Advanced Organic Chemistry - Reaction Mechanisms by Reinhard Bruckner (z-lib.org)

12.3 Diels–Alder Reactions 495 NC CN Fig. 12.21. Diels–Alder NC CN reactions with normal Do electron demand; reactivity Do increase by the use of donor-substituted 1,3- dienes (Do refers to a donor substituent). Do (NC)2 (NC)2 Do (NC)2 (NC)2 (NC)2 (NC)2 k2 + 4, rel Do = Me Ph OMe Do = Me Ph OMe ≡ 1 44 191 1 720 104 386 50 900 An increase in reactivity also can be observed in Diels–Alder reactions with normal electron demand if a given dienophile is reacted with a series of more and more electron-rich dienes. The reaction rates of the Diels–Alder reactions of Figure 12.21 show that the substituents MeO Ͼ Ph Ͼ alkyl are such reactivity-enhancing donors. The tabulated rate constants also show that a given donor substituent accelerates the Diels–Alder reaction more if located in position 1 of the diene than if located in po- sition 2. Diels–Alder reactions also may occur when the electronic situation of the substrates is completely reversed, that is, when electron-rich dienophiles react with electron-poor dienes. [4ϩ2]-Cycloadditions of this type are called Diels–Alder reactions with inverse electron demand. 1,3-Dienes that contain heteroatoms such as O and N in the diene backbone are the dienes of choice for this kind of cycloaddition. The data in Figure 12.22 show the rate-enhancing effect of the presence of donor substituents in the dienophile. Why do the Diels–Alder reactions with both normal and inverse electron demand occur under relatively mild conditions? And, in contrast, why can [2ϩ4]-cycloadditions between ethene or acetylene, respectively, and butadiene be realized only under ex- tremely harsh conditions (Figure 12.1)? Equation 12.2 described the amount of tran- sition state stabilization of [4ϩ2]-cycloadditions as the result of HOMO/LUMO in- teractions between the p MOs of the diene and the dienophile. Equation 12.3 is derived from Equation 12.2 and presents a simplified estimate of the magnitude of the stabi- lization. This equation features a sum of two simple terms, and it highlights the essence better than Equation 12.2. 11 ¢ETS r EHOMO, diene Ϫ ELUMO, dienophile ϩ EHOMO, dienophile Ϫ ELUMO, diene (12.3) The first term of Equation 12.3 is responsible for most of the transition state stabi- lization of a Diels–Alder reaction with normal electron demand. In this case, the first term is larger than the second term because the denominator is smaller. The denomi-

496 12 Thermal Cycloadditions Fig. 12.22. Diels–Alder CO2Me N CO2Me reactions with inverse N electron demand; CO2Me k2 + 4 NN N reactivity increase by the NN MeO2C N use of donor-substituted NN dienophiles (X refers to a +N N ≡ H substituent that may be a donor or an acceptor). X CO2Me X CO2Me X (products undergo subsequent reactions) X O2N H MeO k2 + 4, rel 0.13 ≡ 1 3.8 Fig. 12.23. Frontier orbital nator of the first term is smaller because the HOMO of an electron-rich diene is closer interactions in Diels–Alder to the LUMO of an electron-poor dienophile than is the LUMO of the same electron- reactions with varying rich diene with respect to the HOMO of the same electron-poor dienophile (Figure electron demand. 12.23, column 2). Acceptors lower the energy of all p-type MOs irrespective of whether Stabilizing frontier orbital interactions in the transition states of Diels–Alder reactions with... ... normal ... ... unbalanced ... ... inverse ... i.e., + CO2Me ... electron demand NC CN i.e., N N i.e., + Ph + N NC CN N CO2Me Eπ LUMOs HOMOs 1 large in magnitude small in magnitude small in magnitude E(HOMOdiene) – E(LUMOdienophile) small in magnitude small in magnitude large in magnitude is thus negative and ... 1 E(HOMOdienophile) – E(LUMOdiene) is thus negative and ...

