CP203 LecLure 23

CcLober 27, 2014

1oplclLy revlew
lree radlcals
lree radlcal lnhlblLors


2
1oplclLy
Pydrogens are homoLoplc lf replacemenL does noL generaLe a new chlral cenLer. u
(
2
P) ls someumes used as Lhe LesL replacemenL.

ln dlbromomeLhane, Lhe hydrogens are homoLoplc and so are always ldenucal.
Br
C
Hb
Br Ha
Br
C
D
Br Ha
Br
C
Hb
Br D
1oplclLy
Pydrogens are enanuoLoplc lf replacemenL does generaLe a new chlral cenLer.

ln bromouoromeLhane, Lhe hydrogens are enanuoLoplc and so are ldenucal ln
achlral envlronmenLs.
Br
C
Hb
F Ha
Br
C
D
F Ha
Br
C
Hb
F D
1oplclLy
8rown's denluon: Croups are dlasLereoLoplc lf replacemenL generaLes a new chlral cenLer
ln a molecule wlLh aL leasL one exlsung chlral cenLer.

ln 3-meLhyl-2-buLanol, Lhe Lwo meLhyl groups bonded Lo C3 are dlasLereoLoplc and so are
noL equlvalenL. ulasLereoLoplc groups wlll exhlblL dlerenL chemlcal shls.
C
OH
CH
3
H
3
C
H
3
C
C C
OH
CH
3
H
3
C
D
3
C
C C
OH
CH
3
D
3
C
H
3
C
H
3
C
H
3
C OH
CH
3
H H
1oplclLy
H
3
C
H
3
C OH
CH
3
H H
1.14
3.55
1.62
0.93
0.90
1oplclLy
O
CH
3
H
3
C
H
3
C
1he Lwo meLhyl groups aL C3 ln 3-meLhyl-2-buLanone are noL dlasLereoLoplc and appear
as a clean doubleL aL abouL 1 ppm.
1oplclLy
1he concepL of dlasLereoLoplclLy was rsL lnLroduced durlng Lhe early days of nM8
specLroscopy, when cerLaln klnds of molecules gave unexpecLedly complex nM8
specLra, leadlng Lo some confuslon abouL Lhe orlglns of Lhls hlLherLo undeLecLed
phenomenon. A Lyplcal slLuauon where dlasLereoLoplc proLons are seen ls a CP
2

group ln a chlral molecule.

1he eLher above has one chlral cenLer, so an lnLroducuon of anoLher chlral cenLer
by Lhe subsuLuuon LhoughL experlmenL produces dlasLereomers.
1oplclLy
A more subLle form of dlasLereoLoplsm ls demonsLraLed ln Lhe classlcal example of
dleLhyl aceLal. Lven Lhough dleLhyl aceLal has no asymmeLrlc cenLers, Lhe hydrogens
on boLh CP
2
groups are dlasLereoLoplc. 1hls can be shown by applylng Lhe
subsuLuuon LesL, whlch creaLes a palr of dlasLereomers ! and ".

updaLed denluon of dlasLereoLoplclLy: Croups are dlasLereoLoplc lf replacemenL
generaLes a new chlral cenLer ln a molecule wlLh aL leasL one exlsung cenLer whlch
ls chlral #$ &'(#)'* (+,$-. /0#1 */(+ $'0.-(')'123
1oplclLy
PomoLoplc: - replacemenL does noL generaLe a new chlral cenLer
- always ldenucal
- same chemlcal shls

LnanuoLoplc: - replacemenL generaLes a new chlral cenLer
- ldenucal ln achlral envlronmenLs
- same chemlcal shls ln achlral nM8 experlmenL

ulasLereoLoplc: - replacemenL generaLes a new chlral cenLer ln a molecule
wlLh aL leasL one exlsung cenLer whlch ls chlral #$ &'(#)'*
(+,$-. /0#1 */(+ $'0.-(')'12
- dlerenL chemlcal shls

