Hyperconjugative Aromaticity and Antiaromaticity Control the Reactivities and π-Facial Stereoselectivities of 5-Substituted Cyclopentadiene Diels–Alder Cycloadditions

Abstract

The reactivities and π-facial stereoselectivities of Diels–Alder reactions of 5-substituted cyclopentadienes were studied using density functional theory. Burnell and co-workers previously showed that the π-facial selectivities result from the energies required to distort the reactants into the transition state geometries. We have discovered the origins of these distortions. C₅–X σ-donors predistort the cyclopentadiene into an envelope conformation that maximizes the stabilizing hyperconjugative interaction between the C5–X σ-bond and the diene π-system. This envelope conformation geometrically resembles the anti transition state. To minimize the destabilizing effect of negative hyperconjugation, C₅–X σ-acceptors predistort in the opposite direction toward an envelope geometry that resembles the syn transition state. We now show how hyperconjugative effects of the C₅–X substituent influence the stereoselectivities and have developed a unified model rationalizing the stereoselectivities and reactivities of 5-substituted cyclopentadiene Diels–Alder reactions.

Graphical Abstract

INTRODUCTION

Cyclopentadiene is generally more reactive than other cyclic dienes in the Diels–Alder reaction.¹ Substitution at the 5-position of the cyclopentadiene can alter the reactivity, and perhaps surprisingly, in the normal-electron demand Diels– Alder reaction, electron-withdrawing substituents increase the reactivity! We have shown how this arises by destabilization of the cyclopentadiene.² When the substituent at the 5-position is a σ-acceptor, negative hyperconjugation results in the cyclo-pentadiene having pseudo 4π electron antiaromatic character and accelerated reactivity.

5-Substituted cyclopentadienes (C₅–X) are facially asymmetric and, depending on the substituent, will react on either the syn or anti face of the cyclopentadiene with regard to the C₅–X substituent. As shown in Scheme 1, the π-facial stereoselectivity of the cycloaddition is considered syn when the dienophile (Y = Z) reacts on the same face of the C₅–X substituent, whereas addition to the face opposite of the C₅–X substituent is considered anti. Winstein and Woodward reported the first contrasteric (syn) Diels–Alder reaction of 5-acetoxycyclopentadiene (C₅–OAc) with ethylene (Scheme 2) during their seminal studies on 7-norbornenyl cations.³

scheme 1.

Syn and Anti Diels–Alder π-Facial Selectivity to a C₅–X Cyclopentadiene with the X═Y Dienophile

Scheme 2.

Reaction of C₅–OAc with Ethylene Exclusively Forms the Syn Adduct³

Similar constrasteric cycloadditions have since been reported. Scheme 3 shows the π-facial selectivity in the Diels–Alder reactions of C₅–F, C₅–Cl, and C₅–Br with dimethyl acetylenedicarboxylate (DMAD).^4,5 C₅–F reacts with syn π-facial stereoselectivity; C₅–Cl forms a mixture of syn and anti adducts; and C₅–Br reacts with anti π-facial stereoselectivity.

Scheme 3.

Syn and Anti π-Facial Stereoselectivity in the Diels–Alder Reactions of C₅–F, C₅–Cl, and C₅–Br with DMAD^4,5

Control of π-facial selectivity has been used in the synthesis of aconitine alkaloids. Scheme 4 shows how the reaction between 5-methoxycyclopentadiene 1 and cyclopropene 2 proceeds predominantly with syn selectivity to yield the desired intermediate 3a in the David Gin synthesis of neofinaconitine.⁶ The late David Gin visited our group in early 2011, and he brought the subject of π-facial stereoselectivity in cyclo-pentadienes to our attention. We have worked on this problem since then and now offer a comprehensive explanation for the reactivities and stereoselectivities of Diels–Alder reactions involving 5-substituted cyclopentadienes.

Scheme 4.

