Nucleophilic Substitution and b -elimination

NucleophilicSubstitution and b-elimination

Substitution Process Nucleophiles have a pair of electrons which are used to form a bond to the electrophile. A Leaving Group departs making room for the incoming nucleophile. Note that the nucleophile converts a lone pair into a bond and becomes more positive by +1 Note that the bond from C to the Leaving Group is collapsed into a lone pair on the Leaving Group which becomes more negative by -1. Nucleophiles can also frequently function as Lewis bases. The electrophile can function as Lewis acid.

b-Elimination Instead of substitution a base can remove both the leaving group and an adjacent hydrogen creating a pi bond. Recall dehydrohalogenation. A pi bond is created.

Competition between Nucleophilic Substitution and b-elimination. First the nucleophilic substitution. The ethoxide attacks the carbon bearing the bromine. Note the change in charges on the nucleophile and the Leaving group

Now the b-elimination. Now the b elimination. The ethoxide (base) attacks the hydrogen on a carbon adjacent to the carbon bearing the Br (b). Since we are using Br as the leaving group this could also be called a dehydrohalogenation.

Summary.

Formal Charges and Nucleophilic Substitution In the free nucleophile the pair of electrons is a lone pair belongs exclusively to the nucleophile. In the product, it is a bond and shared. The result is the nucleophile increases its charge by +1 Conversely the leaving group converts a shared pair of electrons (a bond) into unshared electrons (lone pair). The charge of the leaving group becomes more negative by -1.

Negative Nucleophile N: from -1 to 0 ; Br: from 0 to -1 Other things being equal, the more basic species will be a better nucleophile. NH2- is a better nucleophile than NH3 Neutral Nucleophile N: from 0 to +1; Br: from 0 to -1 Negative Nucleophile, positive leaving group Br: from -1 to 0; O: from +1 to 0

Two Nucleophilic Substitution Mechanisms: SN1 & SN2 SN2 mechanism: substitution, nucleophilic, 2nd order Hydrogens flip to the other side. Inversion of configutation Backside attack Examine important points…. Look at energy profile next…

Energy Profile, SN2

Now the alternative mechanism: SN1 SN1 reaction: substitution, nucleophilic, first order. Step 1, Ionization, Rate determining step. Step 2, Nucleophile reacts with Electrophile. Note stereochemistry: nucleophile can bond to either side of carbocation. Get both configurations. Protonated ether.

Step 3, lesser importance, deprotonation of the ether. Next, energy profile….

Energy Profile of SN1, two steps. Slow step to form carbocation. Rate determining. Examine important points….. Fast step to form product. Carbocation, sp2

Kinetics: SN1vs. SN2 SN1, two steps. SN2, one step.

Effect of Nucleophile on Rate:Structure of Nucleophile SN1: Rate Determining Step does not involve nucleophile. Choice of Nucleophile: No Effect SN2: Rate Determining Step involves nucleophile. Choice of nucleophile affects rate. Note the solvent for this comparison: alcohol/water. Talk about it later… Frequently, better nucleophiles are stronger bases. Compare Compare But compare the halide ions!! In aq. solution F – more basic than I -. (HI stronger acid.) But iodide is better nucleophile.

We need to discuss Solvents Classifications Polar vs non-polar solvents, quantified by dielectric constant. Polar solvents reduce interaction of positive and negative ions. Water > EtOH > Acetic acid > hexane

Solvents. Another Classification Protic vs aprotic solvents. Protic solvents have a (weakly) acidic hydrogen having a positive charge which stabilize anions. Alcohols are protic solvents Aprotic solvents ROH --- Br - --- HOR Increasing polarity

Role of Solvents Some solvents can stabilize ions, reducing their reactivity. Many nucleophiles are ions, anions. Protic solvents can stabilize anions. Protic solvents have (weakly) acidic hydrogens bearing a positive charge. Anions may be stabilized Small, compact anions (like fluoride ion) are especially well stabilized and have reduced nucleophilicity. Iodide ion is large diffuse charge and less stabilization occurs. Methanol, protic solvent, stabilizing the fluoride ion, reducing its nucleophilicity.

nucleophilicity nucleophilicity Halide ion problem The problem: basicity and nucleophilicity of the halide ions do not parallel each other in protic solvents. basicity Iodide ion Bromide ion Chloride ion Fluoride ion Protic solvent solvation The explanation. Fluoride most stabilized in protic solvents reducing its nucleophilicity.

