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Chapter 5 Nucleophilic Substitution. Advanced Organic Chemistry (Chapter 5) sh.Javanshir. نمونه واکنش های جایگزینی نوکلِِیوفیلی. 5.1 The Limiting Case-Substitution by the Ionization (SN 1 ) Mechanism. First order, SN 1
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Chapter 5 Nucleophilic Substitution Advanced Organic Chemistry (Chapter 5) sh.Javanshir
نمونه واکنش های جایگزینی نوکلِِیوفیلی
5.1 The Limiting Case-Substitution by the Ionization (SN1) Mechanism First order, SN1 leaving group initiates reaction rate DOES NOT depend on nucleophile concentration
Fig. 5.1. Reaction energy profile for nucleophilic substitution by the ionization SN1 mechanism. حالت گذار طبق پذیره هامت شبیه به حد واسط کربوکاتیونی است
5.2 The Limiting Case-Substitution by the Direct (SN2) Mechanism بر همکنش قوی بین اوربیتال ها
HOMO/LUMO interaction (n/σ*) in the back-side attack. Side attack
وارونگی پیکربندی Fig. 5.3. Reaction energy profile for nucleophilic substitution by the direct displacement SN 2 mechanism. The HOMO at the T.S. is p in character, therefore T.S. energy should be lowered by conjugation with adjacent substituents.
Although many first-order substitutions do give completeracemization, many others do not. Typically there is 5–20% inversion, although in a few cases, a small amount of retention of configuration has been found. These and other results have led to the conclusion that in many SN1 reactions at least some of the products are not formed from free carbocations but rather from ion pairs.
5.3 Detailed Mechanistic Description and Borderline Mechanisms Winstein: Concept of ion pairs مفهوم جفت یون در مکانیسم مرزی حایز اهمیت است. contact or tight ion pair Attacking the Nuclephile or Solvent:
The ion-pair concept thus predicts that SN1 reactions can display either complete racemization or partial inversion.
Intimated and Solvent Ion Pairs: 80% acetone and 20% water تبادل عنصر نشان دار p-chlorobenzhydril p-nitrobenzoate Dissociated Ions: The fact that the rate of isotopic exchange exceeds that of racemization indicates that ion pair collapse occurs with predominant retention of configuration. در 100درجه
Addition of nuclephile to the system (0.14 M NaN3): kex: Unchanged krac: No Racemization The intermediate that can racemize is captured by azide ion and converted to substitution product with inversion of configuration. Slide 8
Isotope Labeling reveals Bond breaking without net substitution about one-fifth of the ion pairs recombine rather than react with the nucleophile. A similar experiment in acetic acid indicated about 75% internal return. Ion pair formation and recombination is occurring competitively with ion pair formation and substitution.
A study of the exchange reaction of benzyl tosylates during solvolysis in several solvents showed that with electron-releasing group (ERG) substituents, e.g., p-methylbenzyl tosylate, the degree of exchange is quite high, implying reversible formation of a primary benzyl carbocation. For an electron-withdrawing group (EWG), such as m- Cl, the amount of exchange was negligible, indicating that reaction occurred only by displacement involving the solvent. When an EWG is present, the carbocation is too unstable to be formed by ionization. This study also demonstrated that there was no exchange with added “external” tosylate anion, proving that isotopic exchange occurred only at the ion pair stage.
Demonstrating the ion pair return The rate of decrease of optical rotation (racemisation) is greater than the rate of product formation. The solvent-separated ion pair is the most likely intermediate to play this role.
راسمیک شدن همواره با تبادل ایزوتوپی همراه نیست. sulfonate can rotate with respect to the carbocation without migrating to its other face. The unlikely alternative مکانیسم هماهنگ
Special Salt Effect: • Addition of salts typically causes an increase in the rate of solvolysis of 2° alkyl arensulfonates that is linear with salt concentration (due to the increase in dielectric constant of the medium). • The addition of LiClO4 or LiBr in the acetolysis of certain tosylates produced an initial steep rate acceleration that then decreased to the normal linear acceleration (caused by the ordinary salt effect). • This is interpreted as follows: the ClO4- (or Br-) traps the solvent separated ion pair to give R+ ClO4- which, being unstable under these conditions, goes to product. Hence, the amount of solvent-separated ion pair that would have returned to the starting material is reduced, and the rate of the overall reaction is increased.
