Organic Chemistry

1. Relative “rates”Relative “rates”
of 4 arrowsof 4 arrows
differdiffer
CC
HH
CC
LL
BB NuNu:
--
:
--
Chapter 7:Chapter 7: SSNN 1, E1, E21, E1, E2,,
notnot
justjust SSNN 22
E1, E2E1, E2
SSNN2, S2, SNN1, E1, E21, E1, E2
E1, E2E1, E2
SSNN2, S2, SNN11
““Lingo”:Lingo”: αα positionposition,, ß position;ß position; further away:further away: γγ,, δδ, and so on., and so on.
SolventMeOHSolventMeOH SolventDMFSolventDMF

2. CHCH33BrBr ++ HH22OO
ButBut
(CH(CH33))33CBrCBr
(CH(CH33))22CHBrCHBr
oror react!react!
++(CH(CH33))33CC BrBr HH OHOH (CH(CH33))33CC OHOH
AcetoneAcetone
HH BrBr++
Weak NuWeak Nu
Despite beingDespite being αα-branched-branched
HydrolysisHydrolysis
++(CH(CH33))22CCHH BrBr HH OCHOCH33 (CH(CH33))22CHCH OCHOCH33
DMFDMF
HH BrBr++
MethanolysisMethanolysis
Generally:Generally: SolvolysisSolvolysis
Recall: SRecall: SNN2 slows with weak Nu2 slows with weak Nu
(and branching). For example:(and branching). For example:

3. Mechanism:Mechanism:
1. Rate = k[R-L],1. Rate = k[R-L], 11stst
orderorder unimolecularunimolecular, only, only
R-L in rate-determining TS:R-L in rate-determining TS: “bottleneck”“bottleneck”..
2. Stereochemistry:2. Stereochemistry: RacemizationRacemization (extensive,(extensive,
although often not complete).although often not complete).
Both observations inconsistent withBoth observations inconsistent with
SSNN 22 mechanismmechanism

4. 3.3. AcceleratesAccelerates withwith polarpolar (best with protic, in(best with protic, in
contrast to Scontrast to SNN2) solvents:2) solvents:
HexaneHexane << CHClCHCl33 << CHCH33CCHCCH33 << CHCH33OHOH
OO
4.4. AcceleratesAccelerates withwith betterbetter LL
L:L: Cl < Br < I < OSOCl < Br < I < OSO22RR
5.5. Product determining steps afterProduct determining steps after
“bottleneck”:“bottleneck”: CompetitionCompetition between Nu’s.between Nu’s.
(CH(CH33))33CClCCl ++ CHCH33OHOH ++ Na NNa N33
++ -- kk11
IntermediateIntermediate
NN NN NN
::
::
:: ::-- --++
kk22 kk33kk22kk33 kk11>> >>
..
CHCH33OOHH..
..
(CH(CH33))33OOCHCH33.. (CH(CH33))33CCNN33winswins

5. MechanismMechanism
1.1.
Electron deficient!Electron deficient!

6. 2.2.

7. 3.3.

8. Unimolecular nucleophilic substitution:Unimolecular nucleophilic substitution:
• 11stst
Order rate lawOrder rate law
• RacemizationRacemization
• Acceleration in polarAcceleration in polar
solventssolvents
• AccelerationAcceleration
with betterwith better LL
• Fast productFast product
determining stepdetermining step
Mechanism explains data:Mechanism explains data:
SSNN11
SSNN11

9. SSNN1PE1PE
Bottleneck:Bottleneck:
““Bottleneck”Bottleneck”

10. IncompleteIncomplete
RacemizationRacemization
May stay closeMay stay close
to form an ion pairto form an ion pair
Planar and achiral,Planar and achiral,
but both sidesbut both sides notnot
equally accessibleequally accessible
inin ion pairion pair withwith BrBr--
Ideally; inIdeally; in
practice:practice: SlightSlight
enantiomer excessenantiomer excess
SSNN1Racem1Racem

11. The Strong Effect of PolarThe Strong Effect of Polar
Solvents on the SSolvents on the SNN 11
ReactionReaction
Increasing solvent polarityIncreasing solvent polarity
speeds reactionspeeds reaction
Increasing solvent polarityIncreasing solvent polarity
retards reactionretards reaction

