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Unformatted text preview: Organic Organic Lecture Series CH 310/318 M LECTURE 22 Textbook Assignment: Chapter 9- Nucleophilic Substitution and β-elimination Today’s Topics: Nucleophilicity; the E1 & E2 Mechanisms Nucleophilicity; Notice & Announcements: Office moved to WEL 4.242 1 Organic Lecture Series Nucleophilic Substitution and β-Elimination
2 Nucleophilicity Organic Organic Lecture Series • Nucleophilicity: A kinetic property measured by the rate at which a Nu: causes a nucleophilic substitution under a standardized set of experimental conditions. • Basicity: A equilibrium property measured by the position of equilibrium in an acid-base reaction. • Because all nucleophiles are also bases, correlations between nucleophilicity and basicity are studied.
3 Organic Lecture Series Effectiveness
Increasing Nucleophilicity Increasing Nucleophilicity Increasing Nucleophilicity Increasing Nucleophilicity Good Nucleophile Br-, I CH S - RS , HO-, C H O- RO , CN - N ,
3 3 3 Cl , F -- C H3 C OO , R COO Moderate CH3 SH, RSH, R2 S NH 3 , RN H2 , R2 NH, R3 N H2 O Poor CH3 O H, ROH CH3 COO H, RCO OH 4 Nucleophilicity Organic Organic Lecture Series • A guiding principle is the “freer” the nucleophile, the greater greater its nucleophilicity. 5 Nucleophilicity Nucleophilicity Organic Lecture Series • Polar aprotic solvents (e.g., DMSO, acetone, acetonitrile, DMF)
– are very effective in solvating cations, but not nearly so effective in solvating anions. – because anions are only poorly solvated, they participate readily in SN2 reactions, and nucleophilicity parallels basicity: F- > Cl- > Br- > I6 Nucleophilicity Organic Organic Lecture Series • Polar protic solvents (e.g., water, methanol)
– Anions are highly solvated by hydrogen bonding with the solvent. – The more concentrated the negative charge of the anion, the more tightly it is held in a solvent shell. – The nucleophile must be at least partially removed from its solvent shell to participate in SN2 reactions. Because F- is most tightly solvated and I- the least, nucleophilicity is I- > Br- > Cl- > F7 Nucleophilicity • Generalization Organic Lecture Series – In a series of reagents with the same nucleophilic atom, anionic reagents are stronger nucleophiles than neutral reagents; this trend parallels the basicity of the the nucleophile.
Increasing Nucleophilicity H2 O ROH N H3 RSH < < < < OH RO RS
- N H2 8 Nucleophilicity • Generalization Organic Organic Lecture Series – When comparing groups of reagents in which the nucleophilic atom is the same, the stronger the base, the greater the nucleophilicity.
N u cleophile RCOO Carb oxylate ion
- HO Hydroxide ion - RO Alk oxide ion - In creasing N ucleoph ilicity Con jugate acid pK a RCOOH 4-5 HOH 15.7 Increasin g A cidity ROH 16-18 (stronger the conj base, the weaker the acid) 9 Rearrangements in SN1 Organic Lecture Series • Rearrangements are common in SN1 reactions if the initial carbocation can rearrange to a more stable one. + CH3 OH CH 3 OH Cl 2-Chloro-3phenylbutane + OCH3 + CH 3 OH + Cl H 2-Methoxy-2-phenylbutane 10 Rearrangements in SN1 Organic Organic Lecture Series • Mechanism of a carbocation rearrangement
A 2° carbocation + : Cl (2) H +
H A 3° benzylic carbocation H + (3) + + : O-CH3 + H CH3 O
11 An oxo ni u m i o n Organic Lecture Series Summary of SN1 & SN2
Type of Alkyl Halide Methyl CH3 X Primary RCH2 X Secondary R2 CHX Tertiary R3 CX Substitution at a stereocenter SN 2 SN 2 is favored. SN 1 SN 1 does not occur. The methyl cation is so unstable, it is never observed in solution. SN 1 rarely occurs. P rimary cations are so unstable, that they are never observed in solution. SN 1 is favored in protic solvents with poor nucleophiles. Carbocation rearrangements may occur. SN 1 is favored because of the ease of formation of tertiary carbocations. Racemization is favored. The carbocation intermediate is planar, and attack of the nucleophile occurs with equal probability from either side. There is often some net inversion of configuration.
12 SN 2 is favored. SN 2 is favored in aprotic solvents with good nucleophiles. SN 2 does not occur because of steric hindrance around the reaction center. Inversion of configuration. The nucleophile attacks the stereocenter from the side opposite the leaving group. Organic Organic Lecture Series β-Elimination β-Elimination: A reaction in which a small molecule, such as HCl, HBr, HI, or HOH, is split out or eliminated from adjacent carbons.
H C β C X α + CH3 CH 2 O N a + CH3 CH 2 OH A haloalkane Base
C C + CH3 CH 2 OH + Na + X An alkene
13 Organic Lecture Series β-Elimination • Zaitsev rule: The major product of a βelimination is the more stable (the more highly substituted) alkene.
