ur. !ames ?oung Slmpson and hls frlends ur. kelLh and ur.

uuncan meL
every evenlng ln ur. Slmpson's Ldlnburgh dlnlng room and lnhaled new
chemlcals Lo see lf Lhey had any anaesLheuc eecL.

Cn november 4, 1847, Lhey Lrled chloroform.
Pe llved.
CP203 LecLure 19
CcLober 17, 2014

Alkyl halldes, aka haloalkanes
3
Paloalkanes
4
Haloalkanes, or alkyl halides, are alkanes containing a halogen atom
bonded to an sp
3
hybridized carbon atom.
Alkyl halides are classified as primary (1), secondary (2), or tertiary
(3), depending on the number of carbons bonded to the carbon with
the halogen atom.
The halogen atom is often represented generically as X.
CLher organlc halldes
3
A haloalkene, or vlnyllc hallde, conLalns a halogen aLom bonded Lo an !"
2
hybrldlzed
carbon.






An aryl hallde, or haloarene, conLalns a halogen aLom bonded Lo an !"
2
hybrldlzed
carbon of an aromauc rlng, oen benzene.

C C
X
R R
R
X
CLher organlc halldes
6
An allyl (or allyllc) hallde conLalns a halogen bonded Lo Lhe carbon aLom ad[acenL Lo
a C=C double bond.




A benzyllc hallde conLalns a halogen bonded Lo Lhe carbon aLom ad[acenL Lo a
benzene rlng.

C C
H
2
C
R R
R X
H
2
C
X
Crganlc halldes - nomenclaLure
7
Crganlc halldes - nomenclaLure
8
Br
2-Bromo-4-methyl-
pentane
1
2
3
4
5
4-Bromo-
cyclohexene
1
2
3
4
5
6
trans-2-Chloro-
cyclohexanol
Br
Cl
OH
luAC names.




Some slmple organlc halldes have common names.
B r
C l
C l
2-Bromobutane
(sec-Butyl bromide)
Chloroethene
(Vinyl chloride)
3-Chloropropene
(Allyl chloride)
Crganlc halldes - nomenclaLure
9
Some polyhaloalkanes are lndusLrlal or laboraLory solvenLs and are oen
referred Lo by Lhelr common or Lrlvlal names.








Pydrocarbons ln whlch all hydrogens are replaced by halogens are commonly
named as perhaloalkanes or perhaloalkenes.
Crganlc halldes
10
olyLeLrauoroeLhylene (1lL) ls a synLheuc uoropolymer of LeLrauoroeLhylene.
uuonL, Lhe lnvenLor, sells 1lL under Lhe Lradename 1eon.
Crganlc halldes
11
eruoroocLanolc acld (lCA) ls a synLheuc peruorlnaLed carboxyllc acld and
uorosurfacLanL used ln Lhe manufacLure of 1lL. lCA has been deLecLed ln
lndusLrlal wasLe, sLaln reslsLanL carpeLs, carpeL cleanlng llqulds, house dusL,
mlcrowave popcorn bags, waLer, food, some cookware and 1lL such as 1eon.

Some sLudles have concluded LhaL Lhere ls probably an assoclauon beLween lCA
exposure and slx healLh ouLcomes: kldney cancer, Lesucular cancer, ulcerauve
collus, Lhyrold dlsease, hypercholesLerolemla (hlgh cholesLerol), and pregnancy-
lnduced hyperLenslon.
Crganlc halldes
12
uleLhyl eLher (above) was rsL demonsLraLed as an anesLheuc ln Lhe LLher uome aL
Massachuseus Ceneral PosplLal. LLher was nlcknamed Lhe ?ankee uodge" because lL was
much more eecuve Lhan mesmerlsm, or hypnosls, aL blocklng paln. LLher was laLer found
Lo have undeslrable slde eecLs, such as posL-anesLheuc nausea and vomlung, myocardlal
depresslon, and lncreased Lracheobronchlal secreuons.

