Archive for November, 2008

C1-C5 cyclization of enediynes – Alternative to the Bergman reaction

Cyclization of enediynes is thoroughly discussed in Chapter 3.3 of my book. The reaction that started all the excitement is the C1-C6 cyclization (the Bergman cyclization, Reaction 1). Meyers and Saito then proposed the alternative C2-C7 cyclization (Reaction 2), and a variant on this, the Schmittel cyclization (Reaction 3) followed soon thereafter. Now, Pascal completes the theme with a report on the C1-C5 cyclization (Reaction 4).1

Pascal begins with the assumption that terminal aryl substitution on the enediyne will both (a) inhibit the C1-C6 cyclization due to steric interactions and (b) the C1-C5 cyclization should be enhanced due to stabilization of the radical by the neighboring aryl group. He computed the activation energies of a series of analogues, some of which are listed in Table 1. The transition state structures are shown in Figure 1 for 1b and 1c. Phenyl substitution does accomplish both suggestions: the activation barrier for the Bergman cyclization increases by 4 kcal mol-1, while the barrier for the C1-C5 cyclization is lowered by nearly 6 kcal mol-1. Further substitution of the phenyl ring by either chloro or methyl groups brings the barriers into near degeneracy.

Table 1. RBLYP/6-31G(d) Activation energies (kcal mol-1) for
competing cyclization reactions of substituted enediynes.1

R

R’

Ea(C1-C6)

Ea(C1-C5)

H (1a)

H

24.6

37.2

Phenyl (1b)

H

28.7

31.4

2,6-dichlorophenyl (1c)

H

30.8

31.6

2,6-dimethylphenyl (1d)

H

30.5

30.9

Phenyl (2a)

Phenyl

38.5
(32.9)a

36.3
(35.1)a

2,4,6-trichlorophenyl (2b)

2,4,6-trichlorophenyl

43.2

38.7

aComputed at BCCD(T)/cc-pVDZ//-BLYP/6-31G(d).

C1-C5 TS of 1b

C1-C6 TS of 1b

C1-C5 TS of 1c

C1-C6 TS of 1c

Figure 1. RBLYP/6-31G(d) optimized geometries of the C1-C5 and C1-C6 transition states for 1b and 1c.1

The di-substituted enediynes were examined next. The C1-C5 and C1-C6 transition states for the phenyl (2a) analogue are shown in Figure 2, and the activation energies for it and the 2,4,6-trichlorophenyl (2b) analogue are listed in Table 1. With BLYP, the C1-C5 cyclization is favored by a significant amount over the Bergman cyclization. This may be an overestimation as the BCCD(T)/cc-pVDZ//-BLYP/6-31G(d) computations predict the opposite energy ordering.

C1-C5 TS of 2a

C1-C2 TS of 2a

Figure 1. RBLYP/6-31G(d) optimized geometries of the C1-C5 and C1-C6 transition states for 2a.1

Pascal synthesized 2b and subjected it to thermolysis. Only indenes were obtained, indicative of the C1-C5 cyclization occurring in total preference over the C1-C6 pathway. The presence of 1,4-cyclohexadiene does improve the yields, suggestive that the transfer hydrogenation mechanism may be operative. However, when the reaction is done in the absence of 1,4-cyclohexadiene and at lower temperature (180 °C), the C1-C5 cyclization is still observed and no Bergman cyclization is seen. It appears that C1-C5 cyclization of enediynes is a viable reaction.

References

(1) Vavilala, C.; Byrne, N.; Kraml, C. M.; Ho, D. M.; Pascal, R. A., "Thermal C1-C5 Diradical Cyclization of Enediynes," J. Am. Chem. Soc. 2008, 130, 13549-13551, DOI: 10.1021/ja803413f.