Nucleophilicity in protic solvents Summary for Halide Ions basicity Protic solvents. Protic solvent solvation Iodide ion Bromide ion Chloride ion Fluoride ion basicity But in aprotic solvents. Protic solvent solvation Nucleophilicity in aprotic solvents

Stereochemistry, SN1 at a chiral center. racemization Frequent complication: the Leaving Group will tend to block approach of the nucleophile leading to more inversion than retention for the SN1

Stereochemistry SN2, Inversion at a Chiral Center Inversion, frequently (but not always) the R,S designator changes Examples Here is the inversion motion!

Another Example The chiral center will undergo inversion. The non-reacting chiral C will not change. How to understand the configurations: simply replace the Br with the OCH3 (retention). Now swap any two substituents (here done with H and OCH3) on the reacting carbon to get the other configuration (inversion). Done.

Stereochemistry, SN2 Two things happening here: 1)Substitution of iodide, 127I, with labeled iodide, 131I. 2) Change in stereochemistry Substitution Recall iodide a good nucleophile, acetone an aprotic solvent resulting in highly reactive iodide ion. SN2 Stereochemistry: Inversion Inverted configuration

Comparison of SN1 and SN2 mechanisms. Substitution vs. Loss of Optical Activity Stereochemistry: RI represents the R configuration of the alkyl iodide; RI represents the S configuration. Substitution:I is the normal 127I isotope; I is the tagged 131I iodine isotope. If racemization: “SN1” I - RI RI RI RI RI RI RI RI RI RI RIRI RI RI RI RIRI RI RI RI Only 20% reacts 20% substituted, 20% racemized, 20 % of optical purity lost (80% optically pure). Rate of Loss of optical activity = Rate of substitution. 100% optically pure If inversion: SN2 I - RI RI RI RI RI RI RI RI RI RI RIRI RI RI RI RIRI RI RI RI Only 20% reacts 20% substituted, 40% racemized, 40% optical purity lost (60% optically pure). Rate of loss of optical activity = 2 x Rate of substitution.

Effect of Structure of the Haloalkane on Rates Recall Stability of resulting carbocation, hyperconjugation SN1 Ease of ionization CH3X CH3CH2X (CH3)2CHX (CH3)3CX Methyl primary secondary tertiary Rate of SN1 Reactions

Now for SN2 SN2 Steric Hinderance, difficultyof approach for nucleophile CH3X CH3CH2X (CH3)2CHX (CH3)3CX Methyl primary secondary tertiary Rate of Reactions Summary: Methyl, primary use SN2 mechanism due to steric ease. Tertiary uses SN1 mechanism due to stability of carbocations Secondary utilizes SN1 and/or SN2 – depending on solvent and nucleophile.

Recall: Resonance Stabilization of Carbocations Allylic and benzylic carbocations are stabilized by resonance. SN2 Both SN1

Leaving Group Recall that the leaving group becomes more negative. Generally, the best leaving groups are groups that can stabilize that negative charge: weak bases; conjugate bases of strong acids. Base Strength Example:

Solvents • Polar solvents stabilize ions, better stabilization if the charge is compact. • Polar Protic solvents stabilize both anions (nucleophiles) and cations (carbocations). Accelerate SN1 reactions where charge is generated in the Rate Determining Step. • R-X  [R + --- X -]  R + + X - • Polar aprotic solvents usually stabilize cations more effectively than anions (nucleophiles). Anions (nucleophiles) are left highly reactive. Accelerates SN2 reactions where an anion (nucleophile) is a reactant. • Nuc - + R-X  [Nuc----R----X] -  Nuc-R + X - Stabilized. Stabilized. Not Stabilized. Note that it is the energy of the transition state relative to the reactant which affects the rate of the forward reaction (but not the equilibrium).

Rearrangements for SN1: 1,2 Shift Recall carbocations can rearrange (1,2 shift) to yield a more stable carbocation. Occurs in SN1 – but not SN2 – reactions. Initial Ionization in protic solvent. 1,2 shift converting 2o carbocation to 3o benzylic Nucleophile attacks. Deprotonate to to yield ether Next elimination…

Return to b elimination: competes with nucleophilic substitution. SN1 and/orSN2 The competition: Zaitsev Rule, prefer to form the more substituted alkene (more stable).