12.3 Diels–Alder Reactions 497 these MOs are bonding or antibonding. This is all the more true the stronger the sub- stituent effects and the more substituents are present. The most important stabilizing interaction of the transition states of Diels–Alder re- actions with inverse electron demand is due to the second term of Equation 12.3. 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 12.3, column 4). We saw the reason for this pre- viously: acceptors lower the energies of all p-type MOs; donors increase these energies. The transition states of Diels–Alder reactions with either normal or inverse elec- Summary tron 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. In the Diels–Alder reactions between ethene and butadiene and between acetylene and butadiene, respectively, the HOMOs are nearly isoenergetic and they are rather far away from the LUMOs (Figures 12.8 and 12.9). According to Equation 12.3, the transition states of these Diels–Alder reactions experience only a minor stabilization and, for this reason, these [2ϩ4]-cycloadditions (Figure 12.23, column 3) are so much slower than the others (columns 2 and 3). 12.3.3 Orientation Selectivity of Diels–Alder Reactions Diels–Alder reactions with symmetrically substituted dienophiles and/or with sym- metrically substituted dienes afford cycloadducts that must be constitutionally homo- geneous. In contrast, Diels–Alder reactions between an asymmetrically substituted dienophile and an asymmetrically substituted diene may afford two constitutionally isomeric cycloadducts. If only one of these isomers is actually formed, the Diels–Alder reaction is said to be orientation selective. 1,3-Butadienes with alkyl substituents in the 2-position favor the formation of the so-called para products (Figure 12.24, X ϭ H) in their reactions with acceptor- substituted dienophiles. The so-called meta product is formed in smaller amounts. This orientation selectivity increases if the dienophile carries two geminal acceptors (Figure 12.24, X ϭ CN). 2-Phenyl-1,3-butadiene exhibits a higher “para” selectivity 2 + Fig. 12.24. Orientation- NC selective Diels–Alder + 20°C X reactions with a 2- NC substituted 1,3-diene I: comparison of the effects NC X exerted by one or two X dienophile substituents. “para product” “ meta product” X = H: 70 : 30 X = CN: 91 :9

498 12 Thermal Cycloadditions Fig. 12.25. Frontier orbital Eπ + coefficients and energy NC NC difference of the HOMO–LUMO gaps in + 0.66 (LUMO) (LUMO) + 0.55 orientation-selective – 0.54 + 0.56 Diels–Alder reactions (cf. ∆E = 204 ∆E = 270 Figure 12.24, X ϭ H). kcal/mol + 0.60 (HOMO) + 0.63 (HOMO) – 0.49 + 0.49 NC in its reactions with every asymmetric dienophile than any 2-alkyl-1,3-butadiene does. This is even more true for 2-methoxy-1,3-butadiene and 2-(trimethylsilyloxy)- 1,3-butadiene. Equation 12.2, 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. One can compute, for example, the stabilizations ⌬ETS for the transition states of the “para”- and “meta”-selective cycloadditions, respectively, of acrylonitrile and iso- prene according to Equation 12.2 with the data provided in Figure 12.25 (HOMO/LUMO gaps, LCAO coefficients at the centers that interact with each other). The result for the Diels–Alder reaction of Figure 12.24 is shown in Equations 12.4 and 12.5: ⌬ETS→“para product” ϰ Ϫ0.0036 kcal/mol (63% of which is due to the HOMOdiene/LUMOdienophile interaction) (12.4) ⌬ETS→“meta product” ϰ Ϫ0.0035 kcal/mol (61% of which is due to the HOMOdiene/LUMOdienophile interaction) (12.5) The transition state leading to the “para” product is slightly more stabilized, and ac- cordingly this product is favored. However, the 70 : 30 selectivity shows the preference to be small, as one would anticipate based on the minuscule energy difference com- puted by means of Equations 12.4 and 12.5. The same kind of computation can be carried out for the substrate pair consisting of isoprene and 1,1-dicyanoethene. Based on the HOMO/LUMO gaps and with the LCAO coefficients at the centers that interact with each other (see Figure 12.26), Equa- tion 12.2 again gives a higher stabilization ⌬ETS for the “para” transition state than for the “meta” transition state (Equations 12.6 and 12.7). ⌬ETS→“para product” ∝ Ϫ0.0038 kcal/mol (67% of which is due to the HOMOdiene/LUMOdienophile interaction) (12.6) ⌬ETS→“meta product” ∝ Ϫ0.0036 kcal/mol (66% of which is due to the HOMOdiene/LUMOdienophile interaction) (12.7) This difference between the stabilization energies is a bit larger than in the case of the addition of acrylonitrile to isoprene (Equations 12.4 and 12.5). This agrees with the

