Transcript NUCLEOPHILIC SUBSTITUTION & ELIMINATION ON Csp 3

ORGANIC CHEMISTRY 1
Chapter 6, Part 1
(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, 7th 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 CCl4:
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-chloropropane
(propylchloride)
2-bromopropane
(isopropylchlride)
1-bromobutane
(butylchloride)
2-chlorobutane
(sec-butylchloride)
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)-bromo2,(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)
Amines
trans-1,2-dimethylepoxide
(2R)-cyanobutane
ethanenitrile
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, 2nd order – SN2
Again - the reaction:
And the kinetics:
The important “players” in an SN2 reaction:
(2R)-bromobutane:
the substrate
– the
nucleophile
Br – the
leaving group, LG
DMSO
= solvent
Make a note:
-CN
substrate (Cα)
leaving group
nucleophile
solvent
(2S)-butylcyanide:
the product
Effects of substrate
on an SN2 reaction:
Rxn rate:
Structure:
fastest
1º Cα, short
fast
1º Cα, longer
slower
1º Cα, but
Cβ branched
slow
NO rxn
2º Cα
3º Ca
Never an SN2 substrate Very good SN2 substrate
The effects of substrate on SN2 rate – practice:
Rank the following triads of SN2 rxn by expected rate; fastest=1st
The effects of substrate on SN2 rate – practice:
Rank the following SN2 rxn by expected rate; fastest=1st
Identify and tag Cα in each
substrate and classify it
as 1º, 2º; then look at Cβ
The next player the nucleophile:
very fast
Observe these
reactions:
What is the
fast
different?
What is
slow
the same?
very slow
SN2 - the nucleophile effect - again:
Observe:
What is common
to all these
compounds?
Make a note:
A nucleophile is an
electron-rich atom
or group of atoms
- a Lewis base
Very good Nu
Good Nu
Fair Nu
Poor Nu
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)
A
t
o
m
i
c
n
u
m
b
e
r
Electronegativity
poor Nu
very
good Nu
excelent 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:
SN2 – player # 3 - the leaving group, LG:
Observe these two SN2 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 SN2 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
SN2 – putting it all (almost) together:
- The substrate: 1o 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:
+ KBr
SN2 – a concerted reaction
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 SN2 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 SN2 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
SN2 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
acetone
DMSO
DMFA
Review of SN2 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, SN2
- SN2 reaction can be shown to depend on substrate,
leaving group, nucleophile and solvent
- Optimal reaction parameters and conditions are
established and the SN2 mechanism is derived
ORGANIC CHEMISTRY 1
Chapter 6, Part 2
(1) Uses of SN2 reactivity in synthesis
(2) Other SN reactions: SN1
- SN1 variables: substrate, nucleophile, leaving
group, solvent
- The carbocation intermediate paths
(3) Elimination, 1st order & competition with SN1
(4) Eliminatino, 2nd order
Based on Organic Chemistry, by L.G. Wade, 7th ed;
Compiled by: Dr. Peter Ilich, St. John’s University
Queens, New York, Spring 2012
Summary of SN2 type reactions – three possible cases:
Part 2: SN2 reactions – what are they good for?
- Example (1) - Preparation of alcohols:
iodomethane
methanol
and thioalcohols:
bromoethane
ethanethiol
(mercaptoethanol)
Uses of SN2–type
rxn in synthesis:
SN2 synthesis example (2) – ethers & tioethers:
Williamson ether synthesis:
Example 1:
Na-methoxide
methylbromide
dimethyl ether
Note: CH3OH (methanol) → CH3O- (methoxide)
Example 2:
Na-cyclopentoxide
ethyliodide
ethylcyclopentyl ether
Uses of SN2
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 SN2
ether cyclization
But note:
SN2 in synthesis – practice Williamson synthesis:
Another example – nucleophilic methylation in biology:
- Nucleic acids (C, A)
N-methylation, for
transcription
regulation
- Neurotransmitters,
NH2-CH2CH2-OPO3
N-methylation
(S)-Adenosylmethionine , AdoMet, SAM,
= the Nature's methylation agent
- Fatty (oleic) acid
C-methylatinon
The rxn: substrate = methyl-sulfonium, leaving group = sulfide
SN2 synthesis – another matter of concern the pKa of the LG and the reaction direction:
pKa(CH3COOH/CH3COO-) = +4.7
pKa(HCl/Cl-) = -7
Note that HCl is ~ 1010 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” SN2 work in the case (b)?
SN2 in synthesis (3) - replacement of OH group:
(1) Acidification of –OH to –OH2+ (hydronium group)
Note: pKa(HOH/HO-) +15.7 and pKa(H3O+/H2O) -1.7
Acidification of –OH to –OH2+ - the mechanism
#1
protonation of OH
#2
nucleophilic attack by Br-
SN2 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) SN2 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:
(CH3)3C-Br + HOH → (CH3)3C-OH + K+Br-
The concentration vs. time - exp data:
The rate of the
reaction changes
with the conc.
of the substrate,
(CH3)3CBr, but
is independent on
the concentration
of water, the
nucleophile:
RR
∝ [HOH]º
RR = k [(CH3)3CBr]1 [HOH]0 = 1st order substitution = SN1
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 1st step a carbocation intermediate forms
Clearly, Ea1 > Ea2, and the 1st 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
192
3º-cation
125
least unstable
SN1 – the substrate effects; practice:
SN1 & SN2 – 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 SN1 reaction determinants:
- The substrate – Csp3 crowded, a good C+
- The nucleophile - It does not matter
- The Leaving Group – same as in SN2 (pKa!)
- The solvent in SN1 reactions – Protic solvents
SN1 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
acetamide
acetic acid
water
dihydrogensulfide
Experimental kinetic data for solvolysis of tert-butyl chloride:
Note that in EtOH/HOH mixtures the HO- is the nucleophile
Explanation of the SN1 reaction mechanism (“strong ion-pair”)
through interactions with a protic solvent
SN1 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: SN2 vs. SN1
SN2
SN1
Substrate:
1 Cº, uncrowded
3º, C crowded
Nucleophile:
good: I-, Br-,
CN-, R3N, N3-
irrelevant
good, low pKa
of conjug acid
good, low pKa
of conjug acid
Solvent:
polar aprotic;
DMSO, acetone
OH, SH, NH
type solvent
Reaction flow:
concerted,
transition state
stepwise,
C+ intermediate
Leaving group:
SN2 vs. SN1 “game” – practice field:
More on SN1 – consider this:
SN1
E1
Make a note:
Every SN1 is accompanied by an E1 reaction.
SN1 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 SN2 reaction.
When the same nucleophile is a strong Broensted base, it can
lead to a concerted elimination, or the so-called E2 reaction:
SN2 - E2 branching -- the effects of substrate:
1º carbon center – SN2 only
Make note: No rearrangement in SN2 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?