(1) Haloalkanes, preparation & properties
(2) Nucleophilic Substitution Reactions -or:
- How to make alcohols, ethers, esters, amines, nitriles, …
(3) Elimination Reactions – or:
-How to make alkenes from haloalkanes and alcohols
Based on Organic Chemistry, by L.G. Wade, 7 th ed;
Compiled by: Dr. Peter Ilich, St. John’s University
Queens, New York, Spring 2012

Halogenation of alkanes – How does it happen:

Halogenation of alkanes – continued – up to CCl
4
:
In branched alkanes regioselectivity becomes important:
2º C: major product
3º C: the only product

Haloalkanes – review of common alkyl groups:
4 butanealkanes:
2 propanealkanes:
1-bromobutane
(butylchloride)
1-chloropropane
(propylchloride)
2-chlorobutane
(sec-butylchloride)
2-bromopropane
(isopropylchlride)
1-bromo-2-methyl propane
(isobutylbromide)
2-choro-2-methyl propane
(tert-butylchloride)

Haloalkane – practice naming, drawing, and determining the type of C center: 1º, 2º or 3º formula: name: iodomethane
(methyl iodide)
2-chloropentane
(isopentyl chloride)
1,2-dichlorocylobutane

Haloalkanes – practice naming, drawing, and determining the type of C center: 1º, 2º or 3º - continued
Note this:
cis-1,3-dichloro cyclobutane, a dihalide
cis-1,2-dichloro cyclobutane, a vicinal dihalide
1,1-dichloro cyclobutane, a geminal dihalide

[6.2-5] Properties and uses of haloalkanes:
(A) Polar C- X bond:
(B) Immiscible with but heavier than water: water alkane water haloalkane

Uses of haloalkanes – many, many ….
(C) Plastics, e.g.
Teflon®
(D) Biocides (herbicides, pesticides,…)
Lindane
1,2,3,4,5,6hexachlorocyclohexane
Chlordane
1,2-dichlorocyclopenta[3,4-e]
(1,2,3,4,7,7-hexachloro)norborn-3-ene
Caution: Lindane and clordane are suspected endocrine disruptors

Not all haloalkanes and C-halogen compounds are manmade; there are thousands of natural C-halogenides, e.g.
(3S)-bromomethyl-(6R)-bromo-
2,(3S),7-trichloro-1-nonene, a human anticancer agent secreted by marine the alga Portieria hornemanii,
[Gribble GW, Acc. Chem. Res. 1998,
31, 141-152].
Thyroxine, T4, a hormone secreted by the human thyroid gland is a natural tetraiodo organic compound

Q: Now that you have a supply of haloalkanes
- made by radical halogenation – what other compounds can you make out of them?
A: Many other kinds of compounds – for example:
- alcohols
- thioalcohols (mercaptanes)
- ethers, linear and cyclic
- thioethers (sulfides), linear and cyclic
- peroxides
- esters
- amines (1º-, 2º-, 3º- and 4º- amines)
- cyanides (nitriles)
- azides
- alkanes
- alkynes

Preview of major types of compounds which can be prepared from haloalkanes by substitution:
Alcohols methanol 2-propanol cyclohexanol
Ethers
(di)ethylether
Nitrile
(cyanides) ethanenitrile
trans-1,2-dimethylepoxide
(2R)-cyanobutane
Amines methylamine
N-ethylmorpholine tetramethyl ammonium

Conversion of a haloalkane to other products:

Example of a reaction of conversion of haloalkane
- conversion of bromobutane to butylcyanide:
The reaction:
(2R)-bromobutane (2S)-butylcyanide
Reaction type:
Substitution, Nucleophilic, 2 nd order – S
N
2

Again - the reaction:
And the kinetics:

The important “players” in an S
N
2 reaction:
(2R)-bromobutane: the substrate
CN – the nucleophile
Br – the
leaving group, LG
DMSO
= solvent
Make a note: substrate (C
α
) leaving group nucleophile solvent
(2S)-butylcyanide: the product