12.3 Diels–Alder Reactions 499 + Fig. 12.26. Frontier orbital coefficients and energy NC C N difference of the HOMO–LUMO gaps in Eπ + 0.66 + 0.55 orientation-selective NC (LUMO) Diels–Alder reactions (cf. NC Figure 12.24, X ϭ CN). – 0.49 (LUMO) + 0.56 CN ∆E = 169 ∆E = 281 kcal/mol + 0.61 + 0.63 (HOMO) (HOMO) + 0.45 – 0.49 CN data in Figure 12.24, which show a“para/meta” selectivity of 91 : 9 for the addition of 1,1-dicyanoethene to isoprene—i.e., somewhat higher than the 70 : 30 ratio of the ad- dition involving acrylonitrile. From Equation 12.2 one may derive the following general rules concerning the ori- entation selectivity of any one-step cycloaddition. The substrates preferentially bind each other with those atoms that exhibit the Rules for the largest LCAO coefficients (absolute values) in the closest pair of frontier orbitals. Orientation Selectivity The orientation selectivity generally increases, the larger the relative significance of of Any One-Step one HOMO/LUMO interaction compared to the other and the greater in each of Cycloaddition the two crucial frontier orbitals the difference in magnitude of the LCAO coeffi- cients (absolute values) at one terminus, compared to the other. We can customize these general statements specifically for the case of the orientation selectivity of Diels–Alder reactions with normal electron demand and make the fol- lowing statement right away: The LCAO coefficient in the HOMO of a 1,3-diene • increases at C1 compared to C4, the better the donor in position 2, • increases at C4 compared to C1, the better the donor in position 1, and • is larger at C4 than at C1 when the same kind of donor is attached both to positions 1 and 2. The consequences thereof for the orientation selectivity of Diels–Alder reactions can be summarized as follows. Asymmetric dienophiles react with 1-donor-, 2-donor-, or 1,2-didonor-substituted Orientation Selectivity 1,3-dienes, preferentially to the “ortho,” “para,” or “ortho,meta” cycloadduct, re- of Diels–Alder spectively. With regard to a given dienophile, the “ortho” selectivity is larger than Reactions the “para” selectivity. Comparison of the upper and the lower pairs of reactions in Figures 12.27 and 12.28 underscores the latter statement.

500 12 Thermal Cycloadditions We go on to state that the LCAO coefficient in the LUMO of a dienophile • increases at C2 in comparison to C1, the more acceptors are bound to C1 [cf. the LCAO coefficients of acrylonitrile (Figure 12.25) compared to those of 1,1-dicya- noethene (Figure 12.26)] and • increases at C2 in comparison to C1, the stronger the acceptor that is attached to C1. What has just been stated regarding the LCAO coefficients of the dienophile LUMO combined with the “rules for the orientation selectivity of any one-step cycloaddition” leads to the following consequences for the Diels–Alder reactions of isoprene: 1) Acrylonitrile shows less “para” selectivity in its addition to isoprene than in its ad- dition to 1,1-dicyanoethene (Figure 12.24). 2) Acrylic acid esters show less “para” selectivity in their additions to isoprene than do AlCl3-complexed acrylic acid esters (Figure 12.27; the complex formation with AlCl3 converts the CO2Me group into a better acceptor than the uncomplexed CO2Me-group). The increase in orientation selectivity of Diels–Alder reactions upon addition of Lewis acid has a second cause aside from the one which was just mentioned. The reaction con- ditions described in Figure 12.27 indicate that AlCl3 increases the rate of cycloaddition. The same effect also was seen in the cycloaddition depicted in Figure 12.20. In both in- stances, the effect is the consequence of the lowering of the LUMO level of the dienophile. According to Equation 12.2, this means that the magnitude of the denomi- nator of the first term decreases and the first term therefore becomes larger than the second term. If, in addition, the numerators of these terms differ by a certain amount for the “para” and “meta” transition states (as determined by the combinations of the LCAO coefficients), the effect is further enhanced. This also increases the “para” selectivity. Fig. 12.27. Orientation- + + selective Diels–Alder MeO2C reactions with a 2- MeO2C MeO2C substituted diene II: selectivity increase by way “para product” “ meta product” of addition of a Lewis acid. 25°C, 41 d: 70 : 30 10–20°C, 1 mol% AlCl3, 3 h: 95 : 5 Finally, the examples of the two Diels–Alder reactions in Figure 12.27 lead us to a general statement: in Diels–Alder reactions with normal electron demand, the addi- tion of AlCl3 increases the reaction rate and the orientation selectivity. This situation marks one of the most notable exceptions from the reactivity–selectivity principle (Sec- tion 1.7.4), which is otherwise so often encountered in organic chemistry. 12.3.4 Simple Diastereoselectivity of Diels–Alder Reactions We saw in Section 12.3.3 that 1,3-butadienes with a donor in the 1-position react with ac- ceptor-substituted alkenes to form cycloadducts with high “ortho” selectivity. The amount