PalogenaLed eLhers were synLheslzed beglnnlng ln Lhe 1930s as replacemenLs for dleLhyl
eLher. 1hese had fewer slde eecLs and had Lhe added bonus of belng nonammable.
PaloLhane Lnurane lsourane
Crganlc halldes
13
19
l has a spln of x and comprlses 100 of naLurally occurrlng uorlne. CLher
halogen lsoLopes capable of glvlng an nM8 slgnal are
33
Cl,
37
Cl,
79
8r,
81
8r, and
127
l.
roperues of haloalkanes - dlpole momenL
14
H
C X
H
H
!+ !-
H
C X
H
H
When Lwo parual opposlLe charges are separaLed, a dlpole momenL arlses.

1he magnlLude of lncreases as Lhe parual charge lncreases and as Lhe dlsLance
beLween Lhem lncreases.
roperues of haloalkanes - dlpole momenL
13
H
C X
H
H
!+ !-
H
C X
H
H
ln a carbon-halogen bond, Lhe dlpole momenL wlll lncrease as Lhe
elecLronegauvlLy of Lhe halogen lncreases and lncrease as Lhe bond lengLh
lncreases.
roperues of haloalkanes - dlpole momenL
16
roperues of haloalkanes
17
1he van der Waals force ls Lhe sum of all forces beLween molecules oLher Lhan
Lhose due Lo covalenL bonds.

1here are Lhree maln forces whlch make up Lhe van der Waals force:

1. 1he keesom force, an auracuon beLween Lwo permanenL dlpoles.
2. 1he uebye force, an auracuon beLween a permanenL dlpole and an lnduced
dlpole.
3. 1he London dlsperslon force, an auracuon beLween Lwo (lnsLanLaneously)
lnduced dlpoles.
roperues of haloalkanes
18
(a) ls a keesom force beLween Lwo molecules wlLh permanenL dlpoles.
(b) ls a uebye force beLween Lhe permanenL dlpole of aceLone and a LranslenL
dlpole lnduced ln hexane by Lhe aceLone dlpole.
(c) ls a London force beLween ocLane and hexane - Lwo LranslenL dlpoles, each
lnduced by Lhe oLher.
roperues of haloalkanes
19
1wo elecLron clouds, elLher an aLom or group of aLoms, wlll auracL one anoLher aL a
dlsLance due Lo Lhe van der Waals forces. AL some polnL, Lhe elecLron clouds wlll
overlap and begln Lo repel each oLher. 1he equlllbrlum dlsLance beLween Lhe Lwo
aLoms or group of aLoms where Lhe force of auracuon and Lhe force of repulslon
balance ls called Lhe van der Waals radlus.
roperues of haloalkanes
20
CovalenL bond lengLhs and van der Waals radll boLh descrlbe Lhe slze and dlsLance
beLween aLoms. 8uL whlle Lhe covalenL bond lengLh refers Lo Lhe dlsLance beLween Lhe
nuclel of Lwo bonded aLoms, Lhe van der Waals radlus measures how close Lwo non-
bonded aLoms or group of aLoms come when Lhey bump lnLo each oLher buL do noL
bond.
Boiling Points
The size of Br and CH
3
about the same but bromo compounds boil
higher due to greater polarizability; more dispersion forces.
Boiling Points
Branching in an alkane decreases the boiling point. Likewise for
haloalkanes.
Boiling Points
Fluoroalkanes and alkanes of same MW have about the same BP. In
both cases the electrons are tightly held, not very polarizable.
roperues of haloalkanes - polarlzablllLy
olarlzablllLy ls a measure of Lhe ease of whlch Lhe elecLron denslLy abouL an aLom
may be dlsLorLed, usually by an lnLeracuon wlLh oLher molecules and lons.

1. 1he greaLer Lhe number of elecLrons ln an aLom, Lhe less conLrol Lhe nuclear
charge exerLs on Lhe shape of Lhe elecLron cloud. 1he aLom ls more polarlzable.

2. 1he greaLer Lhe dlsLance of Lhe elecLrons from Lhe nuclear charge, Lhe less
conLrol Lhe nuclear charge exerLs on Lhe shape of Lhe elecLron cloud. 1he aLom ls
more polarlzable.