12. CC
++HH
CC
CCHH33 CCHH33CCHH22 ((CCHH33))22CCHH ((CCHH33))33CC
++ ++ ++ ++
of neighboringof neighboring CC HH
bond interacts withbond interacts with
empty 2empty 2pp orbitalorbital
StabilizingStabilizing (2e)!(2e)!
Better thanBetter than
radical (3e).radical (3e).
22pp
Bonding MOBonding MO
EE
Too unstableToo unstable The only cationsThe only cations
feasible in solutionfeasible in solution
<<
What makes SWhat makes SNN1 possible? 1. S1 possible? 1. SNN2 is2 is slowslow..
2.2. αα-Branched-Branched carbocationscarbocations areare stabilizedstabilized
byby hyperconjugationhyperconjugation

13. HyperconjugationHyperconjugation

14. X-Ray Structure of theX-Ray Structure of the
1,1-Dimethylethyl Cation1,1-Dimethylethyl Cation
(Laube, 1993)(Laube, 1993)
LipshutzSLipshutzSNN11
DjangoDjango

15. SummarySummary :: RRprimprim-- LL :: nono SSNN1,1, onlyonly SSNN22
RRterttert-- LL :: onlyonly SSNN1,1, nono SSNN22
RRsecsec-- LL :: bothboth,,
SSNN2/S2/SNN1 ratios difficult to predict, except in1 ratios difficult to predict, except in
“extreme" cases, such as:“extreme" cases, such as:
++
(CH(CH33))22CHCH ClCl
(CH(CH33))22CHCHOOHH
CFCF33SOSO33HH
SSNN11
SolventSolvent
(CH(CH33))22CHCH OSOOSO22CFCF33 HH22OO
++ (CH(CH33))22CHCHSSCHCH33 ClCl
--
++
++
CHCH33SS
--
SSNN22
DMFDMF

16. Reactivity of R-XReactivity of R-X

17. S
H2O
Br−
OH
+ HBr
Problem:Problem:
SSNN2 or S2 or SNN1 ?1 ?
-(CH-(CH33))22SS

18. (-)(-)
::
Therefore:Therefore: Elimination EElimination E11,, aa side reactionside reaction of Sof SNN1.1.
SameSame firstfirst dissociationdissociation step to cation:step to cation:
((CCHH33))33CC LL
––LL--
BB
--
::
CC
++
CC
HH
CC CC
ThenThen protonproton
lossloss to baseto base
(solvent)(solvent)
NormallyNormally BB acts asacts as NuNu to giveto give SSNN1.1.:: ::
WhenWhen NuNu acts asacts as BB : Cations are: Cations are deprotonateddeprotonated
Elimination: EElimination: E11 and Eand E22
(-)(-)
::

19. Mechanism of the E1Mechanism of the E1
ReactionReaction
We usuallyWe usually omit the baseomit the base in deprotonations andin deprotonations and
simply writesimply write “-H“-H++
””.. E1LipshutzE1Lipshutz
CarusoCaruso

20. Ratios ofRatios of SSNN11 toto
E1E1 products areproducts are
independent ofindependent of LL

21. E1 Gives MixturesE1 Gives Mixtures
All CAll C HH atat ββ-positions in cation are-positions in cation are acidicacidic::
CHCH33ClCl
ClCl
--
CCHH33OOHH
::::
CHCH33OOHH
::::
++
CHCH33OO
HH
HH
++ ++++
++
MixtureMixture
““Regio-” andRegio-” and
stereoisomersstereoisomers
(“cis/trans”)(“cis/trans”)
..
++

22. E1/SE1/SNN1 ratios are difficult to predict1 ratios are difficult to predict
Generally:Generally: Increasing amounts ofIncreasing amounts of EE11 productsproducts
are formed with:are formed with:
1.1. HigherHigher TT, because, because entropyentropy of elimination isof elimination is
positivepositive: (RX is converted to alkene plus HX).: (RX is converted to alkene plus HX).
Recall: ∆Recall: ∆G°G° = ∆= ∆HH º–º– TT∆∆SºSº, hence positive ∆, hence positive ∆SºSº
makes ∆makes ∆G°G° more negative.more negative.
2. Very2. Very poorly nucleophilicpoorly nucleophilic medium (slows Smedium (slows SNN1),1),
e.g: Acetone solvent.e.g: Acetone solvent.
Why not base? Base (unless very weak) changesWhy not base? Base (unless very weak) changes
the mechanism once again.the mechanism once again.

