the hetero-Diels-Alder reactions of 1-oxabuta-1,3-dienes has been published. Ab initio calculations of the Diels-Alder reactions of prop-2-enethial with a number of dienophiles show that the transition states of all the reactions are similar and synchronous.Thio- and seleno-carbonyl compounds behave as superdienophiles in Diels-Alder reactions with cyclic and aryl-, methyl-, or methoxy-substituted open-chain buta-1,3-dienes.The intramolecular hetero-Diels-Alder reactions of 4-benzylidine-3-oxo[l,3]oxathiolan-5-ones (100) produce cycloadducts (101) and (102) in high yield and excellent endo/exo-selectivity (Scheme 39). A density functional theoretical study of the hetero-Diels-Alder reaction between butadiene and acrolein indicates that the endo s-cis is the most stable transition structure in both catalysed and uncatalysed reactions.The formation and use of amino acid-derived chiral acylnitroso hetero-Diels-Alder reactions in organic synthesis has been reviewed. The 4 + 2-cycloadditions of A-acylthioformamides as dienophiles have been reviewed. ... 

What the PNS cannot deal with is the effect on reactivity by factors that only operate at the transition state level but are not present in either reactant or product. Examples mentioned in this chapter include transition state aromaticity in Diels Alder reactions, steric effects on reactions of the type A + B ty C + D, or hydrogen bonding/electrostatic effects that stabilize the... 

A DFT study of the polar Diels-Alder reaction of 4-aza-6-nitrobenzofuroxan with cyclopentadiene found only one highly asynchronous transition state structure associated with the formation of the 4 + 2-adduct.178 4-Nitrobenzodifuroxan has been shown to be a highly reactive nitroalkene in Diels-Alder reactions with common dienes (cyclopentadiene) to produce stable NED adducts and with ethyl vinyl ether to produce IED adducts.179 Unlike a-acylfuran, 2-nitrofurans have been shown to be active dienophiles in thermal NED Diels-Alder reactions with a variety of buta-1,3-dienes, including Danishefsky s diene.180... 

Stereospecificity, stereoselectivity and regioselectivity combined in Diels-Alder reactions give unprecedented control and you should now see why it is so important. The analgesic tilidine 47, effective in cases of severe pain, is an obvious Diels-Alder product.8 The regioselectivity is correctly ortho and the endo transition state 51 shows that the trans -enamine 49 is needed. This is the geometry we get when the enamine is made in the normal way from the enal 50 and Me2NH. 

Fig. 6. Controlling stereochemistry and regiochemistry in Diels-Alder reactions by the application of very high pressure. The potential for using elevated pressures to obtain asymmetric induction is based upon exploiting the different volumes of activation between the competing diastereoisomeric transition states [48, 54]. In the first example, a AAV of 0.9 cm3 mol-1 favors the formation of diastereoisomer 15 over diastereoisomer 16 as the pressure is increased. In the second example, the increased ratio of 18 relative to 17 illustrates the importance of pressure variations in the control of regiochemistry...

One characteristic stereochemical feature of the Diels-Alder reaction is endo selectivity. The origin of the endo preference in Diels-Alder reactions can be ascribed to secondary orbital interactions [167]. If the carbonyl functions of dienophilic a -unsaturated carbonyl substrates are effectively shielded by complexation with ATPH, secondary interaction is reduced, thereby disfavoring the hitherto preferred endo transition state (Fig. 2). 

The Stille reaction on 4-bromoisothiazolin-3-one V-oxides 261 (R = Et, (A)-2-C(Me)Ph) affords the vinyl intermediates 262 ( =1), which immediately undergo a Diels-Alder dimerization yielding adducts 263 via an 3co-transition state (see Section 4.05.2.2). As a confirmation of the high reactivity of 262 ( = 1) in Diels-Alder reactions, the oxidation of ethenyl derivative 262 (R = Et, = 0) (see Section 4.05.7.7) affords directly the dimer endo-263. By the same reaction in the presence of A -phenylmaleimide, compound endo-264 is formed <1999T12313>. 

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