Gin’s Exploitation of π-Facial Stereoselectivity in the Total Synthesis of Neofinaconitine⁶

Many explanations have been offered, and it seems that the origin of π-facial stereoselectivity in 5-substituted cyclo-pentadiene cycloadditions remains unsettled.⁷ Cieplak proposed that the stereoselectivity of a number of nucleophilic reactions can be explained through the hyperconjugative stabilization of an incipient σ*-bond by an antiperiplanar donor σ-bond in the transition state.⁸ Fallis and Macaulay applied the Cieplak effect to Diels–Alder reactions of 5-substituted cyclopentadienes in order to rationalize the syn and anti π-facial stereoselectivity.⁹ They proposed that the cycloaddition occurs anti to the C₅–X bond that is the better σ-donor. Scheme 5 shows the proposed σ_C5-X–σ* hyperconjugative interaction of the antiperiplanar C₅–X bond with the incipient bonds. Anti stereoselectivity is predicted when the C₅–X substituent is a stronger σ-donor than the hydrogen atom of the C₅–H bond, while a C₅–X substituent that is a worse σ-donor is predicted to give syn selectivity. This explanation does not, however, explain why anti C_5-X σ-donors slow down, instead of accelerate, reactivity.

Scheme 5.

Hyperconjugative Stabilization of the Incipient σ* Bonds by the Antiperiplanar C₅–X σ-Bond (Cieplak Effect)

Inagaki, Fujimoto, and Fukui explained the π-facial stereoselectivity of 5-substituted cyclopentadienes with orbital mixing.¹⁰ They proposed that orbital mixing between the nonbonding orbital (n) of the C₅–X substituent, the diene π-HOMO, and the σ-orbitals of the diene carbon framework determines the π-facial selectivity. When the π-HOMO lies higher in energy than the nonbonding orbital of the C₅–X substituent, the mixing results in an increase in the amplitude of the C₁ and C₄ p-orbitals on the syn face of the 5-substituted cyclopentadiene (Scheme 6). Conversely, when the π-HOMO lies lower in energy than the nonbonding orbital of the C₅–X substituent, the mixing increases the amplitude of the C₁ and C₄ p-orbitals on the anti face of the 5-substituted cyclo-pentadiene. The dienophile then reacts on the face of the cyclopentadiene with the largest p-orbital amplitude at the C₁ and C₄ positions.

Scheme 6.

Deformation of the π-HOMO from Orbital Mixing Proposed by Inagaki, Fujimoto, and Fukui

Burnell and co-workers studied computationally the π-facial selectivities of C₅–X cyclopentadienes.^11,12 They amassed extensive computational evidence to show that the π-facial stereoselectivity is controlled by the energy required to deform the diene into the transition state geometry. They associated the deformation with the change of the C₁–C₅–X angle between the ground and transition state geometries.

We have recently reported cyclopentadienes as potential bioorthogonal reactants¹³ and showed how the C₅–X substituent has a very large effect on the Diels–Alder reactivity.² Understanding the reactivity and stereoselectivity trends in 5-substituted cyclopentadienes will be of further value in the development of new bioorthogonal cyclo-pentadienes. To better understand how the reactivity and the syn and anti π-facial stereoselectivity trends relate to the properties of the C₅–X substituent, we have investigated a wide scope of C₅–X cyclopentadienes (Scheme 7) with the distortion/interaction–activation strain model.¹⁴

Scheme 7.

C₅–X Cyclopentadienes Studied in This Work

COMPUTATIONAL METHODS

All calculations were performed with Gaussian 09.¹⁵ Geometry optimizations and frequency calculations were calculated with the M06–2X¹⁶ functional and the 6–31G(d) basis set. The M06–2X functional has been found to accurately reproduce experimental trends in the reactivity and selectivity of Diels–Alder reactions.¹⁷ Normal mode analysis of each structure verified that each stationary point is either a first-order saddle point or an energy minimum. Single-point energies were computed using the 6–311++G(d,p) basis set. The distortion/interaction model was applied to the transition state structures to disect the activation energies into the distortion and interaction energy components. The procedure to carry out this analysis procedure has been reviewed recently.¹⁴