12.3 Diels–Alder Reactions 501 + + Fig. 12.28. Orientation MeO2C selectivity and simple MeO2C MeO2C diastereoselectivity of a Diels–Alder reaction with “ortho product” “meta product” a 1-substituted diene; selectivity increase by way {25°C, 70 d: 90 : 10 of addition of a Lewis (cis : trans = 57 : 43) (cis : trans = 73 : 27) acid. {10–20°C, 10 mol% AlCl3, 3 h: 98 : 2 (cis : trans = 95 : 5) (mainly cis) of “meta” products formed is usually less than 10% (see example, Figure 12.28). This is particularly true for Diels–Alder reactions that are carried out in the presence of AlCl3, which has the same effect of enhancing the orientation selectivity as seen in Figure 12.27. Here we are primarily concerned with the fact that this almost exclusively formed “or- tho” adduct may occur in the form of two diastereomers. The diastereomers are formed as a 57 : 43 cis/trans mixture in the absence of AlCl3, but a 95 : 5 cis/trans mixture is ob- tained in the presence of AlCl3. In the latter case, thus, one is dealing with a Diels–Alder reaction that exhibits a substantial “simple diastereoselectivity” (see Section 9.3.2 for a definition of the term). Here, the simple diastereoselectivity is due to kinetic rather than thermodynamic control, since the preferentially formed cis-disubstituted cyclo- hexene is less stable than its trans isomer. Simple diastereoselectivity may also occur in Diels–Alder reactions between electron-poor dienophiles and cyclopentadiene (Figure 12.29). Acrylic acid esters or trans-crotonic acid esters react with cyclopentadiene in the presence or absence of AlCl3 with substantial selectivity to afford the so-called endo adducts. When the bi- cyclic skeleton of the main product is viewed as a “roof,” the prefix “endo” indicates that the ester group is below this roof, rather than outside (exo). However, methacrylic acid esters add to cyclopentadiene without any exo,endo selectivity no matter whether the reaction is carried out with or without added AlCl3. R2 30°C R2 H R1 + MeO2C + R1 CO2Me CO2Me R2R1 R1 R2 endo product exo product HH 7.5 h: 78 : 22 1 equivalent AlCl3, 30 min: 95 : 5 H Me 7.5 h: 54 : 46 Fig. 12.29. Simple 1 equivalent AlCl3, 30 min: 94 : 6 diastereoselectivity of the additions of various acrylic Me H 7.5 h: 31 : 69 acid derivatives to 1 equivalent AlCl3, 30 min: 60 : 40 cyclopentadiene.

502 12 Thermal Cycloadditions Fig. 12.30. Transition state H H ≈ 10° structures of Diels–Alder H 34 H additions of butadiene; A, 2 H1 H ≈ 15° side view of the addition H 27° of acrylic acid ester and B, H 21 Newman projection of the 1′ addition of ethene. HH H 2′ H ≈ 15° RO 1′ H O A B The high simple diastereoselectivities seen in Figures 12.28 and 12.29 are due to one and the same preferential orientation of the ester group in the transition states. The stereostructure of the cycloadduct shows unequivocally that the ester group points un- derneath the diene plane in each of the transition states of both cycloadditions and not away from that plane. Figure 12.30 exemplifies this situation for two transition states of simple Diels–Alder reactions of 1,3-butadiene: A shows a perspective draw- ing of the transition state of the acrylic acid ester addition, and B provides a side view of the addition of ethene, which will serve as an aid in the following discussion. Both structures were determined by computational chemistry. One has not identified with certainty the origin(s) for the preference of stereo- structure A in the acrylic acid ester addition. Possibly a steric effect explains the ob- servation. The bulky acceptor substituent of the dienophile might be less hindered— and this is quite counterintuitive—in the endo orientation in the transition state shown in Figure 12.30 than in the alternative exo position. One might interpret the better known geometry of the transition state without an acceptor, B, to suggest that the sub- stituent of the dienophile in A does not try to avoid the C atoms C2 and C3 as much as it tries to stay away from the H atoms cis-H1 and cis-H4. The increase of endo se- lectivity upon addition of a Lewis acid could then be explained by the premise that the complexing Lewis acid renders the ester group more bulky. This increased steric demand enhances its desire to avoid the steric hinderance in its exo position. 12.4 [2ϩ2]-Cycloadditions with Dichloroketene Only a few ketenes can be isolated, and diphenylketene is one of those. The majority of the other ketenes dimerize quickly, as exemplified by the parent ketene H2C“C“O. Cycloadditions with reactive ketenes therefore can be observed only when they are prepared in situ and in the presence of the alkene to which they shall be added. Dichloroketene generated in situ is the best reagent for intermolecular [2ϩ2]- cycloadditions. Dichloroketene is poorer in electrons than the parent ketene and there- fore more reactive toward the relatively electron-rich standard alkenes. The reason is that the dominating frontier orbital interaction between these reactants involves the LUMO of the ketene, not its HOMO (see Section 12.2.4).

