Sigmatropic rearrangements (Example 6.2) are concerted reactions that occur through a cyclic activated complex. They most often involve a hydrogen atom or an alkyl group as the migrating group (R'). Regardless of the migrating group, sigmatropic rearrangements always involve the relocation of π bonds as well as σ bonds. It is important to remember that there are two σ bonds that participate in the sigmatropic rearrangement—one being formed and one being broken. In the activated complex, however, the migrating group is bonded to both ends of the conjugated π system simultaneously, so in-phase (bonding) overlap to the migrating group is required at both ends of the conjugated π system for the reaction to be favored.
R
R' R
R' R'
n
R R
R'R' R'
n R'
R'
n
‡ R R
R'
(6.2)
Like cycloadditions and electrocyclizations, sigmatropic rearrangements can be ana- lyzed in terms of simplified frontier orbital analysis rather than a full orbital correlation
7. For a review containing experimental data for photochemical pericyclic ring openings, see: Lawless, M.K.;
Wickham, S.D.; Mathies, R.A. Acc. Chem. Res. 1995, 28, 493.
(Problems continued)
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analysis. In the activated complex for a sigmatropic rearrangement, the two halves of the activated complex are linked by two partial σ bonds—the rem- nant of the σ bond that is broken during the reaction and the incipient stage of the new σ bond that is formed during the reaction. To designate the rear- rangement type, the two parts of the reactant molecule are numbered from the σ bond that is broken toward the σ bond that is formed. The rearrange- ment is then named for the two loci that specify the place where the new σ bond is formed, with the two numbers in square brackets: an [m,n]- sigmatropic rearrangement. Thus, in the upper example in Figure 6.7, the new bond is being formed between position 3 of the top half of the activated complex and position 3 of the bottom half, making this is a [3,3] sigmatropic rearrange-
ment. In the lower example, the hydrogen atom has number 1, and it migrates to position 5 of the other half of the activated complex, so this is a [1,5]-sigmatropic rearrangement.
By analogy with cycloadditions, the stereochemistry of sigmatropic rearrangements is defined as either suprafacial, where the breaking bond and the forming bond are on the same face of the conjugated system, or antarafacial, where the these bonds are on opposite faces of the conjugated system (Figure 6.8). The stereochemistry of any particular reaction can be predicted from an analysis of the FMOs involved.
[1,n]-Sigmatropic Rearrangements of Hydrogen
Let us begin by discussing the simplest types of this reaction, [1,3]- and [1,5]-sigmatropic rearrangements of hydrogen (Examples 6.3 and 6.4, respectively). The simplest approach to use to predict the stereochemistry of sigmatropic rearrangements is to divide the acti- vated complex into two complementary systems: a cation and an anion. Thus, the stereo- chemistry of sigmatropic rearrangement of hydrogen can be predicted using the orbitals of a proton (LUMO, 1s) and the conjugated anion (HOMO, ψ2), or the orbitals of a hydride anion (HOMO, 1s) and the conjugated cation (LUMO, ψ2). One may also view the reaction as occurring by overlap of the singly occupied molecular orbitals (SOMOs) of two free radicals; the prediction remains the same because, again, the FMOs of the two participat- ing species remain the same (1s, ψ2).
H
H H
H
R R R R
(6.3) (6.4)
1 2 3 1 2 3
‡ old bonds breaking
new bonds forming
1 2 3 1 2 3
H
‡ old bonds breaking
new bonds forming H H
1 5 4 1 2 3
1 5 4 1 2 3
1 5 4 1 2 3
Figure 6.7 Nomenclature of sigmatropic rearrangements
SUPRAFACIAL
ANTARAFACIAL
Figure 6.8 Stereochemistry of rearrangement
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For the [1,3]-sigmatropic rearrangement of hydrogen, the pair of orbitals involved is the same regardless of the choice made: the 1s orbital of hydrogen and ψ2 of the allyl system. Of the two possible combinations, the [1,3]-suprafacial rearrangement is symmetry-forbidden, and the [1,3]-antarafacial rearrangement is symmetry-allowed (Figure 6.9). However, geomet- rical constraints prevent the concerted antarafacial migration, so we expect that this reaction will not proceed by a concerted mechanism.