Robbins: Ion pairs might not only be involved in SN1 and borderline processes but also in displacement exhibiting the stereochemical and kinetic characteristic of the SN2 process.
Fig. 5.4. Schematic relationship between reactants, ion pairs, and products in substitution proceeding through ion pairs.
Fig. 5.6. Reaction energy profiles showing decreasing carbocation stability in change from SN 1(lim) to SN 2(lim) mechanisms.
Nucleophilic participation of the solvents in borderline mechanisms is related to:a) Solvent nucleophilicitySolvents like CF3COOH or CF3CH2OH are used to define the characteristics of reactions proceeding without nucleophilic solvent participationsb) Structure of the reactant(2- adamantyl system has been considered as a model reactant for defining of ionization without nucleophilic solvent participations)Solvation is minimized by steric hindrance and the 2-adamantyl system is regarded as being a secondary reactant that cannot accommodate significant back-side nucleophilic participation.
5.4 Carbocations گرماگیر Ionization in solvent is feasible because of solvation. Evidences:1) solution of Ph3CCl (trityl chloride) in liquid SO2 is conducting. 2) Ph3CClO4 has ionic behavior. Triphenyl methyl chloride
Relative Stability HR: Acidity function of the medium For dilute solutions: HR = pH Advanced Organic Chemistry (Chapter 5) sh.javanshir
Hydride Affinity Carbocation stability in the gas phase can be measured by mass spectrometry and reported as hydride affinity, which is the enthalpy of the reaction: Table 5.5. Hydride Affinity of Some Carbocations
Stability Order of Carbocations Based on Solvolysis Rate: 3° > 2° > 1° > CH3+ Stabilization of Carbocations: سد انرژی چرخشی
The destabilizing effects of CYANO and FORMYL groups are less.They can act as a p donors.
Cyclopropyl Cation: tri-Cyclopropyl methyl Cation > tri-phenyl methyl cation صورت بندی نیمسازی
فقط صورت بندی نیمسازی قدرت پایدارکنندگی دارد
FSO3H - SbF5 - SO2 -30oC Study of Carbocations Rearrangement NMR spectroscopy in super acid media (magic acid): FSO3H - SbF5 - SO2 Powerful protonating ability & Non-Nucleophilic isobutanol t-Bu+ یونش در سوپر اسید ها منجر به تشکیل پایدار ترین کربوکاتیون ها می شود. (طرح 5-3 کتاب) Rearrangement: C4 → t-Bu+ C5 → t-pentyl+ C6 → t-hexyl+
Carbocations have Sp2 hybridization (planar) Decrease of rate of solvolyse Increase of hydride affinity
NUCLEOPHILES AND BASES THE FUNDAMENTAL DISTINCTION kinetic (or rate) parameter Nucleophilicity Basicity thermodynamic (or equilibrium) parameter. All nucleophiles are bases …... and all bases are nucleophiles. A good base is not necessarily a good nucleophile, and vice versa. HOWEVER :
NUCLEOPHILE VERSUS BASE Nu1 Nu2 is a better nucleophile Nucleophilicity = Kinetic ( FASTER RATE ) Rate = k2[RX][Nu] Nu2 good nucleophile increases k2 (I.e., the rate) Nu1 is a better base Basicity = Thermodynamic ( STRONGER BOND ) B:- + H+ B-H strong base shifts equilib.
DIFFERENT PLACES ON THE ENERGY PROFILE DETERMINE NUCLEOPHILICITY AND BASICITY NUCLEOPHILES Nucleophilicity is determined here activation energy and rate (kinetics) faster is better BASES Basicity is determined here strength of bonds and position of equilibrium lower energy is better
5.5 Nucleophilicity and Solvent Effect Factors the Effect on Nucleophilicity: 1)A high Solvation Energy of The Nuclephile lowers the G.S. and increase the activation energy. 2) Stronger bond between nucleophilic atom and carbon cause the stabilization of the T.S. and will reduce the activation energy. 3) A bulky nuclephile will be less reactive than smaller one because of non-bonded repulsions that develop in the T.S. 4) High electronegativity is unfavorable. 5)Polarizibility: The more easily distorted the atom, the better its nucleophilicity. Polarizibility increase with atomic number going down in the periodic table.
