Diels-Alder reaction synchronicity

The mechanism of the carbo-Diels-Alder reaction has been a subject of controversy with respect to synchronicity or asynchronicity. With acrolein as the dieno-phile complexed to a Lewis acid, one would not expect a synchronous reaction. The C1-C6 and C4—C5 bond lengths in the NC-transition-state structure for the BF3-catalyzed reaction of acrolein with butadiene are calculated to be 2.96 A and 1.932 A, respectively [6]. The asynchronicity of the BF3-catalyzed carbo-Diels-Alder reaction is also apparent from the pyramidalization of the reacting centers C4 and C5 of NC (the short C-C bond) is pyramidalized by 11°, while Cl and C6 (the long C-C bond) are nearly planar. The lowest energy transition-state structure (NC) has the most pronounced asynchronicity, while the highest energy transition-state structure (XT) is more synchronous. 

Most Diels-Alder reactions, particularly the thermal ones and those involving apolar dienes and dienophiles, are described by a concerted mechanism [17]. The reaction between 1,3-butadiene and ethene is a prototype of concerted synchronous reactions that have been investigated both experimentally and theoretically [18]. A concerted unsymmetrical transition state has been invoked to justify the stereochemistry of AICI3-catalyzed cycloadditions of alkylcyclohexenones with methyl-butadienes [12]. The high syn stereospecificity of the reaction, the low solvent effect on the reaction rate, and the large negative values of both activation entropy and activation volume comprise the chemical evidence usually given in favor of a pericyclic Diels-Alder reaction. 

A concerted and synchronous Diels Alder reaction occurs only with symmetric nonpolar reagents. 

Beno, B. R., Houk, K. N., Singleton, D. A., 1996, Synchronous or Asynchronous An Experimental Transition State from a Direct Comparison of Experimental and Theoretical Kinetic Isotope Effects for a Diels-Alder Reaction , J. Am. Chem. Soc., 118, 9984. 

Such a conclusion is, nevertheless, connected with the synchronous character of the mechanism. If a stepwise process is involved (nonsimultaneous formation of the two new bonds), as for unsymmetric dienes and/or dienophiles or in hetero Diels-Alder reactions, a specific microwave effect could intervene, because charges are developed in the transition state. This could certainly be so for several cycloadditions [47, 48] and particularly for 1,3-dipolar cycloadditions [49]. Such an assumption has... 

These experimental secondary deuterium KIEs observed in Diels-Alder reactions have been compared with the respective theoretical KIEs for the stepwise mechanism involving a diradical intermediate (equation 88a) and for concerted synchronous and asynchronous mechanisms (equation 88b) for the Diels-Alder reaction of butadiene with ethylene207. 

The well-known Diels-Alder reaction [95,104-106] is a standard method for forming substituted cyclohexenes through the thermally allowed 4s + 2s cycloaddition of alkenes and dienes. In particular, the reaction between ethene and 1,3-butadiene to yield cyclohexene is the prototype of a Diels-Alder reaction (Scheme 28.4). It is now well recognized that this reaction takes place via a synchronous and concerted mechanism through an aromatic boatlike TS [105]. 

In a synchronous Diels-Alder reaction, the following facts have come to light about dienes 1. Simple dienes react readily with good dienophiles and they must adopt a cisoid geometry about the bond (s-cis). 

TWo of the monoclonal antibodies produced, 7D4 and 22C8, proved to be completely stereoselective, separately catalysing the endo and the exo Diels-Alder reactions, with a fccat of 3.44 X 10-3 and 3.17 X 10 3 min-1 respectively at 25°C. That the turnover numbers are low was attributed in part to limitations in transition state representation modelling studies had shown that the transition states for both the exo and endo processes were asynchronous whereas both TSAs [61] and [62] were based on synchronous transition states (Gouverneur et al., 1993). 

Mechanistic and theoretical studies of the Diels-Alder reaction have resulted in the characterization of this reaction as a concerted, although not necessarily synchronous, single-step process28-31 45. The parent reaction, the addition of 1,3-butadiene to ethylene yielding cyclohexene, has been the subject of an ongoing mechanistic debate. Experimental results supported a concerted mechanism, whereas results from calculations seemed to be dependent on the method used. Semi-empirical calculations predicted a stepwise mechanism, whereas ab initio calculations were in favor of a concerted pathway. At the end of the 80s experimental and theoretical evidence converged on the synchronous mechanism29-31. 

Fig. 10.11 The stepwise and concerted mechanisms for the Diels-Alder reaction between butadiene and ethylene. The reactants (lower left) proceed to the product, cyclohexene (lower right) either through a two step, two transition state mechanism involving the formation of a diradical intermediate (top center), or more directly through the symmetric synchronous transition state (bottom center) (Storer, J. W., Raimondi, L., and Houk, K. N., J. Am. Chem. Soc. 116, 9675 (1994))...

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. ... 