For the [1,5]-sigmatropic rearrangement, the FMOs are the hydrogen 1s orbital and ψ3 of the pentadienyl system. This reaction is now symmetry- allowed suprafacially and symmetry-forbidden antarafacially. Because the suprafacial reaction is not prevented by geometric constraints, concerted [1,5]-sigmatropic rearrangements of hydrogen often occur readily.
Extending this analysis, we see that suprafacial [1, m] sigmatropic rearrangements of hydrogen are symmetry-allowed when m + 1 = 4n + 2 and symmetry-forbidden when m + 1 = 4n, with the corresponding antarafacial sigmatropic rearrangements obeying the opposite symmetry rules.
[1,n]-Sigmatropic Rearrangements of Alkyl
Things change when the migrating group becomes alkyl, rather than hydrogen (Figure 6.10) because, unlike hydrogen, carbon atoms may react using either an sp3 hybrid orbital (supra- facial reactions, like hydrogen) or a 2p orbital (antarafacial reactions). Here, if the migrat- ing carbon atom retains its sp3 hybridization (i.e., its stereochemistry), the analysis of the reaction is strictly analogous to that of sigmatropic rearrangements of hydrogen. The su- prafacial migration is symmetry-forbidden in the [1,3]-sigmatropic rearrangement, and symmetry-allowed in the [1,5]-sigmatropic rearrangement. [1,5]-Sigmatropic rearrange- ments occur with retention of configuration at the migrating carbon atom.
Recall that the suprafacial [1,3]-sigmatropic rearrangement of hydrogen is symmetry- forbidden under all conditions. This is not the case for carbon, however, which can and does participate in [1,3]-sigmatropic rearrangements. This is because the FMO of the hy- drogen atom is the spherical 1s orbital, with a single lobe available, and an sp3 carbon atom can rehybridize to sp2, to give a 2p orbital, which has two lobes of equal size and shape, but opposite phase. Under these circumstances, a suprafacial [1,3]-sigmatropic rearrangement can occur, but it must do so with inversion of configuration at the migrating carbon to be symmetry-allowed. If we think about the transition state for this reaction, it looks some- thing like the transition state for the SN2 reaction: the migrating carbon atom is sp2
symmetry forbidden symmetry allowed suprafacial antarafacial
symmetry allowed suprafacial
symmetry forbidden antarafacial
Figure 6.9 Symmetry properties of sigmatropic rearrangements of hydrogen
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symmetry allowed with retention 1,5-suprafacial
symmetry forbidden with retention 1,5-antarafacial
symmetry forbidden
with retention symmetry allowed with retention 1,3-suprafacial 1,3-antarafacial
symmetry allowed with inversion 1,5-suprafacial
symmetry forbidden with inversion
1,5-antarafacial symmetry forbidden
with inversion symmetry allowed
with inversion
1,3-suprafacial 1,3-antarafacial
Figure 6.10 Stereochemistry and symmetry properties of [1,3]- and [1,5]-sigmatropic rearrangements of alkyl groups. Symmetry- allowed reactions are highlighted in boxes.
hybridized with the “nucleophile” partially bonded to one lobe of the 2p orbital and the
“leaving group” partially bonded to the other. Thus, [1,3]- sigmatropic rearrangements of carbon groups can and do occur in a suprafacial manner; [1,3]- sigmatropic rearrangements occur with inversion of configuration at the migrating carbon atom.
[3,3]-Sigmatropic Rearrangements
The [3,3]-sigmatropic rearrangement is a reaction that has been very effectively used to transfer chirality from one part of a molecule to another, as we will discuss in more
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detail below. Therefore, it has become a widely used reaction in modern organic synthe- sis, and there are many versions of this reaction that have been developed since the first report of the rearrangement by Ludwig Claisen in 1912.8 The more common named ver- sions of the reaction are gathered in Table 6.2. Many of the extensions of the Claisen rearrangement have originated from the study of the effects of substituents on the vinyl ether moiety. Generally, it has been found that electron-releasing substituents on the vinyl ether accelerate the reaction, so much of the focus of research has been involved with the study of electron-donating substituents at this site. This work has given rise to several variants of the parent reaction (Table 6.3).
