Organic Chemistry

1. Chapter 6:Chapter 6: NucleophilicNucleophilic
Substitution ofSubstitution of
HaloalkanesHaloalkanes
Guanine baseGuanine base
of DNAof DNA
Leaving groupLeaving group
NucleusNucleusNucleophileNucleophile
ToxicToxic

2. HaloalkanesHaloalkanes
NamesNames:: Halo-Halo-, as a substituent, as a substituent
1-Chlorobutane1-Chlorobutane
(1(1SS,2,2RR)-1-Bromo-2-)-1-Bromo-2-
fluorocyclohexanefluorocyclohexane
2-Iodo-2-2-Iodo-2-
methylbutanemethylbutane
CC
++ --
XX
ClCl
44
33
22
11 FF
BrBrRR
SS
II CHCH33

3. The C-X Bond isThe C-X Bond is
PolarizedPolarized
ClClCCHH33
++ --
ElectrophilicElectrophilic

5. Trends are a function of dipole-Trends are a function of dipole-
dipole and London forcesdipole and London forces
ElectronegativityElectronegativity
(4.0)(4.0) (3.2)(3.2) (3.0)(3.0) (2.7)(2.7)

6. Nucleophilic Substitution:Nucleophilic Substitution:
GeneralGeneral
Color scheme:Color scheme: NuNu,, EE,, LL,, andand curved arrowscurved arrows: e-Flow: e-Flow
CC XXNuNu ++ CC XXNuNu
--
++
NucleophileNucleophile
(Nu)(Nu)
LeavingLeaving
group (L)group (L)
ElectrophileElectrophile
(E)(E)
--

7. Remember: Acid-base reactionsRemember: Acid-base reactions
BB ++ HH AA BB HH ++ AA
-- --
conjugateconjugate
acid baseacid base
--
BB == NuNu
--
wwhenhen HH is attacked, we call itis attacked, we call it base B.base B.
WhenWhen CC (or other nuclei) attacked, we call it(or other nuclei) attacked, we call it
nucleophile Nu.nucleophile Nu.

8. Note: no (simple) ∆H º calculations
possible on ionic reactions; bond
strengths refer to homolytic, not
heterolytic, dissociation.

9. Note: Tertiary halides are notably absent from this list.Note: Tertiary halides are notably absent from this list.

10. MechanismMechanism
In general: how do we study it ?In general: how do we study it ?
1.1. KineticsKinetics
2.2. StereochemistryStereochemistry
3.3. Modify substituents: look for electronic andModify substituents: look for electronic and
steric effectssteric effects
4.4. Isotope effects: Usually H/DIsotope effects: Usually H/D
DHºDHº CC----HH << CC—D—D
5.5. Modify reagents/subtrates: Nu, E, L, solventModify reagents/subtrates: Nu, E, L, solvent

11. KineticsKinetics
ForFor HOHO ++ CCHH33 ClCl CHCH33OH +OH + ClCl
----
Rate =Rate = kk [CH[CH33Cl][ OH]Cl][ OH] 22ndnd
orderorder
Points toPoints to bimolecularbimolecular mechanism (TS)mechanism (TS)
Hence name:Hence name: SSNN22 bimolecular,bimolecular,
nucleophilic substitutionnucleophilic substitution
--

12. [HO[HO······CHCH33Cl]Cl]‡‡
??
CHCH33ClCl
CHCH33OHOH
EE
What is TSWhat is TS
structure?structure?
We can look atWe can look at
stereochemistrystereochemistry..
Two extreme approaches ofTwo extreme approaches of NuNu :: CC XX
BackBack FrontFront
+ Cl+ Cl--
++ --
OHOH
Transition StateTransition State
――

13. FrontsideFrontside attack:attack: RetentionRetention ofof
configuration.configuration.
BacksideBackside attack:attack: InversionInversion ofof
configuration.configuration.
Which one is it?Which one is it?
CC XX
chiralchiral
**
Test: UseTest: Use enantiomerically pureenantiomerically pure

14. Frontside DisplacementFrontside Displacement
FrontsideFrontside

15. Backside DisplacementBackside Displacement
BacksideBackside

16. CC BrBr
SS
HH
HH33CC
CHCH33CHCH22
++
--
II CC BrBrII
--
++
HH
CHCH33
CHCH22CHCH33
RR
Result:Result: InversionInversion ((nono SS -product)-product)