1oplclLy
O
O Cl
Cl
CH
3
CH
3
0 20 40 60 80 100 120
PPM
13
C NMR
3. Based on the chemical shifts or number of signals, how would you use NMR to distinguish between the
following isomers?
1)
O
H
3
C
CH
3
O
O
H
3
C
CH
3
O
I
II
2) O
H
CH
3
O
H
3
C
H
I
II
3)
O
H
H
CH
3
H
f
H
f
H
f
O
H
H
H
CH
3
H
H
I
II
4. Please gure out the highlighted H is homotopic, enantiotopic or diastereotopic.
H H
OH
H
H
3
C H
OH
H
H
3
C
CH
3
Cl
H
H
H
O
Cl
Cl
H H
CH
3
HO
H
H
H
H
3
C
H H
Ya Zhou, 10-13-2014
OH
Hb Ha
CO
2
H
Hb
Ha
OH
Hb Ha
Are Lhe deslgnaLed hydrogens dlasLereoLoplc?

ulasLereoLoplc: replacemenL generaLes a new chlral cenLer ln a molecule wlLh aL leasL
one exlsung cenLer whlch ls chlral #$ &'(#)'* (+,$-. /0#1 */(+ $'0.-(')'12.
1oplclLy
O
O Cl
Cl
CH
3
CH
3
0 20 40 60 80 100 120
PPM
13
C NMR
3. Based on the chemical shifts or number of signals, how would you use NMR to distinguish between the
following isomers?
1)
O
H
3
C
CH
3
O
O
H
3
C
CH
3
O
I
II
2) O
H
CH
3
O
H
3
C
H
I
II
3)
O
H
H
CH
3
H
f
H
f
H
f
O
H
H
H
CH
3
H
H
I
II
4. Please gure out the highlighted H is homotopic, enantiotopic or diastereotopic.
H H
OH
H
H
3
C H
OH
H
H
3
C
CH
3
Cl
H
H
H
O
Cl
Cl
H H
CH
3
HO
H
H
H
H
3
C
H H
Ya Zhou, 10-13-2014
OH
Hb Ha
CO
2
H
Hb
Ha
OH
Hb Ha
All Lhe deslgnaLed hydrogens are dlasLereoLoplc.
1oplclLy
Ha
Hb F
H
3
C
WhaL abouL Lhese gemlnal hydrogens?
X
Hb F
H
3
C Ha
X F
H
3
C
8eplacemenL of Pa and Lhen Pb generaLes a palr of dlasLereomers, so Pa and Pb are
dlasLereoLoplc.
1oplclLy
Comprehenslve denluon of dlasLereoLoplc groups: Croups whose modlcauon
generaLes dlasLereomers.
OH
Hb Ha
OH
Hb Ha
Ha
Hb F
H
3
C
Alkenes - more or less subsuLuLed
H H
H H
H H
R H
H R
R H
H R
R H
R R
R H
R R
R R
more substituted
lree radlcal chaln reacuon sLeps
A-A ! A
.
+
.
A



x
.
+ P-? ! x-P +
.
?
?
.
+ x-x ! ?-x +
.
x


A
.
+
.
A ! A-A
x
.
+
.
x ! x-x
?
.
+
.
? ! ?-?
A
.
+
.
x ! A-x
eLc.
lnluauon sLep
8adlcals are generaLed