Effects of substrate on an S
N
2 reaction: Rxn rate: fastest fast slower
Structure:
1º C
α
, short
1º C
α
, longer
1º C
α
C
β
, but branched slow
NO rxn
2º C
α
3º Ca

Never an S
N
2 substrate Very good S
N
2 substrate

The effects of substrate on S
N
2 rate – practice:
Rank the following triads of S
N
2 rxn by expected rate; fastest=1 st

The effects of substrate on S
N
2 rate – practice:
Rank the following S
N
2 rxn by expected rate; fastest=1 st
Identify and tag C
α in each substrate and classify it as 1º, 2º; then look at C
β

The next player the nucleophile:
Observe these reactions:
What is the different?
What is the same?
very fast fast slow very slow

S
N
2 - the nucleophile effect - again:
Observe:
Very good Nu
Good Nu
What is common to all these compounds?
Make a note:
A nucleophile is an
electron-rich atom or group of atoms
- a Lewis base
Fair Nu
Poor Nu

e r n u m b i c
A t o m
Q: Which elements are nucleophiles?
A: Main Group, the C, N, O, and F–groups
There are two general trends in Nu-strength: (1) The atomic number (down) and (2) the electronegativity (left)
Electronegativity excelent Nu poor Nu very good Nu

Nu-strength: electronegativity & atomic number

Nucleophile as a Brønsted base
It was said that a nucleophile is a Lewis base (el-rich, capable of donating an electron pair)
As a rule, nucleophiles are Brønsted bases (Brønsted base – capable of accepting H + ) but the relation is not simple: Within the same group elements become
weaker Brønsted bases but better nucleophiles:

S
N
2 – player # 3 - the leaving group, LG:
Observe these two S
N
2 reactions:
What do you see? The stronger the conjugate acid the better the leaving group; this holds without exception

Practice – the effects of LG on an S
N
2 raction
No rxn
Rank the reactions by expected rate:

Leaving Group and the pKa of conjugate acid Table: best LG good LG fair LG never a LG

S
N
2 – putting it all (almost) together:
- The substrate: 1 o C (or, not so good, 2º C)
- The nucleophile: good
- The leaving group: low pKa of conjugate acid
- The solvent: polar, aprotic (next slides)
The reaction flow & the transition state :
S
N
2 – a concerted reaction
+ KBr

How does this reaction occur? – practice:
(1) Identify Cα, (2) identify Nu and (3) add el-pairs and partial charges as needed, (4) write down the mechanistic arrows, (5) draw the TS and (6) label it, and (7) complete the reaction:
#2
#1

Energy profile for an S
N
2 reaction contains one barrier only – that of the transition state, TS:
Note: Reaction rate is inversely proportional to the energy height of the transition state, TS

The player # 4 in S
N
2 reactions – the solvent
Observe these exp data:
We explain this effect by different solvation of anions and cations in dipolar aprotic solvents, as in this scheme of solvation of KCN in dimethylsulfoxide, DMSO: unsolvated (bare) and highly active nucleophile

S
N
2 solvent practice – identify dipolar protic solvents
(1) Dipolar (dipole = diff electronegativity: e.g. C-Cl)
(2) Aprotic, i.e. no “loose” H + ; no O-H, N-H, S-H groups sulfur dioxide
DMSO acetone
DMFA

Review of S
N
2 reactivity – three possible cases:

Summary of the Ch. 6, part 1 –
What have we learned today?
- Haloalkanes can be converted to alcohols, thioalcohols, ethers, thioethers, amines, nitriles, azides, peroxides, . . .
and a number of other type compounds
- The predominant reaction types in these conversions are second order nulcleophilic substitutions, S
N
2
- S
N
2 reaction can be shown to depend on substrate, leaving group, nucleophile and solvent
- Optimal reaction parameters and conditions are established and the S
N
2 mechanism is derived