.. : : Y .. .. - : : X .. WHAT IS THE IDEAL NUCLEOPHILE ? SN2 REACTIONS LARGE STERIC PROBLEMS no way ! bad R SMALL : C Br good R R Smaller is better ! For an SN2 reaction the nucleophile must find the back lobe of the sp3 hybrid orbital that the leaving group is bonded to.
.. .. :F: :Cl: .. .. EXPECTED “IDEAL” NUCLEOPHILES cyanide - ROD OR SPEAR SHAPED :C N: - - + :N N N: azide SMALL SPHERES These types should be able to find the target ! - - etc. Generally this idea is correct.
OUR NAÏVE EXPECTATION We would expect the halides to be good nucleophiles: ionic radii: 1.36 A 1.81 A 1.95 A 2.16 A smallest ion - - - - F Br I Cl and we would expect the smallest one (fluoride) to be the best nucleophile, ….. however, that is not usually the case.
EXPERIMENTAL RESULTS RELATIVE RATES OF REACTION FOR THE HALIDES MeOH CH3-I + NaX CH3-X + NaI Rate = k [CH3I] [X-] SN2 k slowest F- 5 x 102 Cl- 2.3 x 104 Br- 6 x 105 fastest I- 2 x 107 * MeOH solvates like water but dissolves everything better.
SOLVATION Solvation reverses our ideas of size.
HEAT OF SOLVATION ENERGY IS RELEASED WHEN AN ION IS PLACED IN WATER - F gas phase - 120 Kcal / mole HEAT OF SOLVATION F- (g) F- (aq) O H H O The interaction between the ion and the solvent is a type of weak bond. Energy is released when it occurs. Solvation lowers the potential energy of the nucleophile making it less reactive. - SOLVATED ION H H F H H O H H O water solution
- X(H2O)n HALIDE IONS IONIC RADIUS 1.36 A 1.81 A 1.95 A 2.16 A smallest ion - - - - F Br I Cl Heats of solvation in H2O - 120 - 90 - 75 - 65 Kcal / mole increasing solvation larger n smaller n SMALL IONS SOLVATE MORE THAN LARGE IONS
SMALL IONS SOLVATE MORE HEAVILY THAN LARGE ONES strong interaction with the solvent - - F I BETTER NUCLEOPHILE O H H H O H O H ...smaller solvent shell ...escapes easily …more potential energy H - O H H H - O H O H H H H H H H O O H O O solvent shell H H “Effective size” is larger. Heavy solvation lowers the potential energy of the nucleophile. weak interaction with the solvent It is difficult for the solvated nucleophile to escape the solvent shell. This ion is less reactive.
PROTIC SOLVENTS water methanol ethanol amines Water is an example of a “protic” solvent. Protic solvents are those that have O-H, N-HorS-H bonds. Protic solvents can form hydrogen bonds and can solvate both cations and anions.
LARGER IONS ARE BETTER NUCLEOPHILES IN PROTIC SOLVENTS THREE FACTORS ARE INVOLVED : In protic solvents the larger ions are solvated less (smaller solvent shell) and they are, therefore, effectively smaller in size and have more potential energy. 1 Since the solvent shell is smaller in a larger ion it can more easily “escape” from the surrounding solvent molecules during reaction. There is more potential energy. 2 3 The larger ions are thought (by some) to be more “polarizable”. see the next slide …..
POLARIZABILITY Polarizability assumes larger ions are able to easily distort the electons in their valence shell, and that smaller ions cannot. C Br VERY HYPOTHETICAL The distortion of large ions is easier because the orbital clouds are more diffuse. The nucleophile “flows” into the reactive site.