12.4 [2ϩ2]-Cycloadditions with Dichloroketene 503 Cl O in situ with NEt3 O Fig. 12.31. Orientation- (basic b-elimination) 1+ selective [2ϩ2]- b cycloaddition with in situ 2 generated dichloroketene H Cl I: the dichloroketene is Cl Cl Cl generated by way of an NEt3-mediated b- O for example O elimination of HCl from H NaOAc, HOAc Cl dichloroacetyl chloride. Cl O The first of the two common preparations of dichloroketene, shown in Figure 12.31, consists of an NEt3-mediated b-elimination of HCl from dichloroacetyl chloride. In- terestingly, dichloroketene does not participate as a dienophile in a Diels–Alder reaction with cyclopentadiene (Figure 12.31), preferring instead a [2ϩ2]-cycloaddition. The [2ϩ2]-cycloaddition occurs with perfect orientation selectivity. The preferred tran- sition state is in line with the rule of thumb formulated in Section 12.3.3 for the ori- entation selectivity of one-step cycloadditions in general. The preferred transition state is the one in which the atoms that have the largest LCAO coefficients (absolute val- ues) in the closest frontier orbitals are connected together. Figure 12.13 shows that the relevant frontier orbital pair includes the LUMO of dichloroketene and the HOMO of cyclopentadiene. The carbonyl carbon possesses the largest LCAO coefficient in the LUMO of dichloroketene (Figure 12.12). The largest LCAO coefficient in the HOMO of cyclopentadiene is located at C1, not at C2, since cyclopentadiene is a 1,3-butadi- ene that bears an alkyl substituent both at C1 and C4 (cf. discussion of the effects of alkyl substituents on the HOMO coefficients of 1,3-dienes in Section 12.3.3). Hence, the carbonyl carbon of the dichloroketene binds to C1 of cyclopentadiene in the most stable transition state of the [2ϩ2]-cycloaddition. Figure 12.32 shows the second commonly employed method for the generation of dichloroketene, which involves the reductive b-elimination of chlorine from trichloroacetyl chloride by zinc (cf. Sections 4.7.1 and 14.4.1 for mechanistic considerations). The ad- dition of the dichloroketene to the trisubstituted alkene A (Figure 12.32) exhibits ori- Cl O in situ with Zn/Cu, POCl3 HO Fig. 12.32. Orientation- (reductive b-elimination) b+ selective and b diastereoselective [2ϩ2]- a cycloaddition with in situ Cl Cl generated dichloroketene Cl H Cl Cl II: the dichloroketene is A generated by way of a reductive b-elimination of HO chlorine from trichloroacetyl chloride. Cl H Cl