InChIs

1a: InChI=1/C10H6/c1-3-9-7-5-6-8-10(9)4-2/h1-2,5-8H
InChIKey=CBYDUPRWILCUIC-UHFFFAOYAY

1b: InChI=1/C16H10/c1-2-15-10-6-7-11-16(15)13-12-14-8-4-3-5-9-14/h1,3-11H
InChIKey=FFEGFMOHMPSHTK-UHFFFAOYAQ

1c: InChI=1/C16H8Cl2/c1-2-12-6-3-4-7-13(12)10-11-14-15(17)8-5-9-16(14)18/h1,3-9H
InChIKey=ZQRAACNBGPDESE-UHFFFAOYAV

1d: InChI=1/C18H14/c1-4-16-10-5-6-11-17(16)12-13-18-14(2)8-7-9-15(18)3/h1,5-11H,2-3H3
InChIKey=XGUCEMJKUJLOHZ-UHFFFAOYAZ

2a: InChI=1/C22H14/c1-3-9-19(10-4-1)15-17-21-13-7-8-14-22(21)18-16-20-11-5-2-6-12-20/h1-14H
InChIKey=XOJSMLDMLXWRMT-UHFFFAOYAD

2b: InChI=1/C22H8Cl6/c23-15-9-19(25)17(20(26)10-15)7-5-13-3-1-2-4-14(13)6-8-18-21(27)11-16(24)12-22(18)28/h1-4,9-12H
InChIKey=FNGRRGHMCFPDDG-UHFFFAOYAU

Bergman cyclization Steven Bachrach 24 Nov 2008 1 Comment

Inverted adamantane

There is a mystique surrounding chemical torture. Just how much strain can one subject a poor old carbon atom to? We construct such tortured molecules as cubane and cyclopentyne and trans-fused bicyclo[4.1.0]heptane. Inverted carbons – think of propellanes – are also a fruitful arena for torturing hydrocarbons. Now, Irikura has examined inverted adamantane inv-1.1

The MP2/6-31G(d) optimized geometries of 1 and inv-1 and the transition state separating them are displayed in Figure 1. The inverted structure is a local energy minimum, lying 105 kcal mol-1 above 1.2 The barrier for rearrangement of the inverted adamantane into adamantane, which involved a cleave of a C-C bond, is 17 kcal mol-1, which implies a half-life of 30 ms at 298K and and 2 days at 195 K. The perfluoro isomer has a higher barrier (32 kcal mol-1) and a longer half-life (110 years at 298K).

1

TS-1

inv-1

Table 1. MP2/6-31G(d) optimized geometries of 1, inv-1, and the transition state connecting them.1

So, inv-1 has some kinetic stability. It also has little computed reactivity with water, oxygen, or a second molecule of inv-1. Irikura, however, did not compute reactions that might lead to loss of a hydride from inv-1, which would give a non-classical cation.

As might be expected, the spectroscopic properties of inv-1 are unusual. The C-H vibrational
frequency for the inverted hydrogen is 3490 cm-1 and the C-C-H bend is also 300 cm-1 higher than in 1. The NMR shifts for the inverted methane group are 7.5 ppm for the hydrogen and 21 ppm for the carbon atom.

Irikura ends the article, “Experimental verification (or refutation) of [inv-1] presents a novel synthetic challenge.” Let’s hope someone picks up the gauntlet!

References

(1) Irikura, K. K., "In-Adamantane, a Small Inside-Out Molecule," J. Org. Chem. 2008, 73, 7906-7908, DOI: 10.1021/jo801806w.

(2) The energies are computed as Eestimate = E[CCSD(T)/6-31G(d)//MP2/6-31G(d)] + E[MP2/aug-cc-pVTZ//MP2/6-31G(d)] – E[MP2/6-31G(d)//MP2/6-31G(d)].

InChIs

1: InChI=1/C10H16/c1-7-2-9-4-8(1)5-10(3-7)6-9/h7-10H,1-6H2
InChIKey=ORILYTVJVMAKLC-UHFFFAOYAG

adamantane Steven Bachrach 17 Nov 2008 1 Comment

Lewis acid catalysis of 6e- electrocyclizations

While catalysis of many pericyclic reactions have been reported, until now there have been no reports of a catalyzed electrocylization. Bergman, Trauner and coworkers have now identified the use of an aluminum Lewis Acid to catalyze a 6e- electrocyclization.1

They start off by noting that electron withdrawing groups on the C2 position of a triene lowers the barrier of the electrocylization. So they model the carbomethoxy substituted hexatriene (1a-d) with a proton attached to the carbonyl oxygen as the Lewis acid at B3LYP/6-31G**. Table 1 presents the barrier for the four possible isomeric reactions. Only in the case where the substituent is in the 2 position is there a significant reduction in the activation barrier: 10 kcal mol-1.

Table 1. B3LYP/6-31G** activation barriers (kcal mol-1) for the catalyzed (H+) and uncatalyzed electrocylication reaction of carbomethoxy-substituted hexatrienes.

