Pharmaceutical Organic Chemistry By Dr. Mehnaz Kamal Assistant Professor Pharmaceutical Chemistry Prince Sattam Bin Abdulaziz University

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

1- Substitution reactions

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

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

The species that attacks an R “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 H2O, CH3OH, CH3NH2 can also act as nucleophiles by their unshared electrons that can be used to form sigma bonds.

Some common electrophiles and nucleophiles 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

Nucleophilic Substitution Reaction 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. SN1 path b. SN2 path Most common reaction of alkyl halides (RX) and alcohols (ROH)

Nucleophilic Substitution Reactions The SN1 Mechanism

SN1 Reaction 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) 2. Fast step: addition of the nucleophile to the carbocation (Carbonium ion)

The SN1 Mechanism 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. (CH3)3CBr + H2O Carbocation intermediate (CH3)3COH+H+ t.s.1 ? t.s. 2 ? Progress of reaction E carbocation

SN1 Reaction: stereochemistry 50% sp2 + - planar carbocation attacks top and bottom equally (R) 50% (S) (R) enantiomers RACEMIZATION

The SN1 Mechanism 1) The rate of SN1 reaction Is in the following order 2) 3° RX undergo SN1 reaction exclusively 3) When weak Nu such as H2O or ROH is used the rate of SN1 reaction Is in the following order: C6H5CH2X > CH2=CHCH2X > 3° RX 4) When a strong Nu as CN- is used 3° RX undergo SN1 reaction exclusively, C6H5CH2X or C6H5CH2OH or CH2=CHCH2OH CH2=CHCH2X C6H5CH2CN or CH2=CHCH2CN SN1 H2O or ROH SN2 CN-

SN1 Reaction: 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. SN1 does not involve the nucleophile in the rate determining step. Thus nucleophile has no effect on the reaction rate.

SN1 Reaction solvents R-X R+ + X- Usually SN1 reactions are run in polar protic solvents, compounds with O-H groups, as Polar solvent stabilizes the carbocation! The polar protic solvent acts as BOTH nucleophile as well as the solvent in SN1 reactions - solvolysis:. Common solvent/nucleophiles include: water, ethanol, methanol, acetic acid, and formic acid. SN1 reactions prefer polar-protic solvents that can solvate the anion and cation formed in the rate-determining step. ions R-X R+ + X- solvation of both ions speeds the ionization rate-determining step Carbocation

SN1 Reaction solvents SN1 SN2 Polar Protic Solvents Nonpolar or Polar Aprotic Solvents SN1 SN2 NONPOLAR

H.W -1 Q1: List the following carbocation in order of increasing stability Q2: Which of the following compounds is more reactive toward SN1 reaction. Explain why 1. C6H5CH2Br 2. CH3Br 3. CH2=CHCH2Br

Substitution Reactions The SN2 Mechanism Substitution Reactions

Bimolecular nucleophilic substitution, one-step mechanism, which SN2 Reactions Bimolecular nucleophilic substitution, one-step mechanism, which involves a transition state. Nu attacks from back-side Bimolecular reaction, because both Nu and RX are involved in the transition state. Transition state

SN2 Reactions The SN2 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]

SN2 Reactions It is second order reaction , because it is proportional to conc. Of Nu & RX Increase the steric hindrance around the halogenated carbon Decreases the rate of SN2 reaction. 3° RX are too hindered to undergo SN2 reaction. CH3X RCH2X R2CHX increasing steric hindrance , decreasing SN2 rate CH3X…… most reactive 2 ° [R2CHX ]…… react slowly 3 ° [R3X ] …….no react by SN2 When strong Nu as CN- is used, the SN2 rate in the following order benzylic halide > Allylic halide > Methyl halide ** CH3X and RCH2X (1° RX) undergo SN2 exclusively, irrespective of the strength of Nu-

SN2 Reactions Mechanism SN2 - SUBSTRATE .. R H O : .. C : Br large groups introduce steric hindrance R R H O : .. H C : Br easy access no steric hindrance H H

SN2 Reactions Mechanism Progress of reaction Potential Energy (E) Energy of T. S. Average energy of reactants of products ∆H for reaction Eact transition state one step

C R H CH3 Br : .. O R .. H O : C .. CH3 H SN2 Reactions Mechanism nucleophilic attack C R H CH3 Br : .. (R)-config. O attacks back lobe R .. H O : C .. CH3 INVERSION (S)-config. H

C R .. Cl: .. H CH3 SN2 Reactions Mechanism SN2 ANIMATION ENERGY PROFILE SN2 Reactions Mechanism SN2 ANIMATION R .. C Cl: .. H CH3 Press the slide show button to see the animation. Press ESC to finish.