17. PotEnergyPotEnergy
LipshutzLipshutz
HolidayHoliday

18. Chemical Consequences ofChemical Consequences of
InversionInversion
1. Retention: By double inversion1. Retention: By double inversion
CC
CHCH33
RR
HH
BrBr CC
CHCH33
RR
HH
SHSHCCII
CHCH33
RR
HH
II
--
BrBr
--
II
--
H SH S
--
++
-- --
++
2. Inversion does not necessarily mean:2. Inversion does not necessarily mean: R SR S
CHCH33CHCH22OO ++ CC
CHCH33SS
HH
HH33CC
BrBr CC
XX
CHCH33CHCH22OO
--++
SCHSCH33
HH
CHCH33
SS
cc
bb
aabb
cc
aa-- SS

19. 3. Diastereoisomerization3. Diastereoisomerization
CHCH33
BrBr
HH
CHCH33
CHCH33CHCH22
HH
CHCH33
HH
HH
CHCH33
CHCH33CHCH22
IIII
-- BrBr RR
RR
RR
SS --
--
BrBr HH
HH33CC HH
SSSS
HH CNCN
HH33CC HH
RRSSCNCN
-- BrBr --
--
CHCH33
BrBr
RR
SS
II --
CHCH33
RR
RR
II
CisCis TransTrans
-- BrBr--

20. Leaving Group AbilityLeaving Group Ability
“L”“L”
(kinetic parameter)(kinetic parameter)
CC LLNuNu ++ BB ++ HH AA
--
What makes a goodWhat makes a good LL--
((AA--
) ?) ?
Remember from the discussion on acidity:Remember from the discussion on acidity:
1.1. Ability toAbility to accommodate e-pairaccommodate e-pair (charge) :(charge) :
e-Negativity + resonancee-Negativity + resonance
2.2. Size of the orbitalSize of the orbital describing the e-pair.describing the e-pair.
3.3. Indirectly:Indirectly: Bond strengthBond strength CC——LL ((HH——AA))

21. F < Cl < Br < IF < Cl < Br < I Increasing,Increasing, goinggoing downdown periodicperiodic
table (PT).table (PT).
HF HCl HBr HIHF HCl HBr HI
ppKKaa 3.2 -2.2 -4.7 -5.23.2 -2.2 -4.7 -5.2
DDHºHº 135 103 87 71135 103 87 71
Why?Why?
Because:Because:
GoesGoes downdown in PTin PT
And:And: Orbital sizeOrbital size increasesincreases from 2p to 3p to 4p…from 2p to 3p to 4p…
As noted earlier: This trend isAs noted earlier: This trend is oppositeopposite thatthat
expected on the basis ofexpected on the basis of electronegativityelectronegativity (goes(goes
down in PT).down in PT).
SameSame trend astrend as HX:HX:
-- -- -- --
Halides asHalides as LL

22. ppKKaa 50 35 15.7 3.250 35 15.7 3.2
DDHºHº 105 107 119 135105 107 119 135 increasesincreases
In practice: onlyIn practice: only FF is a reasonableis a reasonable leaving groupleaving group inin
this row. Hydroxide can be, in special cases.this row. Hydroxide can be, in special cases.
--
CHCH33<< NHNH22<< OHOH<< FF ::
ElectronegativityElectronegativity
wins !wins !
decreasesdecreases,, butbut
And:And: SizeSize of orbitalof orbital decreasesdecreases..
RR LL oror HH AA::
Along a row of PT:Along a row of PT: LL increasesincreases to theto the rightright
(same trend as acidity)(same trend as acidity)

23. For example, for same leaving atom, e.g.,For example, for same leaving atom, e.g.,
Generally:Generally: LL increasesincreases to theto the rightright andand
downdown PT.PT.
But, superimposed on these trends:But, superimposed on these trends:
Resonance.Resonance.
ppKKaa :: 15.5 4.7 -1.215.5 4.7 -1.2
--
-- --
OO OO
OO
--
CHCH33OO << CHCH33COCO << CHCH33S OS O
RORO ::
(of acid)(of acid)

24. Neutral LNeutral L areare goodgood: relatively: relatively nonbasicnonbasic
1. Protonated alcohols:1. Protonated alcohols: L = HL = H22OO
Use ROH plus HBr, or HI, or HUse ROH plus HBr, or HI, or H22SOSO44
2. Diazonium ions:2. Diazonium ions: L = NL = N22 , a superleaving group, a superleaving group
RR OOHH ++ HH RR OO
HH
HH
NuNu--++
RR NuNu ++ HH22OO
RR N NN N ++ NuNu RR NuNu ++ N NN N
--++
++

25. For practical purposes:For practical purposes:
Here is whereHere is where LL--
abilityability
ends (going down PT)ends (going down PT)