504 12 Thermal Cycloadditions entation selectivity. The carbonyl carbon of the dichloroketene is connected to that C atom of the olefinic C“C double bond, which has the larger LCAO coefficient in the alkene HOMO. This C atom is marked with a b. This [2ϩ2]-cycloaddition also shows diastereoselectivity. The alkene can add to the bicyclic alkene A only from the more accessible convex side (cf. Section 8.3.1 regarding the kinetic advantage of reactions on the convex sides of convex/concave molecules). 12.5 1,3-Dipolar Cycloadditions 12.5.1 1,3-Dipoles A 1,3-dipole is a compound of the type a—Het—b that may undergo 1,3-dipolar cy- cloadditions with multiply bonded systems and can best be described with a zwitter- ionic all-octet Lewis structure (“Huisgen ylid”). An unsaturated system that under- goes 1,3-dipolar cycloadditions with 1,3-dipoles is called dipolarophile. Alkenes, alkynes, and their diverse hetero derivatives may react as dipolarophiles. Since there is a considerable variety of 1,3-dipoles—Table 12.2 shows a small selection—1,3- dipolar cycloadditions represent not only a general but also the most universal syn- thetic approach to five-membered heterocycles. Table 12.2. Important 1,3-Dipoles 1,3-dipoles of the 1,3-dipoles of the propargyl/allenyl anion type allyl anion type NNC NNC O O OO OO diazoalkane ozone C NO C NO O O CO CO nitrile oxide carbonyl oxide N NN N NN azide N NN azide ion cf. C C C CCC cf. C C CC CC

12.5 1,3-Dipolar Cycloadditions 505 1,3-Dipoles are isoelectronic either to both propargyl and allenyl anions or to allyl anions. One may thus group these 1,3-dipoles into 1,3-dipoles of the propargyl/allenyl anion types (Table 12.2, left) and 1,3-dipoles of the allyl anion type (Table 12.2, right). The 1,3-dipoles of the propargyl/allenyl anion type contain a linearly coordinated cen- tral atom, as is the case for propargyl and allenyl groups in all sorts of compounds. The linearly coordinated central atom of these 1,3-dipoles is an N atom. This N atom car- ries a formal positive charge in both all-octet resonance forms. This central N atom is connected to C and/or to other heteroatoms, and these carry—one in each of the res- onance forms—the formal negative charge. The azide ion is the only 1,3-dipole of the propargyl/allenyl anion type with a net negative charge. 1,3-Dipoles of the allyl anion type are bent just like allyl anions. The central atom can be an N, O, or S atom, and this atom carries a formal positive charge in both all- octet resonance forms. Centers 1 and 3 of the 1,3-dipole of the allyl anion type carry the formal negative charge, again one in each of the resonance forms. As with the dipoles of the propargyl/allenyl anion type, this negative charge may be located on C atoms and/or on heteroatoms. 12.5.2 Frontier Orbital Interactions in the Transition States of One-Step 1,3-Dipolar Cycloadditions; Sustmann Classification Diazomethane adds to ethene to form ⌬1-pyrazoline (A in Figure 12.33). Its addition to acetylene first leads to the formation of the nonaromatic 3-H-pyrazole (B in Figure 12.33), which subsequently is converted into the aromatic 1-H-pyrazole (C) by way of a fast 1,5-hydrogen migration. Do the transition states of the 1,3-dipolar cycloadditions with diazomethane bene- fit from a stabilizing frontier orbital interaction? Yes! Computations show that the HOMOdiazomethane/LUMOethene interaction (orbital energy difference, Ϫ229 kcal/mol) stabilizes the transition state of the 1,3-dipolar cycloaddition to ethene (Figure 12.34) by about 11 kcal/mol. Moreover, computations also show that the HOMOethene/ LUMOdiazomethane interaction (orbital energy difference, Ϫ273 kcal/mol) contributes a further stabilization of 7 kcal/mol. H2C H2C HH N+ N+ N room temperature N N room temperature N N N B A ~H HN Fig. 12.33. The simplest N 1,3-dipolar cycloadditions C with diazomethane.