The gas-phase Diels-Alder reaction between butadiene and ethene follows a synchronous pathway, while the 1,3-dipolar cycloaddition of fulminic acid to ethyne proceeds in a concerted, almost synchronous fashion, in spite of the different nature of the two bonds closing the isoxazole cycle. 

We now turn to the gas-phase 1,3-dipolar cycloaddition of fulminic acid to ethyne. The concerted, almost synchronous nature of this reaction might create the impression that the electronic mechanism of this process should be very similar to that of the Diels-Alder reaction. Such an expectation is reinforced by frontier orbital theory, which treats both reactions in very much the same way (see Ref. 32). The only significant differences are related to the fact that the lowest unoccupied MO (LUMO) for a linear 1,3-dipole... 

More than one mechanism can account for the experimental observation of the Diels-Alder reaction.521,522,528 However, most thermal [4 + 2]-cycloadditions are symmetry-allowed, one-step concerted (but not necessarily synchronous) process with a highly ordered six-membered transition state.529 Two-step mechanisms with the involvement of biradical or zwitterion intermediates can also be operative.522,528... 

Various reaction mechanisms are known for ene reactions. Both single-step synchronous reaction and stepwise processes involving diradicals or zwitterionic transition states have been discussed. One of the three bonds broken in the course of the reaction is a a bond, which dictates a high activation energy relative to a Diels-Alder reaction (see Chapter 2). For this reason if the reaction is conducted thermally, temperatures above 100 C are required. However, the reactivity of the enophile can be increased by addition of a Lewis acid, permitting milder reaction conditions. The Lewis acid coordi-... 

MO calculations at the MP4SDTP/6-311G //MP2/6-311G level on the Diels-Alder reaction of ethylene with l-phosphabut-3-en-l-yne show that the reaction is endothermic compared with the all-carbon case, which is exothermic.249 Ab initio studies have been presented for hetero-Diels-Alder reactions between phosphorus-containing dienes and dienophiles.250 Ab initio calculations on the Diels-Alder reaction between 21 /-phosphole and phosphaethene indicate that the reaction is concerted and synchronous.251 The Diels-Alder reaction between 1,3,5-triphosphabenzene and phosphaacetylene to form tetraphosphabarrelene was studied at the MP4SDQ/6-... 

Very few mechanistic studies have appeared on this subject and Houk group has studied the hetero-Diels-Alder reaction between thioformaldehyde and butadiene475, using ab initio calculations, to show that the reaction is concerted and nearly synchronous. In the case of unsymmetrical dienes, several rules are known to establish the regiochemistry of the cycloadducts1 471. 

The Diels-Alder reaction and related pericyclic reactions, which can be treated qualitatively by the Woodward-Hoffmann rules (Section 4.3.5), have been reviewed in the context of computational chemistry [39]. The reaction is clearly nonionic, and the main controversy was whether it proceeds in a concerted fashion as indicated in Fig. 9.5 or through a diradical, in which one bond has formed and two unpaired electrons have yet to form the other bond. A subtler question was whether the reaction, if concerted, was synchronous or asynchronous whether both new bonds were formed to the same extent as reaction proceeded, or whether the formation of one ran ahead of the formation of the other. Using the CASSCF method (Section 5.4.3), Li and Houk [40] concluded that the butadiene-ethene reaction is concerted and synchronous, and chided Dewar and Jie [41] for stubbornly adhering to the diradical (biradical) mechanism. 

Determination of 13C KIEs on natural abundance was introduced by Singleton. The reaction of isoprene with maleic anhydride was selected to examine the synchronity of the Diels-Alder reaction.45... 

For hetero Diels-Alder reactions it has been shown by calculations that the transition structures are usually less symmetric than for the all-carbon Diels-Alder reactions also a change from a concerted non-synchronous to a stepwise mechanism depending on the substituents at the reacting species and the reaction conditions can occur. 

In order to test this hypothesis, calculations were carried out by various techniques for various models of asynchronous (biradicaloid) and synchronous transition states. The results of these calculations are shown in Figs. 2 and 3s. For the Diels-Alder reaction, the procedure consisted of optimizing the butadiene-ethylene coordinates by MINDO/3 for certain fixed values of r i i and t 2 (Pig- 2). The resulting geometries were than used as input for calculations by the other techniques. For fulminic acid-ethylene, the Poppinger transition state was chosen as the mid-point, and rcc and rco were varied, while the fulminic acid and acetylene fragments were held fixed. Operationally, this variation was carried out by a variation in a (Fig. 3). 

In a synchronous Diels-Alder reaction, the following facts have come to light about dienes ... 

It is clear from the above figures that the activated complex is not much more dipolar than the initial state. Neutral reactants produce a neutral product in a single, concerted, often synchronous step. Although dienes and dienophiles may have a dipole moment, these dipoles are usually incorporated unchanged into the product, and there is no reason to believe that they increase or decrease greatly during the reaction. The small solvent effects observed are in agreement with this picture of the Diels-Alder reaction. 

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