This rearrangement may be treated—very simplistically—as proceeding through complementary ions (an allyl cation and an allyl anion) or as a pair of free radicals. In either case, ψ2 is the orbital used by both partners in the activated complex, as shown at left. Based on simple FMO analysis, one predicts that the reaction is suprafacial with respect to both allylic substructures, and this is observed experimentally. However, it is important to know the conformation of the activated complex in this reaction, be- cause reactions proceeding through a chairlike transition state will give stereochemi- cal results different from those occurring through boatlike transition states, as illustrated in Figure 6.11.
The Claisen rearrangement emerged as an important reaction for the formation of carbon-carbon bonds in a stereoselective manner during the last third of the twentieth century. This resulted from its ability to generate new chiral centers with predictable ste- reochemistry at a site in the molecule remote from existing chiral centers (“chirality transfer”).9
8. Claisen, L. Ber. Deut. chem. Ges. 1912, 45, 3157.
Ludwig Claisen (1851–1930) studied at Bonn (PhD, 1874), with an interruption for the Franco-Prussian War.
He taught at Bonn (until 1882), at Owens College in Manchester (1882–1885), Munich (1886–1890), Aachen (1890–1897), Kiel (1897–1904), and Berlin (1904–1907) before retiring to Godesberg and his private laboratory.
For more biographical details, see: (a) Pửtsch., W. Lexikon bedeutender Chemiker (VEB Bibliographisches In- stitut: Leipzig, 1989). (b) http://www.uni-kiel.de/ps/cgi-bin/fo-bio.php?nid=claisen&lang=e
9. Reviews: (a) Rhoads, S.J.; Raulins, N.R. Org. React. 1975, 22, 1. (b) Bennett, G.B. Synthesis 1977, 589.
(c) Ziegler, F.E. Chem. Rev. 1988, 88, 1423. (d) Blechert, S. Synthesis 1989, 71. (e) Wipf, P. In Fleming, I.; Trost, B.M., Eds. Comprehensive Organic Synthesis, (Pergamon: Oxford, 1991), vol. 5, p. 827. (f) Nowicki, J. Molecules 2000, 5, 1033.
Monographs and textbooks: (f) Smith, M.B. Organic Synthesis, 2nd. ed. (McGraw-Hill: Boston, 2002), p. 1021. (g) Carruthers, W.; Coldham, I. Modern Methods of Organic Synthesis, 4th ed. (Cambridge University Press: Cambridge, 2004), p. 244. (h) Zwiefel, G.S.; Nantz, M.H. Modern Organic Synthesis: An Introduction (W.H. Freeman & Co.: New York, 2007), p. 390. (i) Hiersmann, M.; Nubbemeyer, U., Eds. The Claisen Rear- rangement. Methods and Applications (Wiley-VCH: Weinheim, 2006).
Table 6.2 [3,3]-Sigmatropic Rearrangements Used in Organic Synthesis
X Y
X Y
X Y Reaction Name
O R Claisen rearrangement
O OSiR3 Ireland ester enolate Claisen rearrangement O OR Johnson orthoester Claisen rearrangement O NMe2 Eschenmoser ketene N,O-acetal Claisen
rearrangement CR2 R Cope rearrangement
CR-O− R Oxyanion Cope (or oxy-Cope) rearrangement
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1011 12 13
10. (a) Johnson, W.S.; Werthemann, L.; Barrett, W.R.; Brockom, T.J.; Li, T.; Faulkner, D.J.; Petersen, M.R. J.
Am. Chem. Soc. 1970, 92, 741. (b) Trust, R.I.; Ireland, R.E. Org. Syn. Coll. Vol. VI 1988, 1781.