26. Nucleophilicity “Nu”
(kinetic parameter)
Affected by charge, basicity, solvent,Affected by charge, basicity, solvent,
polarizability, sterics.polarizability, sterics.
1.1. ChargeCharge (for same atom):(for same atom):
TheThe moremore charged, thecharged, the moremore nucleophilicnucleophilic
HO > HHO > H22O ; HO ; H22N > HN > H33N ; SON ; SO44 > ROSO> ROSO33
-- -- 2-2- --

27. 2.2. BasicityBasicity:: DecreasesDecreases to the rightto the right
in PT, so doesin PT, so does NuNu::
HH33N > HN > H22O ; HO ; H22N > HO ; HO > FN > HO ; HO > F
-- -- -- --
Comparison of neutral and chargedComparison of neutral and charged NuNu: (See: (See
ppKKaa table)table)
HH22N > HO > HN > HO > H33N > F > HN > F > H22OO
-- -- --
As expected: TrendAs expected: Trend oppositeopposite LL
abilityability

28. ProticProtic solventssolvents havehave acidic Hacidic H ; e.g., RO; e.g., RO HH oror
NN HH. They. They surroundsurround chargedcharged NuNu , using, using
hydrogen bonds:hydrogen bonds:
++ ++--
++--
--
--
RR
Down the PT:Down the PT: Murky!Murky! BasicityBasicity goesgoes downdown,,
hence Nu should too (opposite L). But nothence Nu should too (opposite L). But not
true: Nutrue: Nu increasesincreases!!
The reason:The reason: SolventSolvent effects andeffects and
polarizabilitypolarizability (deformability of orbital of(deformability of orbital of
) have a strong influence.) have a strong influence.
For chargedFor charged NuNu--
::
NuNu
NuNu HH OROR

29. Protic Solvents:Protic Solvents: Fluoride is aFluoride is a
WorseWorse Nucleophile Than IodideNucleophile Than Iodide
HydrogenHydrogen
bondsbonds
δ-
δ-
δ-
δ-
δ-
δ+
δ+
δ+
δ+
Solvent shell increases “size” ofSolvent shell increases “size” of NuNu ,,
hencehence NuNu increasesincreases goinggoing downdown PT.PT.
--

30. For unchargedFor uncharged NuNu ,, samesame trend, buttrend, but
now due tonow due to polarizabilitypolarizability
HH22O < HO < H22S < HS < H22Se (CHSe (CH33))33N < (CHN < (CH33))33PP
Polarizability operates also forPolarizability operates also for
charged Nu, which already benefitcharged Nu, which already benefit
from lesser solvation: especially fast.from lesser solvation: especially fast.

31. IncreasingIncreasing
PolarizabilityPolarizability ImprovesImproves
NucleophilicityNucleophilicity
More polarizableMore polarizable
Less polarizableLess polarizable

32. The Story Changes
In Polar Aprotic
Solvents,
Which
• dissolve salts
• do not form H bonds
• enable formation of
“naked” anions
cause huge rate increases
with all Nu
follow trends in basicity

33. SolventMeOHSolventMeOH SolventDMFSolventDMF

34. Review: Range ofReview: Range of
NucleophilicitiesNucleophilicities
• charge
• basicity
• polarizability
• H-bonding
Depends on:Depends on:

35. Summary Trends in theSummary Trends in the
Periodic TablePeriodic Table
L
Nu-
“Naked” anions,
aprotic solvents
or
Protic solvent,
polarizability
e-Negativity > DHº and orbital size
e-Negativity
< DHº and
orbital size

36. Steric EffectsSteric Effects
Sterics forSterics for LL:: LargerLarger == betterbetter
Sterics forSterics for NuNu:: LargerLarger == worseworse,,
e.g., CH3O > (CH3)3CO
-- --
Sterics aroundSterics around EE are theare the mostmost
significant.significant.

37. StericsSterics aroundaround electrophilicelectrophilic CC LL
RR Br + IBr + I RR I + Br relative ratesI + Br relative rates
CHCH33 CHCH33CHCH22 (CH(CH33))22CHCH (CH(CH33))33CC
145 1 0.078 0145 1 0.078 0
MechanismMechanism
changeschanges
CHCH33CHCH22 CHCH33CHCH22CHCH22 (CH(CH33))22CHCHCHCH22 (CH(CH33))33CCHCCH22
1 0.8 0.031 0.8 0.03 slow!slow! 1010-5-5
-- --
αα ::
ββ ::
AlphaAlpha versusversus betabeta branching:branching:

40. WalbaWalba
DireStrDireStr