(1) Uses of S
N
2 reactivity in synthesis
(2) Other SN reactions: S
N
1
- SN1 variables: substrate, nucleophile, leaving group, solvent
- The carbocation intermediate paths
(3) Elimination, 1 st order & competition with S
N
1
(4) Eliminatino, 2 nd order
Based on Organic Chemistry, by L.G. Wade, 7 th ed;
Compiled by: Dr. Peter Ilich, St. John’s University
Queens, New York, Spring 2012

Summary of S
N
2 type reactions – three possible cases:

S
N
2 reactions – what are they good for?
- Example (1) - Preparation of alcohols: iodomethane methanol and thioalcohols: bromoethane ethanethiol
(mercaptoethanol)

Uses of S
N
2–type rxn in synthesis:

S
N
2 synthesis example (2) – ethers & tioethers:
Williamson ether synthesis:
Example 1:
Na-methoxide methylbromide dimethyl ether
Note: CH
3
OH (methanol) → CH
3
O (methoxide)
Example 2:
Na-cyclopentoxide ethyliodide ethylcyclopentyl ether

Uses of S
N
2 in drug design an example:
Ciguatera – a GI and a neuropathological condition caused by a natural toxin, ciguatoxin, found in certain tropical fish
Treating ciguatera required using toxin to study its mode of action; as toxin is difficult to isolate it had to be prepared
de novo – using S ether cyclization
N
2

But note:

S
N
2 in synthesis – practice Williamson synthesis:

Another example – nucleophilic methylation in biology:
- Nucleic acids (C, A)
N-methylation, for transcription regulation
- Neurotransmitters,
NH
2
-CH
2
CH
2
-OPO
N-methylation
3
(S)-Adenosylmethionine , AdoMet, SAM,
= the Nature's methylation agent
- Fatty (oleic) acid
C-methylatinon
The rxn: substrate = methyl-sulfonium, leaving group = sulfide

S
N
2 synthesis – another matter of concern the pK a of the LG and the reaction direction: pKa(CH
3
COOH/CH
3
COO ) = +4.7
pKa(HCl/Cl ) = -7
Note that HCl is ~ 10 10 or ten billion times stronger acid and Cl is a much better leaving group; the reaction (a) will happen but the reaction (b) will not.
Q: How do we “make” S
N
2 work in the case (b)?

S
N
2 in synthesis (3) - replacement of OH group:
(1) Acidification of –OH to –OH
2
+ (hydronium group)
Note: pK a
(HOH/HO-) +15.7 and pK a
(H
3
O + /H
2
O) -1.7
Acidification of –OH to –OH
2
+ - the mechanism
#1 protonation of OH
#2 nucleophilic attack by Br -

S
N
2 in synthesis – the removal of OH group; practice
Try to complete the following 2 reactions;
- observe the differences:
Suggest a way out (or around):

(3) S
N
2 reactions in synthesis - another (more common and more elegant) way to replace the OH group
(2) Conversion of –OH to –O-MsO (or TsO, TfO, …) esters substrate
=ethanol MsCl = Mesyl chloride
(methanesulfonyl chloride)
Ethylmesylate ester product
= ethylbromide pKa(HA) -6.5

[6.13] A new page – and a new chemistry:
The same substrate but a different reaction
Substitution, nucleophilic - but a different one:
The reaction:
(2R)-bromobutane (2S)-butanol (2R)-butanol
(Optically inactive racemic mixture)

[6.13] The reaction rate - experimental data:
The reaction:
(CH
3
)
3
C-Br + HOH → (CH
3
)
3
C-OH + K + Br -
The concentration vs. time - exp data:
The rate of the reaction changes with the conc.
of the substrate,
(CH
3
)
3
CBr, but is independent on the concentration of water, the nucleophile:
RR
[HOH] º
RR = k [(CH
3
)
3
CBr] 1 [HOH] 0 = 1 st order substitution = S
N
1

Reaction flow – how do we explain what happens:
Step # 1: carbocation formation
C + -intermediate
Step # 2: Nu-binding
(R,S)-2-butanol