506 12 Thermal Cycloadditions H NN H Fig. 12.34. Frontier orbital H NN interactions in the H HH transition state of the 1,3- HH dipolar cycloaddition of HH diazomethane to ethene. HH HOMOdiazomethane /LUMOethene LUMOdiazomethane /HOMOethene E(HOMOdiazomethane) – E(LUMOethene) E(HOMOethene) – E(LUMOdiazomethane) = – 229 kcal/mol = – 273 kcal/mol Frontier orbital interactions are stabilizing the transition states of all the 1,3-dipolar cycloadditions. It is for this reason that one-step 1,3-dipolar cycloadditions are gener- ally possible and, aside from some exotic exceptions, one does indeed observe one- step reactions. As in the case of Diels–Alder reactions or of [2ϩ2]-cycloadditions of ketenes, the rate of 1,3-dipolar cycloadditions is affected by donor and acceptor substituents in the substrates. Again, Equation 12.2 can be used to obtain a good approximation of their effects, since this equation applies to any one-step cycloaddition. We restated this equa- tion once before as the approximation expressed in Equation 12.3. In that case, it was our aim to understand the rate of Diels–Alder reactions, and we are now faced with the task of making a statement concerning the rate of 1,3-dipolar cycloadditions. To this end it is advantageous to employ a different approximation to Equation 12.2, and that approximation is expressed in Equation 12.9. ¢ETS r 1 ϩ 1 (12.9) EHOMO,dipole Ϫ ELUMO,dipolarophile EHOMO,dipolarophile Ϫ ELUMO,dipole This approximation again is a crude one, but it allows one to recognize the essentials more clearly. • According to Equation 12.9, the transition state of a 1,3-dipolar cycloaddition is more stabilized and the reaction proceeds faster, the closer the occupied and the unoccu- pied frontier orbitals are to each other. • Especially fast 1,3-dipolar cycloadditions can be expected whenever the HOMOdipole/ LUMOdipolarophile interaction is particularly strong. In this case, the denominator of the first term in Equation 12.9 will be rather small, which makes the first term large. This scenario characterizes the so-called Sustmann type I additions (Figure 12.35, column 2). • Especially fast 1,3-dipolar cycloadditions also can be expected whenever the de- nominator of the second term is very small, so that the magnitude of the second term is high. This scenario characterizes the so-called Sustmann type III additions. Therein, it is essentially the HOMOdipolarophile/LUMOdipole interaction which stabi- lizes the transition state (Figure 12.35, column 4). • Sustmann type II additions occur whenever both terms of Equation 12.9 contribute to a similar (and small) extent to the stabilization of the transition state of 1,3-cycloadditions. These reactions correspondingly represent a reactivity minimum.

12.5 1,3-Dipolar Cycloadditions 507 Stabilizing frontier orbital interactions in the transition states of III 1,3-dipolar cycloadditions of the Sustmann type ... I II MeO2C CO2Me MeO2C CO2Me MeO2C CO2Me Do Examples: N+ EWG N+ N N N+ Eπ LUMOs N HOMOs 1 large in magnitude small in magnitude small in magnitude E(HOMOdipole) – E(LUMOdipolarophile) small in magnitude small in magnitude large in magnitude is thus negative and ... 1 E(HOMOdipolarophile) – E(LUMOdipole) is thus negative and ... Some 1,3-dipoles possess HOMO and LUMO energies that allow for fast Sustmann Fig. 12.35. Frontier orbital type I additions with electron-poor dipolarophiles and for fast Sustmann type III ad- interactions of 1,3-dipolar ditions with electron-rich dipolarophiles. In reactions with dipolarophiles with inter- cycloadditions with varying mediate electron density, such dipoles merely are substrates of the much slower Sust- electron demands. mann type II additions. A plot of the rate constants of the 1,3-dipolar cycloadditions of such dipoles as a function of the HOMO energy of the dipolarophiles—or as a func- tion of their LUMO energy that varies with the same trend—then has a U-shape. One such plot is shown in Figure 12.36 for 1,3-dipolar cycloadditions of diazomalonates. 12.5.3 1,3-Dipolar Cycloadditions of Diazoalkanes The simplest 1,3-dipolar cycloadditions of diazomethane were presented in Figure 12.33. Diazomethane is generated from sulfonamides or alkyl carbamates of N-nitrosomethylamine. The preparation shown in Figure 12.37 is based on the commercially available para-toluenesulfonylmethylnitrosamide (Diazald). In a basic medium, this amide forms a sulfonylated diazotate A by way of a [1,3]-shift, which then undergoes a base-mediated 1,3-elimination (cf. Section 4.1.1).

508 12 Thermal Cycloadditions Me O2C NN N Me O2C + Fig. 12.36. Rate constants of 1,3-dipolar ab cycloadditions of diazomalonic ester as a k110°C function of the HOMO or LUMO energies, respectively, of the dipolarophile. log k110°C N MeO2C N N MeO2C a b O CO2Bu N CN CO2Me N Me O2C Ph Me O2C CO2Me Oct CO2Me OBu increasing HOMO-energy of the dipolarophile and also increasing LUMO-energy of the dipolarophile Diazomethane is an electron-rich 1,3-dipole, and it therefore engages in Sustmann type I 1,3-dipolar cycloadditions. In other words, diazomethane reacts with acceptor- substituted alkenes or alkynes (e.g., acrylic acid esters and their derivatives) much faster than with ethene or acetylene (Figure 12.33). Diazomethane often reacts with asymmetric electron-deficient dipolarophiles with orientation selectivity, as exempli-