Br 2-Bromo-2methylbutane Br CH3 CH2 O - Na + CH3 CH2 O H 2-Methyl-2-butene (major product) + 2-Methyl-1-butene CH3 O - N a+ CH3 OH + 1-Methylcyclopentene (major product) Methylenecyclopentane
14 1-Bromo-1-methylcyclopentane Organic Organic Lecture Series β-Elimination • There are two limiting mechanisms for βelimination 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. • E2 mechanism: At the other extreme, breaking
of the R-Lv and C-H bonds is concerted.
– Both R-Lv and base are involved in the ratedetermining step. 15 E1 Mechanism Organic Lecture Series – Rate-determining ionization of the C-Lv bond gives a carbocation intermediate.
CH3 CH3 -C-CH3 Br s low , rate determinin g CH3 CH3 -C-CH3 + + Br (A carb ocation in termediate) – Proton transfer from the carbocation intermediate to the base (in this case, the solvent) gives the alkene.
H H3 C CH3 O: + H-CH2 -C-CH3 + fast H O H + CH2 =C-CH3 H3 C
16 + CH3 E1 Mechanism Organic Organic Lecture Series • Energy diagram for an E1 reaction. Two transition states and one reactive intermediate. 17 E2 Mechanism Organic Lecture Series • Energy diagram for an E2 reaction. There is considerable double bond character in the transition state. 18 Kinetics of E1 & E2
• E1 mechanism Organic Organic Lecture Series – Reaction occurs in two steps. – The rate-determining step is carbocation formation. – Reaction is 1st order in RLv and zero order is base.
Rate = d[RLv] dt = k[ RLv] • E2 mechanism
– Reaction occurs in one step. – Reaction is 2nd order; first order in RLv and 1st order in base.
Rate = d[RLv] dt = k[ RLv][ Base]
19 Organic Lecture Series Regioselectivity of E1 & E2 E1: major product is the more stable alkene. • Zaitsev rule: The major product of a βelimination is the more stable (the more highly substituted) alkene. 20 Organic Organic Lecture Series Regioselectivity Regioselectivity of E1 & E2 • E2: with strong base, the major product is the more stable (more substituted) alkene.
– Double bond character is highly developed in the transition state. – Thus, the transition state of lowest energy is that that leading to the most stable (the most highly substituted) alkene. • E2: with a strong, sterically hindered base such as tert-butoxide, the major product is often the less stable (less substituted) alkene.
21 Stereoselectivity of E2 Organic Lecture Series • E2 is most favorable (lowest activation energy) when H and Lv are oriented anti and coplanar. CH3 O: - H C C CH3 O H C C Lv Lv -H an d -Lv are anti and cop lanar (dih edral an gle 180°) 22 Stereoselectivity of E2 Organic Organic Lecture Series • There is an orbital-based reason for the anti and coplanar arrangement of -H and -Lv involved in an E2 reaction. 23 Organic Lecture Series Summary of E2 vs E1
Alkyl halide Primary RC H 2 X E1 E1 does not occur. Primary carbocations are so unstable, they are never observed in solution. Main reaction with weak bases such as H 2O, ROH. Main reaction with weak bases such as H 2O, ROH. E2 E2 is favored. Secondary R2 CHX Tertiary R3 CX Main reaction with strong bases such as OH - and OR -. Main reaction with strong bases such as OH - and OR -. 24 Organic Organic Lecture Series SN vs E
• Many nucleophiles are also strong bases (OH- and RO-) and SN and E reactions often compete. • The ratio of SN/E products depends on the relative rates of the two reactions. nucleop hilic sub stitution HC C Lv + HC C Nu + Lv N uβ -elimination C C + H-N u + Lv 25 Organic Lecture Series SN vs E
H alide Methyl CH3 X Pri mary RCH2 X Reaction Comments SN 1 reaction s of methyl halides are never ob served . The methyl cation is s o u nstable th at it is never formed in s olu tion. The m ai n re acti o n w i th g oo d n ucl e o phi l e s /w e ak b ases s uch as I- an d CH3 COO -. The main reaction w ith s trong, bulk y b ases su ch as potass ium t ert -b utoxide. Primary cations are never obs erveded in solution and , therefore, SN 1 an d E1 reactions of primary halides are never observed. SN2 SN 2 E2 26 Organic Organic Lecture Series SN vs E
Secondary R2 CH X SN 2 The main reaction with bases/nucleophiles where pK a o f th e conjugate acid is 11 or les s, as for example I- and CH 3COO -. The main reaction w ith bases /n ucleophiles w here the pK a of the conjugate acid is 11 or greater, as for example OH - and CH 3 CH2 O -. Common in reactions with weak nucleophiles in polar protic solvents, such as water, methanol, and ethanol. Main reaction w ith stron g b ases s uch as HO - and RO -. Main reactions w ith poor n ucleoph iles/w eak bases . S N 2 reactions of tertiary halides are never observed because of the extreme crowding around the 3° carbon.
27 E2 SN 1/E1 Tertiary R3 CX E2 SN 1/E1 ...
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