Mechanistic Possibilities to eliminate the H+ and X- • Possible Sequences for bond making/breaking… • Regard the alkyl halide as an acid. First remove H+ producing a carbanion , then in a second step remove X- producing the alkene. • or • First remove X- producing a carbocation, then in a second step remove H+ yielding the alkene. E1 • or • Remove H and X in one step to yield the alkene. E2

There are two idealized mechanisms for -elimination reactions • E1 mechanism:at one extreme, breaking of the R-Lv bond to give a carbocation is complete before reaction with base to break the C-H bond • only R-Lv is involved in the rate-determining step (as in SN1) • E2 mechanism:at the other extreme, breaking of the R-Lv and C-H bonds is concerted (same time) • both R-Lv and base are involved in the rate-determining step (as in SN2)

E1 Mechanism ionization of C-Br gives a carbocation intermediate proton loss from the carbocation intermediate to a base (for example, the solvent) gives the alkene

Energy Profile for E1 mechanism, carbocations. Reaction can occur in either direction….. Rate Determining Step; formation of the carbocation. Alkyl Halide  (E1) Alkene + HX Alkyl Halide  (Addition) Alkene + HX

E2 Mechanism breaking of the R-Lv and C-H bonds is concerted Needs Strong Base

Kinetics of E1 and E2 E1 mechanism reaction occurs in two steps the rate-determining step is carbocation formation involving only RLv the reaction is 1st order in RLv and zero order in base E2 mechanism reaction occurs in one step involving both RLv and the base. reaction is 2nd order; first order in RLv and 1st order in base

Regioselectivity of E1/E2 E1: major product is the more stable alkene (more substituted, more resonance) E2: with strong base, the major product is the more stable (more substituted, more resonance) alkene Special notes about sterically hindered basessuch as tert-butoxide, (CH3)3CO -. E2 – anti-Zaitsev: with a strong, sterically hindered base the major product is often the less stable (less substituted) alkene. Reason: hydrogens on less substituted carbons are more accessible. Also E2 vs SN2: In competition of SN2 vs E2: steric bulk in either the alkyl halide or the base/nucleophile prevents the SN2 reaction and favors the E2.

Stereochemistry of E2 • E2 is most favorable (lowest activation energy) when H and Lv are anti and coplanar D E A D E B A B

Examples of E2 Stereochemistry Explain both regioselectivity and relative rates of reaction. Faster reaction Major product. Zaitsev product cis But Slower reaction Only product Anti-Zaitsev trans

Principles to be used in analysis Stereochemical requirement: anti conformation for departing groups. This means that both must be axial. Dominant conformation: ring flipping between two chair conformations, dominant conformation will be with iso propyl equatorial. First the cis isomer. Reactive Conformation; H and Cl are anti to each other In order for the H and the Cl to be anti, both must be in axial positions Iso-propyl groups is in more stable equatorial position. Dominant conformation is reactive conformation.

Now the trans • In the more stable chair of the trans isomer, there is no H anti and coplanar with Lv, but there is one in the less stable chair Reactive but only with the H on C 6 Unreactive conformation Most of the compound exists in the unreactive conformation. Slow reaction. Anti Zaitsev

Example, Predict Product Problem!: Fischer projection diagram represents an eclipsed structure. Task: convert to a staggered structure wherein H and Br are anti and predict product. We will convert to a Newman and see what we get… Now anti and we can see where the pi bond will be. H & Br not anti yet!

Alternative Approach: CAR Anti Geometry A A The H and Br will be leaving: just indicate by disks. CR C < -- > R Note: As we have said before it may take some work to characterize a compound as “racemic” or “meso”. Relationship works in both directions. Should get cis isomer. Meso or Racemic?? This may be recognized as one of the enantiomers of the racemic mixture.

E1 or E2 (Carbocation)

1o good nucleophiles, aprotic solvents 2o good nucleophiles but also poor bases, aprotic solvents 30 1o, 2o, 3o polar solvents, weak nucleophiles, weak bases 1o 2o heat, more hindered 3o heat, more hindered 1o 2o lower hinderance, better nucleophile than base 3o lower hinderance, better nucleophile than base SN2 SN1 ionization Rearrange ? 1o strong, bulky bases 2o strong bases 3o strong bases E1 E2

Recall Halohydrins and Epoxides Internal SN2 reaction with inversion Creation of Nucleophile Creation of good leaving group. Attack by poor nucleophile

Neighboring Group Effect Mustard gases contain either S-C-C-X or N-C-C-X what is unusual about the mustard gases is that they undergo hydrolysis rapidly in water, a very poor nucleophile N S C l C l C l C l Bis(2-chloroethyl)sulfide Bis(2-chloroethyl)methylamine (a sulfur mustard gas) (a nitrogen mustard gas)

Nucleophilic Substitution and b -elimination