11. (a) Ireland, R.E.; Mueller, R.H. J. Am. Chem. Soc. 1972, 94, 5897. (b) Ireland, R.E.; Mueller, R.H.; Willard, A.K. J. Am. Chem. Soc. 1976, 98, 2868. (c) Ireland, R.E.; Wilcox, C.S. Tetrahedron Lett. 1977, 2839. (d) Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17.
12. Wick, A.E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425.
13. (a) Carroll, K.F. J. Chem. Soc. 1940, 704. (b) Kimel, W.; Cope, A.C. J. Am. Chem. Soc. 1943, 65, 1992.
(c) Samochvalov, G.I.; Preobazhenskii, N.A. Zh. Obshch. Khim. 1957, 27, 2501. (d) Nazarov, I.N. Zh, Obshch.
Khim. 1958, 28, 1444.
Table 6.3 Representative Claisen-type Rearrangements
O R
R
O R
R
O ∆
CHO
(6.5)
O R
R
‡
Claisen rearrangement8
CH3C(OMe)3
EtCO2H/∆/3 h
O O
OH OH
H H
83% O O
OAc
H H
CO2Me
OH O OR O OR
(6.6)
Johnson orthoester variant10
O O
1) LDA/THF/–78°C 2) TBDMSCl 3) 25-65°C
HO O
O O
1) LDA/THF/HMPA/–78°C 2) TBDMSCl
3) 25-65°C
HO O O
O R R
HO O
R R O
OSiR3 R R
(6.7)
(6.8)
Ireland variant11
100-120°C/2 h
>75%
Me OMe NMe2
OMe O
OH MeO
O MeO
OH O NR2 O NR2
HO CONMe2 HO
(6.9)
Eschenmoser variant12
O O
R O
O OH
R O
R O O
OH
R O (–CO2)
O ∆
O
O O
(95%) E:Z 54:46
(6.10) Carroll variant13
O
O ‡
CHO
OHC
O ‡
H CHO H H
H
OHC
chair-like boat-like
Figure 6.11 Stereochemical outcomes of suprafacial [3,3]-sigmatropic rearrange- ment of the E,E enol ether through chair and boat tran- sition states
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In this reaction, an allyl vinyl ether (or a substituted variant of an allyl vinyl ether) is heated to form a carbonyl compound. In general, the reaction proceeds through a chair- like transition state, which has been calculated to be favored by approximately 2-5 to 3.0 kcal mol−1.14 It is one of the consequences of this preferred stereochemistry that in simple systems capable of producing both the E and Z isomer of the double bond, the E isomer tends to be strongly preferred, because the substituent occupies a quasiequatorial position in that activated complex.15
The [3,3]-sigmatropic rearrangement of 1,5-dienes16 is known as the Cope17 rear- rangement. Unlike the Claisen rearrangement, where the equilibrium almost always favors the carbonyl product, the Cope rearrangement and certain of its congeners (e.g., the aza-Cope rearrangement, where the carbon atom at the 2- position of the 1,5-diene is replaced by the nitrogen atom of an iminium ion) tend to be more easily reversed.
When a 1,5-diene is heated, a new 1,5-diene is formed where the σ and π bonds of the two allyl groups comprising the two halves of the diene system have reversed their posi- tions. The stereospecificity of these rearrangements is illustrated by the two reactions shown here: meso-3,4- dimethyl-1,5-hexadiene gives (2E,6Z)-2,6-octadiene as the prod- uct (Example 6.11), whereas (±)-3,4- dimethyl-1,5-hexadiene gives (2E,6E)-2,6-octadiene (Example 6.12).
∆ (280°C)
‡
Me Me
‡ H
H Me
MeH H
Me MeH
H
∆ (280°C)
‡
(6.11)
(6.12)
Like the Claisen rearrangement, the Cope rearrangement proceeds through a chair- like transition state,18 so one need only draw the transition state in the most stable chair conformation to assign the stereochemistry of the two π bonds in the product (e.g., meso-3,4-dimethyl-1,5-hexadiene gives the E,Z isomer of the product).