Reactant

Product

Ea

Ea (protonated)


1a


2a

31

35


1b


2a

34

33


1c


2c

24

14


1d


2d

26

24

With these calculations as a guide, they synthesized compounds 3 and 5 and used Me2AlCl as the catalysts. In both cases, significant rate enhancement was observed. The thermodynamic parameters for these electrocylizations are given in Table 2. The aluminum catalyst acts primarily to lower the enthalpic barrier, as predicted by the DFT computations. The effect is not as dramatic as for the computations due likely to a much greater charge dispersal in over the aluminum catalyst (as opposed to the tiny proton in the computations) and the omission of solvent from the calculations.

Table 2. Experimental thermodynamic parameters for the electrocylcization of 3 and 5.


 

Thermal

Catalyzed


ΔH (kcal mol-1)

22.4

20.0

ΔS (e.u.)

-9.2

-11.8

ΔG (kcal mol-1)

25.2

23.5


 

Thermal

Catalyzed


ΔH (kcal mol-1)

20.3

18.1

ΔS (e.u.)

-12.4

-11.6

ΔG (kcal mol-1)

24.0

21.6


References

(1) Bishop, L. M.; Barbarow, J. E.; Bergman, R. G.; Trauner, D., "Catalysis of 6π Electrocyclizations," Angew. Chem. Int. Ed. 2008, 47, 8100-8103, DOI: 10.1002/anie.200803336

InChIs

1a: InChI=1/C8H10O2/c1-3-4-5-6-7-8(9)10-2/h3-7H,1H2,2H3/b5-4-,7-6+
InChIKey=INMLJEKOJCNLTL-SCFJQAPRBY

1b: InChI=1/C8H10O2/c1-3-4-5-6-7-8(9)10-2/h3-7H,1H2,2H3/b5-4-,7-6-
InChIKey=INMLJEKOJCNLTL-RZSVFLSABV

1c: InChI=1/C8H10O2/c1-4-5-6-7(2)8(9)10-3/h4-6H,1-2H2,3H3/b6-5-
InChIKey=QALYADPPGKOFPQ-WAYWQWQTBX

1d: InChI=1/C8H10O2/c1-4-6-7(5-2)8(9)10-3/h4-6H,1-2H2,3H3/b7-6+
InChIKey=BRDQFYBEWWPLFX-VOTSOKGWBR

2a: InChI=1/C8H10O2/c1-10-8(9)7-5-3-2-4-6-7/h2-5>,7H,6H2,1H3
InChIKey=LUFUPKXCMNRVLT-UHFFFAOYAU

2c: InChI=1/C8H10O2/c1-10-8(9)7-5-3-2-4-6-7/h2-3,5H,4,6H2,1H3
InChIKey=KPYYGHDMWKXJCE-UHFFFAOYAC

2d: InChI=1/C8H10O2/c1-10-8(9)7-5-3-2-4-6-7/h3,5-6H,2,4H2,1H3
InChIKey=YCTXQIVXFOMZCV-UHFFFAOYAU

3: InChI=1/C17H20O2/c1-5-16(17(18)19-4)14(3)11-13(2)12-15-9-7-6-8-10-15/h5-12H,1-4H3/b13-12+,14-11-,16-5-
InChIKey=DPBZDJWWRAWHQX-USTKDYFJBV

4: InChI=1/C17H20O2/c1-11-10-12(2)16(17(18)19-4)13(3)15(11)14-8-6-5-7-9-14/h5-10,13,15H,1-4H3/t13-,15-/m1/s1
InChIKey=JFBDOBRQORXZEY-UKRRQHHQBP

5: InChI=1/C16H16O/c1-13(12-14-6-3-2-4-7-14)10-11-15-8-5-9-16(15)17/h2-4,6-8,10-12H,5,9H2,1H3/b11-10-,13-12+
InChIKey=OAQIPONHGIZOBU-JPYSRSMKBG

6: InChI=1/C16H16O/c1-11-7-8-13-14(9-10-15(13)17)16(11)12-5-3-2-4-6-12/h2-8,14,16H,9-10H2,1H3/t14-,16-/m0/s1
InChIKey=MJUGKTLVECDOOO-HOCLYGCPBO

DFT &electrocyclization Steven Bachrach 03 Nov 2008 No Comments