ropagauon sLeps
8adlcals become oLher radlcals


1ermlnauon sLeps
8adlcals are consumed
lree radlcal chaln reacuon sLeps
A-A ! A
.
+
.
A lnluauon sLep
8adlcals are generaLed
Cl Cl
heat or light
Cl Cl
+
lree radlcal chaln reacuon sLeps
x
.
+ P-? ! x-P +
.
?
?
.
+ x-x ! ?-x +
.
x
ropagauon sLeps
8adlcals become oLher radlcals
ropagauon sLeps are Lhe 'chaln' parL of chaln reacuons. 1he number of umes Lhls cycle ls
able Lo repeaL ls called Lhe chaln lengLh.
lree radlcal chaln reacuon sLeps
A
.
+
.
A ! A-A
x
.
+
.
x ! x-x
?
.
+
.
? ! ?-?
A
.
+
.
x ! A-x
eLc.
1ermlnauon sLeps
8adlcals are consumed
Cl
Cl
Cl Cl
Cl C H
H
H
C H
H
H
Cl
C H
H
H
C H
H
H
H
H
H C H
H
H
C
lree radlcal chaln reacuon lnhlbluon
1he o-Locopherol form of vlLamln L, a faL-soluble anuoxldanL. 8adlcal absLracuon of Lhe
phenollc hydrogen leaves a resonance-sLablllzed radlcal whlch ls less reacuve and also
Lraps by reacuon anoLher radlcal
.
CC8.
O
H-O
H
O
O
H
O
H
O
O
R
O
O
O
H
A phenoxy radical
A peroxide derived from vitamin E
3
a peroxide
group
Vitamin E
3
3 3
OOR
lree radlcal chaln reacuon lnhlbluon
8P1 ls a synLheuc vlLamln L analog. AbsLracuon of Lhe 8P1 phenollc hydrogen leaves a
radlcal sLablllzed by resonance and by Lhe sLerlc shleldlng of Lhe LerL-buLyl groups. 1he
8P1 radlcal reduces anoLher molecule of a reacuve oxygen specles. Cne molecule of
8P1 removes Lwo radlcal molecules from Lhe chaln.
OH

O O R
O

HO O R
+
+
Butylated hydroxytoluene; BHT
resonance stabilized
O

O O R +
O
HO O R
+
Allyllc bromlnauon
22
ln a 300-ml. round-bouomed ask ued wlLh a surrer, nlLrogen lnleL Lube, and reux condenser are
placed 40 g. (0.41 mole) of 2-hepLene, 48.1 g. (0.27 mole) of n-bromosucclnlmlde, 0.2 g. of benzoyl
peroxlde, and 230 ml. of carbon LeLrachlorlde. 1he reacuon mlxLure ls surred and heaLed under
reux ln a nlLrogen aLmosphere for 2 hours. 1he succlnlmlde ls removed by sucuon lLrauon, washed
Lwlce wlLh 13-ml. poruons of carbon LeLrachlorlde and Lhe carbon LeLrachlorlde washlngs are
comblned wlLh Lhe lLraLe. 1he carbon LeLrachlorlde soluuon ls Lransferred Lo a 300 ml Clalsen ask
modled so LhaL Lhe dlsulllng arm carrles a 23 300 mm. secuon packed wlLh glass hellces. 1he
caplllary ls auached Lo a source of nlLrogen and Lhe carbon LeLrachlorlde removed aL 36-38/190
mm. 1he resldue ls Lransferred Lo a 123-ml. Clalsen ask modled so LhaL Lhe dlsulllng arm carrles an
18 180 mm secuon packed wlLh glass hellces. nlLrogen ls led lnLo Lhe caplllary, and, aer a forerun
of 1-3 g., Lhere ls collecLed 28-31 g. (38-64) of 4-bromo-2-hepLene, b.p. 70-71/32 mm.

(Zlegler and coworkers lndlcaLed LhaL allyllc meLhylene groups undergo bromlne subsuLuuon more
readlly Lhan allyllc meLhyl groups.)