12.5 1,3-Dipolar Cycloadditions 509 H SO2Tol K OH in H – OTs H2C N N Fig. 12.37. Preparation of H2C N N O aq. EtOH H2C N N O3STol diazomethane by way of a 1,3-elimination. Diazald A fied in Figure 12.38 for the case of the 1,3-dipolar cycloaddition between diazomethane and the methyl ester of 2-methyl-2-butenoic acid. This 1,3-dipolar cycloaddition also shows stereoselectivity. From the trans-configured ester the trans-configured cycloadduct is formed with a diastereoselectivity exceeding 99.997 : 0.003. This finding provides compelling evidence that this cycloaddition occurs in a single step. If the reaction were a two-step process, either dipole A or biradical C would occur as an intermediate. None of the intermediates would have to possess ex- actly the conformations shown in Figure 12.38, but the conformation depicted certainly is correct in one detail: the trans configuration of the 2-methyl-2-butenoic acid moiety is initially conserved. The reactive intermediates A and C could be so short-lived that they cyclize ex- tremely fast. They certainly could cyclize so fast that the trans configuration of the 2-methyl-2-butenoic acid moiety by and large is carried over into the cycloadduct. Intermediates A and C would therefore hardly have enough time to isomerize to con- formers B and D, respectively, by way of a rotation about the C—C single bond be- tween the two C atoms that used to be connected by a configurationally stable C“C H N < 0.003% N H NN N, H N CO2Me + H CO2Me trans cis H CO2Me N at least a few dipoles N OMe N make use of the opportunity N H for rotation O O OMe H A B Fig. 12.38. Orientation- selective and N at least a few diradicals N stereoselective 1,3-dipolar N make use of the opportunity cycloaddition of N diazomethane. The trans- H for rotation O configured 2-methyl-2- O butenoic acid is converted OMe to the trans-configured C cycloadduct with a OMe H diastereoselectivity of better than 99.997 : 0.003. D

510 12 Thermal Cycloadditions Fig. 12.39. Preparation of double bond in the starting ester. However, it seems unbelievable that not even as lit- diazomalonic ester via tle as 0.003% of either of the potential intermediates would have an opportunity to diazo group transfer rotate. The resulting isomerized intermediates B and D would then have cyclized to according to Regitz. give the cis-cycloadduct about as fast as the original intermediates A and C would be assumed to give the trans-cycloadduct. Hence, for a multistep course of the 1,3- dipolar cycloaddition of Figure 12.38, one would expect more cis-cycloadduct to form than the amount (Ͻ 0.003%) that actually occurs. Diazomalonic ester is another important 1,3-dipole for synthesis. We saw the kinet- ics of 1,3-dipolar cycloadditions of diazomalonic ester earlier, in the discussion of Fig- ure 12.36. The preparation of this 1,3-dipole is accomplished most conveniently with the procedure shown in Figure 12.39: diazo group transfer according to Regitz. O HNEt2 O N N N SO2Tol Me O O Me O Me O Me O H Me O Me O N N N SO2Tol O O O ~H O O O O NN+ H H H N S Tol N S Tol O N N N SO2Tol Me O OO Me O Me O Me O O O H N S Tol O 12.5.4 1,3-Dipolar Cycloadditions of Nitrile Oxides Nitrile oxides have the structure R—C‚Nϩ—OϪ or Ar—C‚Nϩ—OϪ. Aliphatic ni- trile oxides usually can be prepared only in situ, while the analogous aromatic com- pounds, which are resonance-stabilized, generally can be isolated. The most common preparation of nitrile oxides is the dehydration of aliphatic nitro compounds. Figure 12.40 shows in detail how this dehydration can be effected by the reaction of ni- troethane with a mixture of NEt3 and Ph—N“C“O. NEt3 deprotonates a fraction of the nitro compound to give the nitronate A. One of its negatively charged O atoms adds to the C“O double bond of the isocyanate and the negatively charged adduct D is formed. This mode of reaction is reminiscent of the addition of carboxylic acids, alcohols, or water to isocyanates (Section 7.1). Adduct D undergoes a b-elimination of phenyl carbamate. This elimination proceeds via a cyclic transition state that resembles the transition state of the Chugaev reaction (Figure 4.13). The nitrile oxide is formed and immediately adds to the trans-butene, which must be