Fund. Theor. Org. Chem 1 SE Fundamentals of Theoretical Organic Chemistry Lecture 9 1 Fund. Theor. Org. Chem 2 SE 2.2.2 Electrophilic substitution The reaction which takes place between a reactant with an electronegative carbon and an electropositive reagent forming a polarized covalent bond is called electrophilic. In addition, if substitution occurs (i.e. there is a similar polarized covalent bond on the electronegative carbon, which breaks up during the reaction, so the reagent „substitutes” the „old” group or the leaving group) then this specific reaction is called electrophilic substitution. The electronegative carbon is called the reaction centre. In general, the good reactant are molecules having electronegative carbons like aromatic compounds, alkenes and other compounds containing electron-rich double bonds. These are called Lewis bases. On the contrary, good electrophilic reagents are electron poor compounds/molecule groups like acid-halides, which easily form covalent bond with an electronegative centre, thus creating a new molecule. These are often referred to as Lewis acids. According to molecular orbital (MO) theory the driving force for the electrophilic substitution (SE) is a Lewis complex formation involving the LUMO of the Lewis Acid Reagent and the HOMO of the Lewis Base Reactant. Reactant Reagent LUMO LUMO HOMO Lewis base Lewis acid Lewis complex Types of reactions: There are four types of reactions as illustrated below: 2 Fund. Theor. Org. Chem 3 SE Table. 2.2.2-1. Saturated Aromatic SE1 SE1 (Ar) SE2 SE2 (Ar) SE reaction on saturated atom: (1)Unimolecular electrophilic substitution (SE1): The reaction proceeds in two steps. After the departure of the leaving group, the negatively charged reaction intermediate will combine with the reagent. + − + SE1: Y R Y +R E R E 2.2.2-1. Since the reaction speed is only depending on the concentration of the reactant, the reaction follows first order kinetics. d[RE]/dt=k[YR] (first order reaction kinetics) The basis catalysed halogenation of ketones is a classical SE1 reaction. O O B: + H3CCCH3 H3CCCH2 H O O Br− H3CCCH2 Br Br H3CCCH2Br 2.2.2-2. (2) Bimolecular electrophilic substitution (SE2): A bimolecular reaction proceeds in one step through an intermedier complex. + δ δ− δ+ + [ YR E ] + SE2: Y R E Y + R E 2.2.2-3. The speed of the reaction is depending on the concentration of both the reactant and the reagent, thus the reaction has second order kinetics d[RE]/dt=k[YR][E+] (second order kinetics). Halogenation of metal-alkilates is an SE2 reaction 3 Fund. Theor. Org. Chem 4 SE s-Bu SnR3 Br Br s-Bu Br + SnR3Br 2.2.2-4. Unsaturated/Aromatic C-atom: Aromatic electrophilic substitution (SEAr) There are two mechanisms of aromatic electrophilic substitution SE1 and SE2: (3) SE1:Thermal decrboxylation of benzoate Na δ+ O C O O CO H δ− Na A ∆ HA (4) SE2: Nitration of benzene δ+ H NO + O2NH 2 NO2 δ− 15oC + H cc.H2SO4 cc.HNO3 Stereochemistry of Electrophilic Substitution. Saturated C-atom SE1: Mechanism of the unimolecular electrophilic substition is quite similar to that of the unimolecular nucleophilic substitution. Accordingly, the SE1 reaction proceeds in two steps. First, the electropositive leaving group generally catalaysed by a Lewis-acid departures from the substrate. Thus, an electronegative planar intermedier is reached, which -unlike intermediate of SE2 reaction- could be detected in the reaction mixture. Second, an electropositive reagent will react with 4 Fund. Theor. Org. Chem 5 SE H H H + + + -BX E δ − − δ δ H δ C X B C− E C + H − δ H δ C E H H H H H inverzió H retenció Racemizáció the electronegative substrate, thus forming the product. Considering the planar electronegative intermediate, the reaction could be followed by retention or inversion of the C-atom of the reaction centre. SE2: While bimolecular nucleophilic reaction usually proceeds with inversion due to the orientation of the bonding orbitals and lone pairs, electrophilic substitution could induce retention and inversion as well. Both reaction path is accepted by the Fukui FMO (Frontal Molecular Orbital theory). The reaction path of retention is explained by the attack of the electropositive reagent to the electronegative bonding orbital. On the contrary inversion could be favoured by a larger substituent. The simplest example is SE2 reaction of methane with different reagents (NEXT FIGURE) E.D.Jemmis, J. Chanrasekhar and P.v.R. Schleyer, JACS, 101, 527 (1979) és a benne levő referenciák. Hydrogen as a reagent is small enough to attack the bonding orbital of the reaction centre, thus forming a three centered two e− bond, which then proceeds further to the departure of the leaving group (i.e the