1. and 2. boLh lncrease golng down Lhe perlodlc Lable ln an elemenL group.

lluorlne has a very low polarlzablllLy. lodlne has a very hlgh polarlzablllLy.

was recently approved by the FDA. Introduction of fluorine
atoms prevent oxidation of the phenyl ring to phenol and
dealkylation of the methoxy group.
Another interesting recent example demonstrating the
strong effect of fluorine on metabolic stability, is the discovery
of the cyclo-oxygenase 2 (COX 2) inhibitor Celecoxib
(Scheme 2).
[10, 14]
In this case, the extremely high metabolic sta-
bility of the lead compound, which results in a very long bio-
logical half life, could be reduced to more acceptable levels by
replacing a fluorine atom by a metabolically labile methyl
group.
Interestingly, there are also a few cases known for which the
introduction of a fluorine substituent does not prevent oxida-
tion at that site.
[5, 17, 18]
This phenomenon is observed in particu-
lar for phenyl rings with a nitrogen substituent in the para po-
sition to the fluorine substituent. During P450-catalyzed oxida-
tion, a rearrangement takes place in which the fluorine atom
moves to an adjacent carbon and the phenol metabolite is
formed para to the nitrogen substituent.
3. The Effect of Fluorine on Physicochemical
Properties
3.1 The effect of fluorine on the pK
a
As the most electronegative atom, fluorine has a very strong
effect on the acidity or basicity of nearby functional groups.
Depending on the position of the fluorine substitu-
ent relative to the acidic or basic group in the mole-
cule, a pK
a
shift of several log units can be observed.
For example, the pK
a
's of acetic acid and its a-
fluorinated analogues are 4.76 (CH
3
COOH), 2.59
(CH
2
FCOOH), 1.24 (CHF
2
COOH), and 0.23
(CF
3
COOH).
[15]
Likewise, the basicities of ethylamine
and its b-fluorinated analogues, measured by the
pK
a
's of the protonated amines, decrease in an ap-
proximately linear fashion upon introduction of
fluorine, the pK
a
's being 10.7 (CH
3
CH
2
NH
2
), 8.97
(CH
2
FCH
2
NH
2
), 7.52 (CHF
2
CH
2
NH
2
), and 5.7
(CF
3
CH
2
NH
2
).
[19]
Similarly, a fluorine substituent at the
3 and 4 position of a piperidine ring lowers the pK
a
by about 2 log units.
[2021]
Quite often, a change in the pK
a
has a strong effect on both
the pharmacokinetic properties of the molecule and its bind-
ing affinity. For example, a strongly basic group may be re-
quired for binding within a certain lead series, but at the same
time this basic group may also be found to result in com-
pounds with low bioavailability due to the limited ability of a
strong basic group to pass through membranes. The drug dis-
covery project team is then faced with the challenge of finding
an optimum between these conflicting effects.
This challenge is very nicely highlighted by the work of
van Niel et al.
[22]
on the discovery of novel fluorinated indole
derivatives as selective 5HT
1D
receptor ligands. The incorpora-
tion of fluorine was found to significantly reduce the pK
a
of
the compounds, and this reduction of basicity, with a concomi-
tant weakening of the affinity to the receptor, was shown to
have a strong beneficial influence on oral absorption
(Figure 1).
3.2 The effect of fluorine on molecular lipophilicity
Lipophilicity is a key molecular parameter in medicinal chemis-
try. Typically, groups of substantial lipophilicity on the ligand
are required to obtain a good binding affinity to the target
protein.
[23]
However, a high lipophilicity typically results in a re-
duced solubility and a number of other undesirable properties
for a compound. Therefore, the right balance between a re-
quired lipophilicity and a certain minimal overall polarity of the
molecule is one of the recurring challenges for medicinal
chemists.
We investigated the effect of replacing a hydrogen by a fluo-
rine atom on the lipophilicity of a compound. We selected 293
pairs of molecules from the Roche in-house database with
measured logD values that just differ by one fluorine atom.
LogD is the logarithmic coefficient of the distribution of the
compound between octanol and water at a given pH (typically
7.4). A histogram of changes in logD upon one H/F exchange
is shown in Figure 2. The plot reveals a Gaussian distribution
with the maximum slightly higher than 0. On average, the sub-
stitution of a hydrogen atom by fluorine increases lipophicity
slightly, by roughly 0.25 log units. This is in line with expecta-
tions and atomic increments published by others.
[24]
Interest-
Scheme 2. Development of the COX 2 inhibitor Celecoxib.
[14]
Replacement of a
fluorine group by a methyl group reduces the very long half-life to an accepta-
ble level.
Scheme 1. Development of Ezetimibe (SCH58235) by optimization of the lead
SCH48461.
[12, 13]
As part of the optimization, two metabolically labile sites are blocked by flu-
orine substituents.
638 2004 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim www.chembiochem.org ChemBioChem 2004, 5, 637 643
H.-J. Bhm et al.
lncorporauon of a uorlne aLom can block meLabollc degradauon of a drug.
roperues of haloalkanes - uorlnaLed drugs
roperues of haloalkanes - uorlnaLed drugs
MeLabollc sLablllLy ls one of Lhe key facLors ln deLermlnlng Lhe bloavallablllLy of a
compound. 8apld oxldauve meLabollsm by Lhe llver enzymes, ln parucular Lhe 430
cyLochromes, ls oen found Lo llmlL bloavallablllLy. A frequenLly employed sLraLegy
Lo clrcumvenL Lhls problem ls Lo block Lhe reacuve slLe by Lhe lnLroducuon of a
uorlne aLom.