RESULTS AND DISCUSSION

The anti and syn transition structures and the activation free energies (ΔG^⧧) for the Diels–Alder reactions of the 5-substituted cyclopentadienes with ethylene are shown in Figure 1. Syn π-facial stereoselectivity is favored when the C₅ substituent is F, OH, NH₂, or Cl. Poor π-facial selectivity is predicted when the substituent is Br, SH, or Me. Anti π-facial stereoselectivity is favored when the C₅–X substituent is SiH₃. The activation free energies of the syn and anti transition states range from 24 to 38 and from 29 to 33 kcal/mol, respectively. There is a correlation between the electronegativity of the C₅– X substituent and the activation barriers, as observed earlier by Burnell.^11,12 Electron-withdrawing substituents accelerate the reactivity, and electron-donating substituents decrease the reactivity, with a range in activation energies of 10 kcal/mol.

Figure 1.

Transition state structures with forming bond lengths reported in Å and activation free energies (ΔG^⧧) in kcal/mol for the syn and anti Diels–Alder reactions of the 5-substituted cyclopentadienes with ethylene.

Extensive computational and experimental studies by the Schleyer group on the aromaticity of cyclic π-systems with one saturated linkage (cyclopropene, cyclopentadiene, and cyclo-heptatriene) show that the substituents at the saturated linkage contribute to the π-electron count as pseudo π-donors or π-acceptors via hyperconjugative interactions with the π-system.¹⁸ The effect of the C₅–X substituent on the stability on the cyclopentadiene was estimated here with the isodesmic equation shown in Figure 2. This isodesmic equation measures the aromatic stabilization enthalpy (H_ASE) of the cyclo-pentadiene relative to nonconjugated cyclopentadienes for which cyclic electron delocalization of the π-bonds is not possible. A positive reaction enthalpy in the isodesmic equation indicates that cyclic delocalization of the π-electrons via hyperconjugation is stabilizing. The weak hyperconjugative donors, C₅–H and C₅–Me, are stabilized by 2–3 kcal/mol, which arises mostly from the favorable π-conjugation. Silyl substitution further stabilizes the cyclopentadiene to 7.4 kcal/mol, whereas fluorine substitution destabilizes the cyclo-pentadiene to −3.4 kcal/mol in the isodesmic equation. When the C₅–X substituent is a σ-acceptor, the hyper-conjugative π–σ*_C5-X interaction destabilizes the cyclopenta-diene by giving it pseudo 4π electron antiaromatic character. When the C₅–X substituent is a σ-donor, positive hyperconjugation stabilizes the cyclopentadiene by giving it pseudo 6π electron aromatic character. The aromatic stabilization energies influence the activation and reaction energies.²

Figure 2.

Isodesmic equation (specifically hypohomodesmotic)¹⁹ and calculated aromatic stabilization enthalpies of the cyclopentadienes.

Figure 3a shows a plot of ΔH of reaction for the reactions of the C₅–X cyclopentadienes vs the aromatic stabilization energy (ΔH_ASE) of the diene. The linear correlation suggests that the exothermicities of these cycloadditions are related to the stabilities of the C₅–X cyclopentadienes. The norbornene π-bond donates into the σ*_C5-X bond of substituent anti to the norbornene π-bond.²⁰ The syn adducts are more stable than the anti adduct with the exception of C₅–SiH₃. The syn preference becomes increasingly favored as the C₅–X substituent becomes a stronger σ-acceptor, a result of a more stabilizing π–σ*_C5-X interaction.

Figure 3.

Plots of the reaction enthalpies (a) and activation enthalpies (b) against the calculated aromatic stabilization enthalpies. Syn: red, (a) ΔH = 1.2ΔH_ASE – 33, r2 = 0.95; (b) ΔH^⧧ = 1.1ΔH_ASE + 16, r2 = 0.90. Anti: blue, (a) ΔH = 1.5ΔH_ASE – 34, r2 = 0.95; (b) ΔH^{⧧ =} 0.33ΔH_ASE + 17, r2 = 0.98.