Note 2 things:
(i) The reaction occurs in steps; it is consecutive
(ii) In the 1 st step a carbocation intermediate forms
Clearly, Ea1 > Ea2, and the 1 st step, formation of carbocation intermediate, is the rate-determining step

The more “expensive” [in kJ] the cation, the higher the
Ea1 and the more difficult the reaction
ΔE [kJmol -1 ]
(tropilium-C + )
Me-cation
473
! does not form !
1º-cation
301
2º-cation
3º-cation
192
125 least unstable

S
N
1 – the substrate effects; practice:

S
N
1 & S
N
2 – the leaving group properties & ranking: best LG good LG fair LG never a LG

Leaving group competition – practice:
Assign pKa values: pKa=+3.9, pKa=0.0, pKa=-13
Fastest: pKa =
Medium fast: pKa =
Slow: pKa =

Review of the S
N
1 reaction determinants:
- The substrate – Csp 3 crowded, a good C+
- The nucleophile - It does not matter
- The Leaving Group – same as in SN2 (pKa!)
- The solvent in S
N
1 reactions – Protic solvents

S
N
1 solvent practice – identify (dipolar) protic solvents
(1) Dipolar (dipole = diff electronegativity: e.g. C-Cl)
(2) Protic, i.e. has “loose” H + ; the O-H, N-H, S-H groups ethanol acetic acid dihydrogensulfide acetamide water

Experimental kinetic data for solvolysis of tert-butyl chloride:
Note that in EtOH/HOH mixtures the HO is the nucleophile
Explanation of the S
N
1 reaction mechanism (“strong ion-pair”) through interactions with a protic solvent

S
N
1 alert – Carbocation Rearrangement:
Frank C. Whitmore (UPenn, 1887-1947):
... carbocation rearrangements result when ... "an atom in an
electron-hungry condition seeks its missing electron pair from the next atom in the molecule".
A reaction: solvolysis of neopentyl iodide.

The mechanism of C + rearrangement: methide shift

Carbocation intermediate → rearrangement practice the substrate the product

Summary of differences: S
N
2 vs. S
N
1
Substrate:
S
N
2
1 Cº, uncrowded
S
N
1
3º, C crowded
Nucleophile:
Leaving group:
Solvent:
Reaction flow: good: I , Br ,
CN , R
3
N, N
3
good, low pKa of conjug acid polar aprotic;
DMSO, acetone concerted, transition state irrelevant good, low pKa of conjug acid
OH, SH, NH type solvent stepwise,
C + intermediate

S
N
2 vs. S
N
1 “game” – practice field:

More on S
N
1 – consider this:
S
N
1
E1
Make a note:
Every S
N
1 is accompanied by an E1 reaction.

S
N
1 vs. E1:

E1 reaction:
- Reaction flow & product regioselectivity:
Carbocation formation:
β-Elimination:

Again – E1 product regioselectivity: minor product
Hoffmann regioselect
MAJOR product
Zaytsev regioselect.

What a carbocation can do?
(4 things)
(1) Go forward & form a racemic mixture of products
(2) Go backward & form a racemic mixture of the reactant
(3) Undergo β-elimination and from an alkene
(4) Rearrange and do (1), (2), (3)

E1 + carbocation rearrangement – practice:

Other types of elimination reactions: E2
When a nucleophile Nu: replaces the leaving group on Csp3 in a concerted (smooth, continuous) way this is an S
N
2 reaction.
When the same nucleophile is a strong Broensted base, it can lead to a concerted elimination, or the so-called E2 reaction:

S
N
2 - E2 branching -- the effects of substrate:
1º carbon center – S
N
2 only
Make note: No rearrangement in S
N
2 and E2 reactions

Stereochemistry in E2 reaction: the H and LG must be in the same plane – or the reaction does not take place:

More on E2 stereochmistry:

Summary Ch. 6 – What have we learned today?