other hydrogen) and finishing with retention. On the other hand, according to theoretical calculations the larger Li and Be-H favors the SE2 reaction with inversion. E.D.Jemmis, J. Chanrasekhar and P.v.R. Schleyer, JACS, 101, 527 (1979) retenció inverzió inverzió H H H H C Li C Li H BeC Be H H H H HH HH három centrumú - két e -os kötés Unsaturated/Aromatic C-atom 5 Fund. Theor. Org. Chem 6 SE SEAr: The only significant difference between aromatic electrophilic substitution and SE2 reaction on an aliphatic C-atom is the approach of the reaction centre. In case of SEAr the electrophilic reagent approaches to the π electron cloud of the aromatic ring forming a so called π-complex, which is located approximately 3 Å-s above the aromatic ring.Proceeding along the reaction coordinate the substrate and the reagent forms a σ-complex on one of the aromatic carbons, and finally the leaving group (i.e. hydrogen) departures. When the carbon atoms of the ring could be distinguished, the reaction leadsto several isomers. Hydrogen-Deuterium exchange in benzene- σ-complex, π-complex When benzene is dissolved in liquid HF, a phase separation leads to a 1:1 molar mixture that poorly conducts electricity. Nevertheless, the 1:1 molar composition suggests that we are dealing with, not only a mixture, but also a stoichiometric complex. In the (+) (-) presence of BF3 (in addition to HF), a salt-like complex [C6H7] [BF4] is formed which can be crystallized. The melted crystal conducts electricity very well as expected for a salt. This benzenium tetrafluoroborate has the following structure. H H (+) (-) BF4 2.2.2-5. For the cation, three resonance structures may be given [2.2.2-6] which suggest an average of +1/3 of the charge at the two ortho and para positions [2.2.2-7]. HH HH HH (+) (+) (+) 2.2.2-6. H H 1 1 + + 3 3 1 + 3 2.2.2-7. 6 Fund. Theor. Org. Chem 7 SE A slightly more sophisticated MO theory than SHMO yields a somewhat different charge distribution [2.2.2.-8]. However, the two equivalent ortho and the para positions are still the most electron deficient. H H +0.25 +0.25 +0.10 +0.10 +0.30 2.2.2-8. Using DF instead of HF, one of the protons of benzene is exchanged to deuterium. (+) C6H6 + DF + BF3 = [C6H6D] + HF + BF3 2.2.2-9. The H/D exchange is envisioned to occur according to the following mechanism in which a π–complex is formed first and then converted subsequently to an σ-complex. H D + DF + HF H HDD HDH D DF : F : F : F HF π - σ - π - l l The energy profile for this reaction is shown schematically in Figure 2.2.2-1. This energy profile is symmetrical, showing mirror image symmetry with respect to the central intermediate, the σ-complex. 7 Fund. Theor. Org. Chem 8 SE Figure 2.2.2-1. A schematic free-energy profile for the H/D exchange reaction in benzene with H[BF4]. Various methylated benzenes are more basic than benzene itself and they form σ- complexes with HF. In contrast, HCl also dissolves in these hydrocarbons but only forms π– complexes. The concentration of the σ-complex and, consequently, the equilibrium constant (K) can be determined by conductivity measurements, while that of the π–complex can be determined spectroscopically since these complexes are colored. The following table summarizes such relative stabilities as a function of methylation. These relative stabilites are presented as σ- and π-basicities. Table. 2.2.2-2. Sigma and pi-basicities of selected methylated benzenes. CH3 CH3 CH CH 3 3 H3C CH3 CH 3 H3CCH3 H3C CH3 π-basicity 1 1.5 2.0 2.6 4.5 σ-basicity 1 790 106 630x106 2x109 It should be emphasized that the larger σ-basicity values, which measure relative stabilites, do not mean that the σ-complex is more stable than the π–complex. In fact, Figure 2.2.2-1 shows the opposite; the σ–complex is less stable, in the thermodynamic sense, than the π–complex. These σ– and π–basicities do give, however, relative stabilities with respect to the benzene σ– and π– complex. It is interesting to note that the π–basicities hardly change at all, while the σ– basicities change drastically with the number of methyl groups (c.f. Table 2.2.2-2). This implies that the π–complex [2.2.2-10] formation represents only a minor perturbation on the π–aromatic sextet. 8 Fund. Theor. Org. Chem 9 SE F δ− H δ+ HF (a) (b) 2.2.2-10. In contrast to this in the σ–complex [2.2.2-5], the aromatic character ceases to exist and the various methyl groups stabilize the conjugated cation [2.2.2.-6] to various degrees. 15.3 Electrophilic aromatic substitution of benzene The mechanism of electrophilic aromatic substitution in benzene with an electrophile X(+) can be depicted by the following stoichiometric equation: (+) (+) C6H6 + X → C6H5X + H 2.2.2-11.