Figure 3b shows a plot of the ΔH^⧧ for the C₅–X cycloadditions with ethylene against the diene aromatic stabilization energies. Here the correlations are quite different for the syn and anti reactions with slopes of 1.1 and 0.33, respectively. The syn reactions are clearly favored for electron-withdrawing substituents, while the silyl-substituted cyclo-pentadiene reacts with a strong preference for the formation of the anti adduct.

We applied the distortion/interaction-activation strain analysis¹⁴ in order to understand the origins of the syn and anti π-facial stereoselectivity in Diels–Alder reactions of 5-substituted cyclopentadienes. This analysis dissects the electronic activation energies in the distortion and interaction energies of the reaction. The distortion energy (ΔE_d) is the energy required to deform the reactants into the corresponding transition structures, and the interaction energy (ΔE_i) comprises of the interactions that occur between the diene and dienophile as they approach each other and adopt the geometries of the transition state. Figure 4 shows a plot of the stereoselectivity measured as the difference in the anti and syn electronic activation energies (ΔE^⧧(syn) – ΔE^⧧(anti)) with the difference in the distortion (ΔE^⧧(syn) – ΔE^⧧(anti)) required to achieve the anti and syn transition states.

Figure 4.

Plot of π-facial selectivity (ΔΔE^⧧(syn–anti)) against the differences in the distortion energies (ΔΔE_d^⧧(syn–anti)) (ΔΔE^⧧ = 0.95ΔΔE_d^⧧ – 1.5, r2 = 0.98).

The excellent linear correlation suggests that the π-facial selectivity results from differences in the energies required to distort the reactants into the syn and anti geometries, as originally proposed by Burnell.^11,12 We also performed the distortion/interaction-activation strain analysis along the intrinsic reaction coordinate defined by the length of the forming C–C bonds. These plots are provided in the Supporting Information. When the forming bond lengths of the stereoisomers in the transition state are similar, as observed in these reactions, performing the distortion/interaction-activation strain analysis at the TS and along the IRC leads to the same conclusion, that the syn and anti stereoselectivity is distortion controlled.

As shown in Figure 5, the cyclopentadiene (C₅–H) ground state is planar. The electronic nature of the C₅–X substituent predistorts the cyclopentadiene into an envelope geometry. The angle θ_env is defined as the angle at which the C₅ atom of the cyclopentadiene puckers above or below the plane of the cyclopentadiene. The value of θ_env is negative when the C₅ atom extends below the plane and positive when it extends above the plane of the cyclopentadiene. When C₅–X is a σ-donor, the C₅ atom distorts above the plane of the cyclopentadiene. This distortion aligns the C₅–X bond with the cyclopentadiene π-system to maximize the stabilizing hyperconjugation interaction that induces hyperconjugative aromaticity.^2,18 The C₅ atom in C₅–SiH₃ is distorted 3° above the plane of the cyclopentadiene. When C₅–X is a σ-acceptor, the C₅ atom distorts below the plane of the cyclopentadiene to minimize the overlap of the diene π-system with the σ*_C5-X and reduce the destabilizing effect of the hyperconjugative aromaticity. For σ-acceptors, C₅–F, C₅–OH, and C₅–Cl, the C₅ atom is predistorted 2 to 4° below the plane of the cyclopentadiene ring. The poor σ-donors/acceptors, C₅–Br, C₅–CH₃, C₅–SH, and C₅–NH₂, are nearly planar with the C₅ atom predistorted less than 2° relative to the plane of the cyclopentadiene.

Figure 5.

Optimized M06–2X/6–31G(d) ground state geometries of the C₅–X cyclopentadienes with θ_env, the angle measuring the out-of-plane distortion of the C₅ atom, reported in degrees.

In the syn and anti transition structures θ_env ranges from −18° to −19° and from 16° to 19°, respectively. Figure 6 shows θ_env for the syn and anti Diels–Alder reactions of C₅–F, C₅–Br, and C₅–SiH₃ with ethylene. For the syn and anti reactions of C₅–F, the syn reactions require a −14° change about θ_env and a change of 21° to achieve the anti transitiond state geometry. To achieve the syn and anti transition state geometries, θ_env in C₅–Br distorts 17° and −18°, respectively. For C₅–SiH₃, the change about θ_env to achieve the syn and anti transition state geometries is 16° and −21° from the ground state geometry, respectively.

