1-What is substitution reaction? 2-What are can Nucleophilic Substitution Reaction? 3- SN1 reaction. 4-SN2 reaction 5- mechanisms of SN1&SN2

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3 1-What is substitution reaction? 2-What are can Nucleophilic Substitution eaction? 3- SN1 reaction. 4-SN2 reaction 5- mechanisms of SN1&SN2

4 1- SUBSTITUTION EACTIONS

5 1-Substitution eaction In this type of reaction one atom, ion, or group is substituted for another. Its two types: A. Nucleophilic Substitution eaction B. Electrophilic Substitution eaction

6 X + Y Y + X X is called leaving group, a term meaning any group that can be displaced from a carbon atom. alide ions are good leaving groups as they are very week bases. Strong bases such as O - are very poor leaving group. In substitution reaction of alkyl halides, the Iodide ion is the halide most easily displaced.

7 F Cl Br I Increase of eactivity The species that attacks an usually alkyl in substitution reaction is called a nucleophile (abbreviated Nu: - ). Generally, a nucleophile is any species that is attracted to positive center. It is a Lewis base. Most nucleophiles are anions, however, some neutral polar molecules such as 2 O, O, N 2 can also act as nucleophiles by their unshared electrons that can be used to form sigma bonds.

8 Substitutions by nucleophiles are called nucleophilic substitution or nucleophilic displacement. The electrophile (abbreviated E + ) is any species that is attracted toward a negative center. It is a Lewis acid. Some common electrophiles and nucleophiles common electrophiles (E + ) + (Cl) + (-X) -C + =O (COX) NO 2 + (NO 3 ) X + (X 2 ) AlCl 3 AlBr 3 Common nucleophiles (Nu: - ) O - ( 2 O), O - (O), COO - Na + N - 2, 3 N: X - (Cl -, Br - ) Na + CN - - Mg + X, Ar - Mg + X () 2 C=C( 1 ) 2 C 6 6

9 A. Nucleophilic Substitution eaction Q: What is nucleophilic substitution reaction? A species which has ability to donates a pair of electrons is termed as a nucleophile A reaction in which Nu is substituted by another Nu can occur by an: a. S N 1 path b. S N 2 path Most common reaction of alkyl halides (X) and alcohols (O)

10 Nucleophilic Substitution eactions The S N 1 Mechanism

11 S N 1 eaction Unimolecular Nucleophilic Substitution It is a 2 step mechanism involving: 1. Slow: (rate determining) step - ionization of the alkyl halide to form a carbocation (Carbonium ion) Slow X + X 2. Fast step : addition of the nucleophile to the carbocation (Carbonium ion) + Nu Fast Nu

12 The S N 1 Mechanism Acetone is used to dissolve everything! Water is the solvent and nucleophile (solvolysis). This sequence of reactions can be represented on an energy diagram. The formation of the carbocation (carbonium ion) is the high energy (slow) step. Addition of the nucleophile to the carbocation (carbonium ion) is very rapid. 1) 2) C : Br: C + carbocation slow + : O : _ C + + : Br : fast C + : O E C Br t.s.1? t.s. 2? Carbocation intermediate C Nu 3) C + : O fast + C + : O ( ) 3 CBr + 2 O ( ) 3 CO+ + Progress of reaction

13 S N 1 eaction: stereochemistry () Br planar carbocation sp2 50% + C - O 50% attacks top and bottom equally (S) O O + enantiomers () ACEMIZATION

14 Pr C Br 3 C Et 3 o substrate (S) enantiomer Slow -O- polar protic solvent! Pr C 3 C Et planar carbocation Pr C -O- front side attack Pr 3 C Et C O fast Pr C O Et 50% (S) 3 C Et -O- Fast back side attack 3 C O Pr Et fast 3 C O Pr Et 50% ()

15 The S N 1 Mechanism 1) The rate of SN1 reaction Is in the following order C Br > C Br > -C 2 -Br > -Br 2) 3 X undergo SN1 reaction exclusively tertiary secondary primary 3) When weak Nu such as 2 O or O is used the rate of S N 1 reaction Is in the following order: C + + C + C 2 + C 6 5 C2X > C 2 =CC 2 X > 3 X 4) When a strong Nu as CN- is used 3 X undergo SN1 reaction exclusively, tertiary carbocation (very stable) three methyl groups secondary carbocation two methyl groups primary carbocation (unstable) one methyl group very unstable carbocation no methyl groups C 6 5 C 2 X or C 2 =CC 2 X S N 1 2 O or O S N 2 CN - C 6 5 C 2 O or C 2 =CC 2 O C 6 5 C 2 CN or C 2 =CC 2 CN

16 S N 1 eaction: kinetics The 1 indicates that the reaction is unimolecular - only one reactant is involved in the slow step of the reaction. The rate depends only on the concentration of the alkyl halide, not the nucleophile. S N 1 does not involve the nucleophile in the rate determining step. Thus nucleophile has no effect on the reaction rate.