The Cope rearrangement is generally more facile when the reaction leads to the re- duction of strain in the molecule, as illustrated in Figure 6.12. Thus, the energy barrier for
14. (a) Vitorelli, P.; Winkler, T.; Hansen, J.-H.; Schmid, H. Helv. Chim. Acta 1968, 51, 1457. (b) Hansen, H.J.;
Schmid, H. Tetrahedron 1974, 30, 1959. (c) Vance, R.L.; Rondan, N.G.; Houk, K.N.; Jensen, F.; Borden, W.T.;
Komornicki, A.; Wimmer, E. J. Am. Chem. Soc. 1988, 110, 2314.
15. (a) Faulkner, D.J.; Petersen, M.R. J. Am. Chem. Soc. 1969, 95, 553. (b) Faulkner, D.J.; Petersen, M.R. Tetra- hedron Lett. 1969, 3243.
16. (a) Cope, A.C.; Hardy, E.M. J. Am. Chem. Soc. 1940, 62, 441. (b) Rhoads, S.J.; Raulins, N.R. Org. React.
1975, 22, 723. (c) Schrửder, G.; Oth, J.F.M.; Merộny, R. Angew. Chem. Int. Ed. Engl. 1965, 4, 752.
17. Arthur Clay Cope (1909–1966) was educated at Butler University (BS, 1929) and the University of Wis- consin (PhD, 1932). After postdoctoral study at Harvard University, he was on the faculty of Bryn Mawr College (1934–1941), Columbia (1942–1945), and MIT (1945–1965). Cope was President of the American Chemical Soci- ety in 1961. For more details, see: Roberts, J.D.; Sheehan, J.C. Biogr. Mem. Nat. Acad. Sci. 1981, 60, 17.
18. (a) Doering, W.v.E.; Roth, W.R. Tetrahedron 1962, 18, 67. (b) Doering, W.v.E.; Roth, W.R. Angew. Chem.
1963, 75, 27.
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the Cope rearrangement of 1,5-hexadiene is 33.5 kcal mol−1,19 whereas the corresponding values for cis-1,2-divinylcyclobutane20 and cis-1,2-divinylcyclopropane21 are 23.1 kcal mol−1 and 19.4 kcal mol−1, respectively. Substituents capable of conjugating with the newly formed double bonds in the product are also effective at lowering the activation energy for the reaction. For example, the Cope rearrangement of 1,5-hexadien-3-ol initially leads to 1,5-hexadien-1-ol, which immediately tautomerizes to the aldehyde, thus also making the reaction irreversible. This reaction, known as the oxy-Cope rearrangement,22 becomes even faster (by a factor in excess of 1010) when the conjugate base of the alcohol is the reactant.23 The activation energy for the rearrangement of the conjugate base of 1,5- hexadien-3-ol is 18.2 kcal mol−1,24 even lower than the activation energy for the rear- rangement of cis-1,2-divinylcyclopropane.
Reaction Synopses Sigmatropic Rearrangements
a b
a b
R a
b
R a
b
[1,n] [m,n]
Rearrangement designated as [m.n]-sigmatropic rearrangement, where m and n indicate loci of new σ bond formation based on locus of broken σ bond in starting material
Stereochemistry: suprafacial if [m + n]=4x + 2; antarafacial if [m+n] = 4x
19. Doering, W.v.E.; Toscano, V.G.; Beasley, G.H. Tetrahedron 1971, 27, 5299.
20. Hammond, G.S.; Deboer, C.D. J. Am. Chem. Soc. 1964, 86, 899.
21. Brown, M.J.; Golding, B.T.; Stofko, J.J., Jr. J. Chem. Soc., Chem. Commun. 1973, 319.
22. (a) Berson, J.A.; Walsh, E.J., Jr. J. Am. Chem. Soc. 1968, 90, 4729. (b) Viola, A.; Padilla, A.J.; Lennox, D.M.;
Hecht, A.; Proverb, R.J. J. Chem. Soc., Chem. Commun. 1974, 491.
Reviews: (c) Marvell, E.N.; Whalley, W. In Patai, S., Ed. The Chemistry of the Hydroxyl Group, Part 2 (Wiley:
New York, 1971), p. 738. (d) Paquette, L.A. Angew. Chem. Int. Ed. Engl. 1990, 29, 609. (e) Paquette, L.A. Synlett 1990, 67.
