Course code : CEM 43244 Course title : Advanced rganic Chemistry I Physical rganic Chemistry (15 h) Dr. Dinesh Pandithavidana E-mail: dinesh@kln.ac.lk Mobile: 0777-745-720 ffice: B1 222/3
Stereochemical Principles Stereoselective Reactions: A stereoselective reaction can produce multiple stereoisomers theoretically, but more of some produced than others Br + Br base (2R)-2-bromo-1,1-dimethylcyclohexane + (2S)-2-bromo-1,1-dimethylcyclohexane (1Z)-3,3-dimethylcyclohexene no E (trans) isomer is formed
Stereospecific Reactions: A stereospecific reaction produces different stereoisomer products from different stereoisomer reactants. S N 2 mechanism stereospecific S N 1 mechanism non-stereospecific
Regioselective Reactions: A regioselective reaction is one in which multiple constitutional isomers possible, but more of some formed than others. Br Br major product + Br no measurable quantity formed
Prochiral: Definitions A molecule is prochiral if the addition of a new group or an exchange of one group on the molecule would create a new stereocenter and, therefore, a chiral molecule. A prochiral atom must be bonded to three different groups before any change is made. * * The molecule on the left is prochiral because a new stereocenter can be made by replacing one group on the carbon marked with an asterisk (*) with a new one. The molecule on the right is prochiral because a new stereocenter can be made by adding a new group to the carbon marked with an asterisk.
Proton Equivalence Proton NMR is much more sensitive than 13 C and the active nucleus ( 1 ) is nearly 100 % of the natural abundance. Shows how many kinds of nonequivalent hydrogens are in a compound. Theoretical equivalence can be predicted by seeing if replacing each with X gives the same or different outcome. Equivalent s have the same signal while nonequivalent are different and as such may cause additional splitting (diastereotopic effect). There are degrees of nonequivalence
Nonequivalent ydrogens Replacement of each with X gives a different constitutional isomer. Then the ydrogens are in constitutionally heterotopic environments and will have different chemical shifts they are nonequivalent under all circumstances.
Equivalent ydrogens Two s that are in identical environments (homotopic) have the same NMR signal. Test by replacing each with X if they give the identical result, they are equivalent Protons are considered homotopic
Enantiotopic Distinctions If ydrogens are in environments that are mirror images of each other, they are enantiotopic. Replacement of each with X produces a set of enantiomers. The ydrogens have the same NMR signal in the absence of chiral materials (optically active solvents, co-solvents or Lewis acids)
Diastereotopic Distinctions In a chiral molecule, paired hydrogens can have different environments and different shifts. Replacement of a pro-r hydrogen with X gives a different diastereomer than replacement of the pro-s hydrogen. Diastereotopic hydrogens are distinct chemically and spectrocopically.
Symmetry in NMR Spectra Protons and other nuclei in NMR spectra can be classified as heterotopic, diastereotopic, enantiotopic and homotopic. eterotopic and diastereotopic protons will have different chemical shifts and couplings to neighboring magnetic nuclei. Enantiotopic and homotopic protons will have identical chemical shifts. They may or may not have identical couplings to other nuclei. Distinction can be made by the substitution test. The Substitution Test for Equivalance of Protons: For a pair of protons to be tested, replace one with another group (which is not present in the molecule). Compare the two structures formed: If they are identical, the protons are homotopic, If they are enantiomers, the protons are enantiotopic. If they are diastereomers then the protons are diastereotopic. If they are structural isomers, the protons are heterotopic.
Correlation of Structures with Reactivity The structural changes which are used to bring about electronic perturbations are substituent groups, which may be introduced, near to the reaction center and which do not themselves take part directly in the reaction being considered. It is the change in reaction, brought about by substitution, which are of interest, so structural changes must be determined relative to some standard substituent which is electronically neutral. ydrogen is normally adopted as the zero substituent. This is because that most reactions studied, occur at carbon as one reaction center, and the electronegativities of carbon & hydrogen are almost equal. So that C bond has no polarity. Furthermore, the hydrogen substituent has no unshared pairs of π-electrons. X k a + + X
We can measure the ionization of substituted benzoic acid in water and then determine equilibrium constant, K a. X k a + + X X N 2 CN Cl C 3 C 3 Log K a -3.45-3.56-4.00-4.20-4.37 -.4.47 a σ +0.75 +0.64 +0.2 0.00-0.17-0.27 K a has been increased by substitution of for an electron-withdrawing groups which weakens the - bond, and conversely decreased by an electron donating group. This reveals the carboxylic acid acts as a the electrophile and water acts as the nucleophile. Relative to hydrogen, in this series, electron withdrawing sustituents increase the acidity and electron donating susbtituents decrease the acidity.