17 S N 1 eaction solvents Usually S N 1 reactions are run in polar protic solvents, compounds with O- groups, as Polar solvent stabilizes the carbocation! The polar protic solvent acts as BOT nucleophile as well as the solvent. Common solvent/nucleophiles include: water, ethanol, methanol, acetic acid, and formic acid.

18 S N 1 eaction solvents Usually S N 1 reactions are run in polar protic solvents, compounds with O- groups, as Polar solvent stabilizes the carbocation! Water O Methanol O OMe The polar protic solvent acts as BOT nucleophile as well as the solvent in S N 1 reactions - solvolysis:. Common solvent/nucleophiles include: water, ethanol, methanol, acetic acid, and formic acid. Ethanol Acetic acid Formic acid O C 2 OEt O C O O C O OAc S N 1 reactions prefer polar-protic solvents that can solvate the anion and cation formed in the rate-determining step. -X + + X - rate-determining step ions solvation of both ions speeds the ionization Carbocation

19 S N 1 eaction solvents Nonpolar Polar Aprotic Solvents Polar Protic Solvents CF 3 COO 2 O POLA S N 2 O C N O - O + S C S N 1 CF 3 C 2 O COO O C 2 O COO Water O Methanol O OMe C 2 O C 2 CCl 4 Ethanol O C 2 OEt C 2 C 2 C 2 Acetic acid O C O OAc Formic acid O C O NONPOLA

20 .W -1 Q1: List the following carbocation in order of increasing stability C 2 3. C( ) 2 Q2: Which of the following compounds is more reactive toward SN1 reaction. Explain why 1. C 6 5 C 2 Br 2. C3Br 3. C 2 =CC 2 Br

21 The S N 2 Mechanism Substitution eactions

22 S N 2 eactions Bimolecular nucleophilic substitution, one-step mechanism, which involves a transition state. Nu attacks from back-side Bimolecular reaction, because both Nu and X are involved in the transition state. Transition state

23 S N 2 eactions The S N 2 mechanism: a) is a single step process b) involves no intermediates c) involves only one transition state, which is of low polarity d) follows second order (bimolecular) kinetics. That is, rate=k[substrate][nucleophile]

24 S N 2 eactions It is second order reaction, because it is proportional to conc. Of Nu & X Increase the steric hindrance around the halogenated carbon Decreases the rate of S N 2 reaction. 3 X are too hindered to undergo S N 2 reaction. X C 2 X 2 CX increasing steric hindrance, decreasing S N 2 rate X most reactive 2 [ 2 CX ] react slowly 3 [ 3 X ].no react by S N 2 When strong Nu as CN- is used, the S N 2 rate in the following order benzylic halide > Allylic halide > Methyl halide ** X and C 2 X (1 X) undergo S N 2 exclusively, irrespective of the strength of Nu-

25 S N 2 eactions Mechanism O + O + Br Br Energy of T. S. O C Br Potential Energy (E) E act transition state for reaction one step O: C Br Average energy of reactants Average energy of products O C Br - Progress of reaction

26 Nu 1 C X Nu 1 C X 1 Nu C + X PC 211/ Dr. Ahmed M. Alafeefy

27 S N 2 eactions Mechanism nucleophilic attack O : attacks back lobe C ()-config. : Br : O : C INVESION (S)-config.

28 S N 2 eactions Mechanism ENEGY POFILE S N 2 ANIMATION C Cl: Press the slide show button to see the animation. Press ESC to finish.

29 S N 2 eactions Mechanism ENEGY POFILE S N 2 ANIMATION :Br: C Cl:

30 S N 2 eactions Mechanism ENEGY POFILE S N 2 ANIMATION :Br: C Cl:

31 S N 2 eactions Mechanism ENEGY POFILE S N 2 ANIMATION :Br: C Cl:

32 S N 2 eactions Mechanism ENEGY POFILE S N 2 ANIMATION :Br: C Cl:

33 S N 2 eactions Mechanism ENEGY POFILE S N 2 ANIMATION :Br C Cl: d- d- Transition State Activated Complex

34 S N 2 eactions Mechanism ENEGY POFILE S N 2 ANIMATION :Br C :Cl:

35 S N 2 eactions Mechanism ENEGY POFILE S N 2 ANIMATION :Br C :Cl:

36 S N 2 eactions Mechanism ENEGY POFILE S N 2 ANIMATION :Br C :Cl:

37 S N 2 eactions Mechanism ENEGY POFILE S N 2 ANIMATION :Br C

38 S N 2 eactions Mechanism The rate depends on both the concentration of the -X and the nucleophile. Stereochemistry of S N 2 eactions When the nucleophile attacks in an S N 2 it is on the opposite side to the position of the leaving group. As a result, the reaction will proceed with an inversion of configuration. O 3 C C C 6 13 Br O C Br C 6 13 O C + C 6 13 Br ()-(-)-2-Bromooctane (S)-(+)-2-Octanol () (S)

39 o Effects of - S N 2 eactions Mechanism The rate of S N 2 reaction is inversely proportional to the streic hindrance around the carbon attached to the leaving group. eactivity order - > C 2 - > ( ) 2 C- > ( ) 3 C- -Br > -C 2 -Br > C C Br Br > primary secondary tertiary eactivity order---- fastest to slowest!