23. (a) Evans, D.A.; Nelson, J.V. J. Am. Chem. Soc. 1980, 102, 774. (b) Miyashi, H.; Tazato, A.; Mukai, T. J. Am.
Chem. Soc. 1978, 100, 1008. (c) Paquette, L.A.; Pegg, N.A.; Toops, D.; Maynard, G.D.; Rogers, R.D. J. Am. Chem.
Soc. 1990, 112, 277. (d) Gajewski, J.J.; Gee, K.R. J. Am. Chem. Soc. 1991, 113, 967. (e) Wender, P.A.; Ternansky, R.J.;
Sieburth, S.M. Tetrahedron Lett. 1985, 26, 4319.
24. Evans, D.A.; Golob, A.M. J. Am. Chem. Soc. 1975, 97, 4765.
O O
Ea 33.5
Ea 23.1 Ea 19.4
Ea 18.2
Figure 6.12 Variation of acti- vation energy of the Cope rearrangement
(continues)
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Cope Rearrangement
R1 R2
R3 R4
R1 R2
R3 R4
∆ X
X
Stereochemistry: suprafacial with respect to both halves of the activated complex Reaction occurs through a chairlike transition state.
Accelerated by electron-rich substituents (e.g., OH, O−, NR2) at position X (e.g., oxy-Cope rearrangement)
Claisen Rearrangement R1
X R2 R3
R1 X
R2 R3
∆
Y Y
Stereochemistry: suprafacial with respect to both halves of the activated complex Reaction occurs through a chairlike transition state.
Variants: Ireland (X=O, Y=OSiMe3); Johnson (X=O, Y=OR); Eschenmoser (X=O, Y=NR2); Carroll (X=O, Y=OH, R1=RCO)
Worked Problem
6-1 Under what conditions should the following reaction occur?
§Answer below
Problems
6-4 Electrocyclization of dienes is a poor method for forming stereochemically pure cyclobutenes. Why?
6-5 When the conjugated tetraene below is heated, the bicyclic product shown is the only product of the reaction. Write a mechanism that accounts for its formation and rationalize the stereochemistry.
§ Answer to Worked Problem:
This reaction is a [1,5]-sigmatropic shift of hydrogen.
H H H
The reaction is symmetry-allowed in the ground state with suprafacial stereochemistry, so the reaction will proceed under thermal conditions. One only needs to heat the diene to cause the isomerization. Note how the product is the Z diene.
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Me Me
∆ H Me
H Me (±) (2E,4Z,6Z,8E)
6-6 What is the major organic product of each of the following reactions? Designate the stereochemistry of the major product.
(a) (b)
H
H
∆ ∆ (c) ∆
(d) ∆ (e) ∆ (f) ∆
H
H
(g) ∆ (h) ∆ (i) ∆
H
H
H
H H
H
6-7 5-Methyl-1,3-cyclopentadiene is formed from the reaction between the sodium salt of cyclopentadiene and methyl iodide at −78°C. If this diene is stored at room temperature, it becomes a mixture of 1-methyl-1,3-cyclopentadiene, 2-methyl-1,3- cyclopentadiene, and 5-methyl-1,3-cyclopentadiene in just a few hours. Why?
Which isomer should be formed in greatest amount and which in least?
C5H5 MeI
–78°C Me Me Me
6-8 The reaction below is concerted. Show the stereochemistry of the final product and rationalize its formation.
AcO H
H OAc
∆
6-9 Predict the products of each of the following reactions.
(e) ∆
HO
OH Me
NMe2
OMe H OMe
(f) O ∆
(g) O ∆
O 1) LDA (2 eq), THF, -70—65°C 2) CCl4, 77°C, 1 h (–CO2)
(a)
O O
O O O
1) LDA, THF, –78°C 2) CCl4, 77°C
(b)
(c) O
O O
H
∆ (product has
cis ring fusion) (d) ∆
O H
O
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