Quantitatively, the effect of each substituent, relative to that of hydrogen, may be obtained by a comparison of G for dissociation constants of substituted benzoic acid (K X ) with that of the parent compound (non substituted benzoic acid) K. Substituent effect = G X G K = log K X =σ σ is called substituent constant because it s value depends on the nature of substituent. Energy G - G X - 2 N
For ydrogen, as a reference point; σ = 0.0 Because if so if there is no substituent, log K = log1 = 0 K log K K X X k a + X + electron donating groups. p-me. m-me p-f.. m-me.p-n2 m-cn...... p-i p-cl p-br m-br, Cl m-i Gradient = 1 electron withdrawing groups σ
Let s see the hydrolysis of methyl benzoate and ionization of phenyl acetic acid with compared to ionization of benzoic acid. X X C 3 Rates are evidently increased by electron withdrawing substituents on the ester, which must accordingly be the electrophiles. In case of phenyl acetic acid, ionization center, C and benzene ring with the substituent have been isolated by the C2- group. So the reaction is less sensitive to substituents than benzoic acid ionization reaction. X + k a X
log K K X for Methyl benzoate (m > 1) ammett Plot for Benzoic acid (m = 1) electron donating groups for Phenyl acetate (m < 1) electron withdrawing groups σ *** This σ corresponds to ionization of Benzoic acid which is our standard reaction
Now it is evident that the linear relationship of previous plots implies; log K K X ασ K X log =ρ.σ K Introducing a constant of proportionality, ρ, known as the reaction constant. The ammett Equation: The equation describing the straight line correlation between a series of reactions with substituted aromatics and the hydrolysis of benzoic acids with the same substituents is known as the ammett Equation.
The reaction constant, ρ, describes the susceptibility of the reaction to substituents, compared to the ionization of benzoic acid. It is equivalent to the slope of the ammett plot. Information on the reaction and the associated mechanism can be obtained based on the value obtained for ρ. If the value of: ρ>1, the reaction is more sensitive to substituents than benzoic acid and negative charge is built during the reaction (or positive charge is lost). 0<ρ<1, the reaction is less sensitive to substituents than benzoic acid and negative charge is built (or positive charge is lost). ρ=0, no sensitivity to substituents, and no charge is built or lost. ρ<0, the reaction builds positive charge (or loses negative charge).
Significance of ρ
Reaction center is perturbed by the substituents through, 1) Inductive effect 2) Resonance effect 3) Filed effect Resonance Effect (R) The effect is described as a +R effect, if it results in donation of electrons from substituent to reaction center. And a R effect, if a withdrawal of electron results. Donor groups typically possess unshared π-electron pairs or electrons on an atom directly attached to the ring. E.g. -NR 2,-R, -SR, -PR 2, -X, C C 2 These groups are all capable of exerting +R effect which stabilizes an acceptor center when they are at ortho- or para- positions.
C C Stabilization via +R effect C3 C3 Substituents which have π-acceptor center, adjacent to the ring, which can act as electron acceptors. E.g: C N C N C C C C Stabilization via -R effect C C
In case of Resonance Effect, many substituents give rise to a perturbation which is greater when they are located at ortho- or para- than they are at meta- position. C C This is because little interactions between donor and acceptor centers will occur, if they are located at meta, so resonance structures cannot be drawn due to the presence of high energy. C 3 C 3
Inductive Effect & Field Effect Inductive effect is caused by differences in electronegativity which polarize both σ and π bonds. This also depends on number of bonds between the reaction center and substituent. Inductive ef f ect +δ Me 3 N C Fieldeffect C +δδ The Field effect is propagated through space and depends more for its intensity and proximity than on the number of bonds between the reaction center and substituent. When inductive effect is there, field effect is also should be associated with it.
Can you explain differences of σ values? F C C σ = 0.15 σ = 0.34 F C C σ = - 0.4 σ = + 0.12
Deviations from Linearity in ammett Plots Modified Substituent Constants σ _ Scale: We can develop new σ values for these substrates by separating out these throughconjugation effects from inductive effects. Develop line with ρ value based on m-substituents only, which cannot exhibit resonance effects. The amount by which certain substituents deviate from the line can be added to their σ values to produce a new scale of σ _ value. Substituent effect by the enhanced resonance = ( σ σ)
Modified Substituent Constants σ + Scale: Similarly, in some cases,we find that strongly electron-donating substituents don t fall on the line predicted by the ammett correlation. Example: SN 1 solvolysis of p-substituted tertiary halides Substituent effect by the enhanced resonance = ( σ + σ)
Uses of ammett Plots (1) Calculation of k or K for a specific reaction of a specific compound: K X log =ρ.σ K If we know ρ for a particular reaction, then we can calculate the rate or equilibrium constant for any substituent relative to that for the unsubstituted compound (because we also know σ for the substituent). (2) To provide information about reaction pathways: Magnitude and sign of ρ tell about development of charge at reaction centre. If σ + or σ gives a better correlation than σ, then we know we have a reaction where through conjugation is important.
The ammond Postulate 29
The ammond Postulate In an endothermic reaction, the transition state resembles the products more than the reactants, so anything that stabilizes the product stabilizes the transition state also. Thus, lowering the energy of the transition state decreases E a, which increases the reaction rate. If there are two possible products in an endothermic reaction, but one is more stable than the other, the transition state that leads to the formation of the more stable product is lower in energy, so this reaction should occur faster. 30
The ammond Postulate. In the case of an exothermic reaction, the transition state resembles the reactants more than the products. Thus, lowering the energy of the products has little or no effect on the energy of the transition state. Since E a is unaffected, the reaction rate is unaffected. The conclusion is that in an exothermic reaction, the more stable product may or may not form faster, since E a is similar for both products. 31
The ammond Postulate: The ammond postulate estimates the relative energy of transition states, and thus it can be used to predict the relative rates of two reactions. According to the ammond postulate, the stability of the carbocation determines the rate of its formation. Energy diagram for carbocation formation in two different S N 1 reactions 32