40 S N 2 eactions Mechanism O : C : Br S N 2 - SUBSTATE large groups introduce steric hindrance O : C : Br easy access no steric hindrance

41 S N 2 eactions Mechanism Effects of Nucleophile Since the nucleophile is involved in the rate determining step, the nature of the nucleophile is very important in an S N 2 reaction. More reactive nucleophiles will favor an S N 2 reaction. elative Nucleophilicity O - > O - >>CO 2 - > O > 2 O O 2 O O C _ O _ O _ O _ O I S _ C N Increasing Nucleophilicty 1 ) In general, stronger bases are better nucleophiles 2) owever, iodide doesn t fit that pattern (weak base, but great nucleophile!) 3) Cyanide is an excellent nucleophile because of its linear structure 4) Sulfur is better than oxygen as a nucleophile

42 S N 2 eaction solvents Nonpolar Polar Aprotic Solvents Polar Protic Solvents CF 3 COO 2 O POLA S N 2 O C N O - O + S C S N 1 CF 3 C 2 O COO O C 2 O COO Water O Methanol O OMe C 2 O C 2 CCl 4 Ethanol O C 2 OEt C 2 C 2 C 2 Acetic acid O C O OAc Formic acid O C NONPOLA O

43 S N 2 eaction solvents S N 2 reactions prefer non-polar solvents, or polar-aprotic solvents that do not solvate the nucleophile. S N 2 reactions are accelerated in polar, aprotic solvents S N 2 reactions are retarded (slowed) in polar, protic solvents : X : SMALL, UNSOLVATED C : Br

44 Examples on S N 2 eaction C 2 Cl + O - C 2 O + Cl - C 2 Br + S - C 2 S + Br - C 2 I + O - C 2 O + I - C 2 Br + S - C 2 S + Br - C 2 Cl + 2 N C 2 N 2 + Cl - C 2 Br + CC - C 2 CC + Br - C 2 I + NC - C 2 CN + I -

45 .W -2 Q: Outline all steps in the mechansim of each of the following reaction: 1. C 6 5 C 2 Br + NaCN C 6 5 C 2 CN + NaBr 2. C 6 5 C 2 Br + 2 O C 6 5 C 2 O + Br 3. ( ) 3 CCl + O - Na + ( ) 3 CO + NaCl

46 .W -3 Which member of the following pairs of compounds will react more rapidly with Nu in an SN2 reaction? Explain a. Br or C 2 C 2 Br b. C 2 C 2 Cl or C c. Cl or I d. C 2 C 2 C 2 Cl or 3 CC Cl

47 General concepts for S N 1 & S N 2

48 Solvents Protic solvents: Aprotic solvents: those that contain -O or -N groups worst solvents for S N 2 reactions. Typical protic solvents: water, methanol, ethanol, acetic acid, formic acid have strong dipoles but don t have -O or -N groups. Best for S N 2 reactions. Typical aprotic solvents: acetone, DMF, DMSO, acetonitrile

49 Summary of S N 1 & S N 2 Mechanisms S N 2 A bimolecular reaction Back-side attack 2 ed order in rate Inversion of configuration X > 1 o X > 2 o X S N 1 A unimolecular reaction An ionization reaction 1 st order in rate No inversion of configuration 3 o X > 2 o X

50 Summary of S N 1 & S N 2 Mechanisms Benzylic and allylic undergo both type of substitution S N 1 & S N 2 Mechanisms Depending on the strength of Nu if weak Nu S N 1 if strong Nu. S N 2 Energy required for 3 o alkylhalid is very high, not obtained even with heating, but tertiary alkylhalid is very reactive and proceed via S N 1 reaction. Factors egulate S N 2 and S N 1 Mechanism 1) Nature of the nucleophile 2) Nature of the solvent 3) Nature of the halogen atom

51 Linkage with the life sciences Information Enrichment

52 Medically Speaking Pharmacology And Drug Design Pharmacology is the study of how drugs interact with biological systems, including the mechanisms that explain drug action. Pharmacology is a very important field of study because it serves as the basis for the design of new drugs.

53 Chlorambucil