23. Bimolecular EliminationBimolecular Elimination
E2E2
WithWith strong basestrong base: Mechanism changes, base attacks: Mechanism changes, base attacks
R-LR-L directlydirectly atat ββ-H:-H: E2E2 (faster than S(faster than SNN1/E1)1/E1)
Mechanism:Mechanism:
1. Rate = k [R-L][ B]1. Rate = k [R-L][ B] 22ndnd
order bimolecular TSorder bimolecular TS
3. H3. H removed in TS: Deuterium isotoperemoved in TS: Deuterium isotope++
2. L leaves in TS: RCl RBr RI2. L leaves in TS: RCl RBr RI
effecteffect kkHH//kkDD~ 7~ 7
4. Stereochemistry:4. Stereochemistry:
CCCC
HH
LL
BB:
--
Anti-TSAnti-TS ** **
::--

24. One diastereomer of RX (e.g.One diastereomer of RX (e.g. R,R/S,SR,R/S,S below) givesbelow) gives
only oneonly one stereoisomer of alkene product:stereoisomer of alkene product:
The E2 Reaction is StereospecificThe E2 Reaction is Stereospecific

25. Or theOr the S,RS,R--R,SR,S pair:pair:

26. Mechanism of the EMechanism of the E22
ReactionReaction
TS:TS: staggered, best overlap, least e-repulsionstaggered, best overlap, least e-repulsion
E2E2 WalbaWalba LipshutzLipshutz
CreamCream RayRay

27. E2 in Cyclic SystemsE2 in Cyclic Systems

28. Hindered Base EnsuresHindered Base Ensures
E2E2

29. SummarySummary

30. Factor 1:Factor 1: Base strengthBase strength of the nucleophileof the nucleophile
HHOO
--
RROO
--
RR22NN
--
HH22NN
--
,, ,, ,,
Weak BasesWeak Bases Substitution moreSubstitution more
likelylikely
Strong BasesStrong Bases Likelihood of elimination increasedLikelihood of elimination increased
Factor 2:Factor 2: Steric hindranceSteric hindrance around thearound the reactingreacting
carboncarbon
Primary haloalkanesPrimary haloalkanes
Substitution more likelySubstitution more likely
Sterically unhinderedSterically unhindered Sterically hinderedSterically hindered
Likelihood of elimination increasedLikelihood of elimination increased
Branched prim, or sec and tert haloalkanesBranched prim, or sec and tert haloalkanes
HH22OO RROOHH PPRR33 halideshalides NN33 RRCCOOOORRSS
--
NCNC
--
,, ,,HH22OO RROOHH,, ,, ,, ,, ,, ,, ,,
Factors that Affect theFactors that Affect the
Competition between SCompetition between SNN and Eand E
-- --

31. Factor 3:Factor 3: Steric hindranceSteric hindrance inin nucleophilenucleophile
(strong base)(strong base)
Sterically unhinderedSterically unhindered Sterically hinderedSterically hindered
Substitution maySubstitution may
occuroccur
Elimination strongly favoredElimination strongly favored
HHOO
--
HH22NN
--
CHCH33OO
-- --
CCHH33CCHH22OO,, ,, ,, ((CCHH33))33CCOO [([(CCHH33))33CCHH]]22NN
--
,,
--

32. (CH3)3COH
-H2O
H+
, CH3OH, 100°C
An alkene
1. Mechanism: SN
2 SN
1 E2 E1?
2. At lower temperatures one of the following ratios will increase:
SN
2 / SN
1 SN
1 / E1 E2 / E1 SN
2 / E2
Problem:Problem:

33. No (or exceedingly slow) reaction with poor nucleophilesNo (or exceedingly slow) reaction with poor nucleophiles
Reactivity of Prim HaloalkanesReactivity of Prim Haloalkanes
R-X with Nucleophiles (Bases)R-X with Nucleophiles (Bases)
CHCH33CHCH22CCHH22BrBr BrBr--CNCN
--
CHCH33CHCH22CCHH22CNCN
AcetoneAcetone
++ ++
CHCH33CHCH22CCHH22BrBr BrBr--CHCH33OO
--
CHCH33CHCH22CCHH22OCHOCH33++ ++
CHCH33OHOH
SSNN2 with good nucleophiles that are not strongly basic2 with good nucleophiles that are not strongly basic
SSNN2 with good nucleophiles that are also strong bases2 with good nucleophiles that are also strong bases
But E2 with strong, hindered basesBut E2 with strong, hindered bases
CHCH33CCHH22CHCH22BrBr ++ CHCH33CCOO
CHCH33
CHCH33
-- (CH(CH33))33COHCOH
HHBrBr
CHCH33CCHH CHCH22
For unhindered primaryFor unhindered primary R XR X ::
(CH(CH33OH)OH)

34. BrBr--
++CHCH33CCCCHH22BrBr
CHCH33
HH
II
--
CHCH33CCCCHH22II
CHCH33
HH
++
AcetoneAcetone
SSNN2 with good nucleophiles (although slow compared with2 with good nucleophiles (although slow compared with
unhindered RX)unhindered RX)
For branched primary R XFor branched primary R X ::
No (or exceedingly slow) reaction with poor nucleophiles orNo (or exceedingly slow) reaction with poor nucleophiles or
neopentyl systems (in which E is not possible)neopentyl systems (in which E is not possible)
CHCH33CCCCHH22BrBr CHCH33CHCH22OO
-- CHCH33CHCH22OHOH
HHBrBr
CHCH33
HH
CHCH33CC CCHH22
CHCH33
++
E2 with strong base (not necessarily hindered)E2 with strong base (not necessarily hindered)

35. Reactivity of Sec Haloalkanes R-XReactivity of Sec Haloalkanes R-X
with Nucleophiles (Bases)with Nucleophiles (Bases)
CHCH33CCBrBr
CHCH33
HH
CHCH33CHCH22OOHH
HHBrBr
++ CHCH33CCHH CHCH22CHCH33CCOCHOCH22CHCH33
CHCH33
HH
MajorMajor Minor (more onMinor (more on
increasing T)increasing T)
SSNN1 and E1, when X is a good leaving group in a1 and E1, when X is a good leaving group in a
highly polar medium with weak nucleophileshighly polar medium with weak nucleophiles

36. EE22 with high concentrations of strong basewith high concentrations of strong base
(for example, H(for example, HOO or Ror ROO in alcohol solvent)in alcohol solvent)
CHCH33CCBrBr
CHCH33
HH
CHCH33CHCH22OHOH
++CHCH33CCSCHSCH33
CHCH33
HH
BrBr--
CHCH33SS
--
++
SSNN2 with high concentrations of good, weakly basic2 with high concentrations of good, weakly basic
nucleophilesnucleophiles
-- --
CHCH33CHCH CCHH22CHCH33CCBrBr
CCHH33
HH
CHCH33CHCH22OO --
++
CHCH33CHCH22OHOH
HHBrBr

37. Reactivity of Tert HaloalkanesReactivity of Tert Haloalkanes
R-X with Nucleophiles (Bases)R-X with Nucleophiles (Bases)
SSNN1 and E1 and E11 in polar solvents when X is a good leaving groupin polar solvents when X is a good leaving group
and only dilute or no base is presentand only dilute or no base is present
CHCH33CHCH22CCBrBr
CHCH33
CHCH33
CHCH33CHCH22CCOHOH
CHCH33
CHCH33
++
HHBrBr
alkenesalkenes
HHOHOH, acetone, acetone
EE22 with high concentrations of strong basewith high concentrations of strong base
CHCH33CHCH22CCClCl
CHCH22
CCHH22
CHCH33CHCH22CC
CHCH22
CHCH33OO, CH, CH33OHOH
HHClCl
HH33CC
HH33CC
CCHHCHCH33
HH33CC--