lluorlne can change Lhe baslclLy of a compound. Plghly baslc groups can have a
llmlung eecL on Lhe bloavallablllLy. A uorlne aLom lnLroduced close Lo a baslc
group reduces lLs baslclLy, Lhls resulLs ln beuer membrane permeauon of a
compound and Lhus lmproved bloavallablllLy.

lluorlne subsuLuenLs may lncrease Lhe blndlng amnlLy of a compound Lo lLs LargeL
recepLor. Some call Lhls eecL 'maglcal' because classlcal CuanuLauve SLrucLure-
AcuvlLy 8elauonshlp (CSA8) modellng cannoL accounL for Lhls sLrong eecL of
uorlne.
lluoxeune (rozac)
(#$)-%-meLhyl-3-phenyl-3-[4-(LrluoromeLhyl)
phenoxy]propan-1-amlne
roperues of haloalkanes - denslues
27
roperues of haloalkanes - denslues
28
8romoform's (CP8r
3
) hlgh denslLy makes lL useful for separauon of some mlnerals. A
crushed sample of ore ls shaken wlLh bromoform and Lhen allowed Lo seule. A Lop layer
wlll conLaln mlnerals llghLer Lhan bromoform, and a bouom layer wlll conLaln heavler
mlnerals.
roperues of haloalkanes
29
ln 1910, 1he yrene ManufacLurlng Company of uelaware led a paLenL Lo
use carbon LeLrachlorlde Lo exungulsh res.

1he llquld vaporlzed and
exungulshed Lhe ames by lnhlblung Lhe chemlcal chaln reacuon of Lhe
combusuon process.

A formerly common form of re exungulshers conslsLed of a glass globe
lled wlLh carbon LeLrachlorlde, known as a "re grenades". 1he bulb was
slmply Lhrown aL Lhe base of Lhe ames.
roperues of haloalkanes
30
roperues of haloalkanes - bond lengLh and bond sLrengLh
31
1he bond dlssoclauon enLhalpy (8uL) ls Lhe amounL of energy needed Lo break
a bond lnLo a palr of radlcals. (one mole, gas phase, 23
o
C)
reparauon of haloalkanes - halogenauon of alkanes
32
C H
H
3
C
H
3
C
H
3
C
C H
H
3
C
H
3
C
H
3
C
C H
H
3
C
H
3
C
H
3
C
C H
H
3
C
H
3
C
H
3
C
F
2
Cl
2
Br
2
I
2
+
+
+
+
C Cl
H
3
C
H
3
C
H
3
C
C Br
H
3
C
H
3
C
H
3
C
C H
H
3
C
H
3
C
H
3
C
I
2
+
HCl
+
HBr
+