C R .. .. :Br: Cl: .. H CH3 SN2 Reactions Mechanism SN2 ANIMATION ENERGY PROFILE SN2 Reactions Mechanism SN2 ANIMATION R :Br: .. .. C Cl: .. H CH3

C R .. .. :Br: Cl: .. H CH3 SN2 Reactions Mechanism SN2 ANIMATION ENERGY PROFILE SN2 Reactions Mechanism SN2 ANIMATION R :Br: .. .. C Cl: .. H CH3

C R .. .. :Br: Cl: .. H CH3 SN2 Reactions Mechanism SN2 ANIMATION ENERGY PROFILE SN2 Reactions Mechanism SN2 ANIMATION R :Br: .. .. C Cl: .. H CH3

C R .. .. :Br: Cl: .. H CH3 SN2 Reactions Mechanism SN2 ANIMATION ENERGY PROFILE SN2 Reactions Mechanism SN2 ANIMATION R :Br: .. .. C Cl: .. H CH3

C R .. .. :Br Cl: H CH3 SN2 Reactions Mechanism SN2 ANIMATION d- d- ENERGY PROFILE SN2 Reactions Mechanism SN2 ANIMATION R Transition State :Br .. Cl: .. d- d- C H CH3 Activated Complex

C R .. .. :Br :Cl: H CH3 SN2 Reactions Mechanism SN2 ANIMATION ENERGY PROFILE SN2 Reactions Mechanism SN2 ANIMATION R :Br .. :Cl: .. C H CH3

C R .. .. :Br :Cl: H CH3 SN2 Reactions Mechanism SN2 ANIMATION ENERGY PROFILE SN2 Reactions Mechanism SN2 ANIMATION R :Br .. :Cl: .. C H CH3

C R .. .. :Br :Cl: H CH3 SN2 Reactions Mechanism SN2 ANIMATION ENERGY PROFILE SN2 Reactions Mechanism SN2 ANIMATION R :Br .. :Cl: .. C H CH3

SN2 Reactions Mechanism ENERGY PROFILE SN2 ANIMATION R :Br .. C H CH3

SN2 Reactions Mechanism The rate depends on both the concentration of the R-X and the nucleophile. Stereochemistry of SN2 Reactions When the nucleophile attacks in an SN2  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. (R) (S)

Reactivity order---- fastest to slowest! SN2 Reactions Mechanism Effects of R- The rate of SN2 reaction is inversely proportional to the streic hindrance around the carbon attached to the leaving group. Reactivity order CH3-  >  CH3CH2-  >  (CH3)2CH-  >  (CH3)3C- Reactivity order---- fastest to slowest!

SN2 Reactions Mechanism Effects of Nucleophile Since the nucleophile is involved in the rate determining step, the nature of the nucleophile is very important in an SN2 reaction. More reactive nucleophiles will favor an SN2 reaction. Relative Nucleophilicity 1) In general, stronger bases are better nucleophiles 2) However, 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

SN2 Reaction solvents SN1 SN2 Polar Protic Solvents Nonpolar or Polar Aprotic Solvents SN1 SN2 NONPOLAR

SN2 Reaction solvents .. R : : .. C : Br R R X SN2 reactions prefer “non-polar” solvents, or polar-aprotic solvents that do not solvate the nucleophile. SN2 reactions are accelerated in polar aprotic solvents SN2 reactions are retarded (slowed) in polar protic solvents .. R : : .. X C : Br SMALL, UNSOLVATED R R

Examples on SN2 Reaction CH3CH2Cl + HO- CH3CH2OH + Cl- CH3CH2Br + HS- CH3CH2SH + Br- CH3CH2I + RO- CH3CH2OR + I- CH3CH2Br + RS- CH3CH2SR + Br- CH3CH2Cl + H2N CH3CH2NH2 + Cl- CH3CH2Br + RCC- CH3CH2CCR + Br- CH3CH2I + NC- CH3CH2CN + I- ..

H.W -2 Q: Outline all steps in the mechansim of each of the following reaction: 1. C6H5CH2Br + NaCN C6H5CH2CN + NaBr 2. C6H5CH2Br + H2O C6H5CH2OH + HBr 3. (CH3)3CCl + CH3O-Na+ (CH3)3COCH3 + NaCl

H.W -3 Which member of the following pairs of compounds will react more rapidly with Nu in an SN2 reaction? Explain

General concepts for SN1 & SN2

Solvents Protic solvents: “…those that contain -OH or -NH groups …worst solvents for SN2 reactions.” Typical protic solvents: water, methanol, ethanol, acetic acid, formic acid Aprotic solvents: “…have strong dipoles but don’t have -OH or -NH groups. Best for SN2 reactions.” Typical aprotic solvents: acetone, DMF, DMSO, acetonitrile

Summary of SN1 & SN2 Mechanisms A bimolecular reaction Back-side attack 2nd order in rate Inversion of configuration CH3X > 1oRX > 2oRX SN1 A unimolecular reaction An ionization reaction 1st order in rate No inversion of configuration 3oRX > 2oRX

Summary of SN1 & SN2 Mechanisms Benzylic and allylic undergo both type of substitution SN1 & SN2 Mechanisms Depending on the strength of Nu if weak Nu ……… SN1 if strong Nu ………. SN2 Energy required for 3o alkyl halide is very high, not obtained even with heating, but tertiary alkyl halide is very reactive and proceed via SN1 reaction. Factors Regulate SN2 and SN1 Mechanism 1) Nature of the nucleophile 2) Nature of the solvent 3) Nature of the alkyl halide

Linkage with the life sciences Information Enrichment

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.

Chlorambucil