Figure 6.

Ground and syn and anti transition state structures of C₅–F, C₅–Br, and C₅–SiH₃ with θ_env shown in degrees.

The stereoselectivity of C₅–X cyclopentadiene Diels–Alder reactions is determined by the distortion energies, which are related to how the C₅–X cyclopentadiene is predistorted in the ground state. Figure 7a shows a strong linear correlation when the difference in the diene distortion energies of the syn and anti transition states is plotted against the difference in the cyclopentadiene envelope angle, θ_env, required to achieve the syn and anti transition state geometries. The transition state that requires less of a change in θ_env is the stereoselectively favored reaction. When the substituent is a σ-donor, the ground state is predistorted into an envelope geometry that resembles and favors the anti transition state, whereas σ-acceptors predistort the cyclopentadiene ground state into an envelope geometry that resembles and favors the syn transition state.

Figure 7.

(a) Plot of differences in the diene distortion energies (ΔΔE_d-diene^⧧(syn–anti)) against the change in the envelope angle required to achieve the syn and anti transition state geometries ΔΔθ_env(syn–anti) (ΔΔE_d-diene^⧧ = 0.88ΔΔθ_env + 1.2, r2 = 0.97). (b) Plot of differences in the diene distortion energies (ΔΔE_d-diene^⧧(syn–anti)) against the change in the bending of the C_5-X bond required to achieve the syn and anti transition state geometries (ΔΔE_d-diene^⧧ = 0.37ΔΔθ_C5-X – 1.6, r2 = 0.99).

We have also considered the contribution of the bending of the C₅–X bond to the distortion energy as proposed by Burnell.¹² The C₅–X (θ_C5-X) bond angle is measured relative to the plane of the cyclopentadiene defined by the C₁C₄C₅ atoms. Figure 7b shows a plot of the differences in the diene distortion energies against the difference in the bending of the C₅–X (θ_C5-X) bond from the plane of the cyclopentadiene between the syn and anti transition state. There is a strong linear correlation between the diene distortion and the bending of the C₅–X bond from the plane of the diene with the exception of C₅–SH, which is an outlier in the distribution.

The x-intercept shows that for diene distortion of the syn and anti transition states to be equal (ΔΔE_d-diene^⧧ = 0) an additional 5° distortion of the C₅–X bond toward the anti transition state is required about the C₅–X bond. Figure 7a shows the plot of the difference in the diene distortion energies against the difference in θ_env between the syn and anti transition states. From the x-intercept there is only a 1° difference between the envelope geometry of the syn and anti transition states when the distortion energy of the syn and anti transition states is equal (ΔΔE_d-diene^⧧ = 0).

The diffculty of distorting a bond is related to the strength of the bending force constants. Table 1 summarizes the computed force constants associated with the bending of the C₅–X bond and the C₅ carbon relative to the plane of the cyclopentadiene in the C₅–X cyclopentadiene ground states. The force constants for the bending of the C₅–X bonds range from 0.032 to 0.097 millidynes/Å and are significantly lower than the out-of-plane bending force constants associated with the out-of-plane bending of the C₅ carbon atom, which ranges from 0.56 to 1.20 millidynes/Å. The bending of the C₅–X alkyl bonds contributes less to the diene distortion energies of the syn and anti transition states than the distortion associated with the bending of the C₅ carbon from the plane of the cyclopentadiene and as a result has less influence on the stereoselectivity.

Table 1.

Force Constants Computed at the M06–2X/6–31G(d) Level of Theory for Bending of the C₅–X Bonds and for the out-of-Plane Motion of the C₅ Atom from the Plane of the Cyclopentadiene

C5–X	bending of C5–X bond (mDyne/Å)	out-of-plane bending of C5 atom (mDyne/Å)
C5–F	0.097	1.20
C5–Cl	0.064	1.12
C5–Br	0.047	0.80
C5–CH3	0.047	0.56
C5–NH2	0.049	0.79
C5–OH	0.066	0.97
C5–SH	0.048	1.20
C –SiH	0.032	0.84

The strength of the hyperconjugation interaction between the π-system and the C₅–X substituent determines the extent of the predistortion. The electronegativity of the C₅–X substituent correlates with the envelope angle θ_env in the ground state geometries of the C₅–X cyclopentadienes (Figure 8a) and is a useful way to predict the π-facial stereoselectivity in Diels–Alder reactions of C₅–X cyclopentadiene with ethylene (Figure 8b). As the C₅–X substituent becomes a stronger σ-acceptor it predistorts increasingly toward the envelope conformation of the syn transition state and becomes increasingly selective for the syn reaction.

Figure 8.

(a) Plot of θ_env in the ground state of the C₅–X cyclopentadienes against the electronegativity of the C₅–X substituent (θ_env = 3.2χ – 8.7, r₂ = 0.96). (b) Plot of π-facial selectivity against the electronegativity of the C₅–X substituent (ΔΔG^⧧ = −4.2χ + 11.2, r₂ = 0.90).

The influence of the dienophile on the π-facial stereoselectivity was investigated by calculating the syn and anti Diels–Alder stereoselectivities for the concerted reactions with maleic anhydride (MA), tetracyanoethylene (TCNE), 1,2,4-triazoline-3,5-dione (TAD), and acetylene. Figure 9 summa-rizes the syn and anti π-facial stereoselectivity of the C₅–X cyclopentadienes with these dienophiles. For C₅–Br, C₅–SH, and C₅–Me, which are poor σ donor/acceptors, the π-facial stereoselectivity can be influenced by interactions between the C₅–X substituent and the dienophile. Steric interactions destabilize the syn transition state when TCNE is the dienophile, and anti π-facial selectivity becomes favored for C₅–Cl, C₅–Br, C₅–SH, and C₅–Me. Lone pair repulsions between the nitrogens of TAD with the halogen lone pair on the Cl and Br destabilize the syn transition states and result in poor stereoselectivity for the Diels–Alder reaction of C₅–Cl and anti stereoselectivity in the reaction of C–Br with TAD. The predistortion of the C–F, C – ground 5 OH, and C₅₂ states toward the syn transition state geometry is significant enough that the destabilizing interactions between the C₅–X substituent and the dienophile in the syn transition state do not overrule the syn selectivity of these dienes. The Diels–Alder reaction of C₅–SiH₃ strongly favors the anti cycloaddition with all of the studied dienophiles.

Figure 9.

Histogram showing the syn and anti π-facial stereoselectivity in the Diels–Alder reactions of the C₅–X cyclopentadienes with ethylene (red), maleic anhydride (blue), 1,2,4-triazoline-3,5-dione (green), tetracyanoethylene (purple), and acetylene (orange).

CONCLUSION

The π-facial selectivity of C₅–X cyclopentadienes is distortion controlled. When the C₅–X substituent is a strong σ-acceptor (X = F, OH, and NH₂) the cyclopentadiene adopts an envelope geometry that minimizes the destabilizing π–σ*_C5-X hyperconjugative interaction that provides the cyclopentadiene with antiaromatic character. This distortion causes the cyclopentadiene to resemble the envelope geometry of the syn transition and lessens the distortion energy required of the syn cycloaddition. Conversely, when the C₅–X substituent is a σ-donor (X = SiH₃) the C₅ atom distorts to maximize the effect of the stabilizing hyperconjugative interaction that provides the cyclopentadiene with aromatic character. This distortion of the ground state causes the cyclopentadiene to resemble the envelope geometry of the anti transition state, and anti π-facial selectivity is favored. When the C₅–X substituent is a poor σ-acceptor/donor (X = Cl, Br, SH, and Me), the π-facial selectivity is sensitive to the nature of the dienophile.