Creenwood and kellerL, !" $%" &'(%" )*+", 45, 4842 (1933)
Br
NBS
benzoyl peroxide
CCl
4
heat
Allyllc bromlnauon - observauons
23
Br
NBS
radical bromination
An allyllc meLhylene group (A) undergoes bromlne subsuLuuon more readlly Lhan an
allyllc meLhyl group (8).
Br
NBS
radical bromination
A
B
1he ma[or producL ln Lhls and slmllar reacuons ls Lhe one wlLh Lhe more subsuLuLed
double bond.
8adlcal addluon of P8r Lo alkenes
24
Br
Br Br
Br
2
Addluon Lo alkenes
23
Markovnlkov's rule rule sLaLes LhaL ln Lhe addluon of Px Lo an unsymmeLrlcal alkene,
Lhe hydrogen becomes auached Lo Lhe carbon wlLh fewer alkyl subsuLuenLs, and Lhe
hallde becomes auached Lo Lhe carbon wlLh more alkyl subsuLuenLs.
vladlmlr vasllyevlch Markovnlkov
8adlcal addluon of P8r Lo alkenes
26
Br
HBr
H
H
Br Markovnlkov addluon
non-Markovnlkov addluon
Addluon of PCl and Pl glves only Markovnlkov producLs. Addluon of P8r glves one or
Lhe oLher.
8adlcal addluon of P8r Lo alkenes
27
Careful observauon showed LhaL Lhe non-Markovnlkov addluon of P8r happened ln
Lhe presence of peroxldes. ChemlsLs Lherefore proposed a radlcal chaln mechanlsm.
8adlcal addluon of P8r Lo alkenes
28
Careful observauon showed LhaL Lhe non-Markovnlkov addluon of P8r happened ln
Lhe presence of peroxldes. ChemlsLs Lherefore proposed a radlcal chaln mechanlsm.
8adlcal addluon of P8r Lo alkenes
29
8oLh mechanlsms are regloselecuve. 1he radlcal mechanlsm ma[or producL comes
from Lhe addluon of a bromlne radlcal Lo Lhe double bond Lo glve Lhe more sLable 3
o

carbon radlcal. 1he polar mechanlsm ma[or producL comes from Lhe addluon of P+ Lo
Lhe double bond Lo glve Lhe more sLable 3
o
carbon cauon.
Allyllc bromlnauon
30
,-./*%*-0-.*+-123+45( 6(/6-78632 (96(/. ln a 1-L, round-bouomed ask are placed 20.0 g (0.0863 mol)
of n-8oc-glyclne LerL-buLyl esLer and 16.2 g (0.0912 mol) of n- bromosucclnlmlde . Carbon
LeLrachlorlde (330 mL) ls added, Lhe ask ls connecLed Lo a clean roLaLory evaporaLor and Lhe
apparaLus ls ushed wlLh argon. 1he ask ls cooled, whlle belng roLaLed, by means of a waLer baLh
and ls lrradlaLed wlLh Lwo 130-W LungsLen lamps for 1 hr. 1he colorless soluuon becomes dark red
and a preclplLaLe forms. 1he suspenslon ls lLered Lhrough a Schlenk Lube and Lhe carbon
LeLrachlorlde (CCl4) ls evaporaLed under reduced pressure. 1he remalnlng yellowlsh oll ls employed
ln Lhe nexL sLep wlLhouL purlcauon.
Clarlsse Muhlemann, eLer ParLmann, and !ean-lerre CbrechL, Clba-Celgy lanL roLecuon ulvlslon
(ulsease ConLrol), ueberlandsLrasse 138, CP-8600 uuebendorf, SwlLzerland
Organic Svntheses, Coll. Jol. 9, p.526 (1998), Jol. 71, p.200 (1993).
TITANIUM-MEDIATED ADDITION OF SILYL DIENOL ETHERS
TO ELECTROPHILIC GLYCINE: 4-KETOPIPECOLIC ACID
HYDROCHLORIDE
Pipecolic acid, 4-oxo-, hydrochloride]

Submitted by Clarisse Mhlemann, Peter Hartmann, and Jean-Pierre Obrecht
1
.

Checked by Eugene Ho and David L. CoIIen.
1. Procedure
A. 2-Bromo-N-Boc-glvcine tert-butvl ester. In a 1-L, round-bottomed Ilask are placed 20.0 g
(0.0865 mol) oI N-Boc-glycine tert-butyl ester (Note 1) and 16.2 g (0.0912 mol) oI N-
bromosuccinimide (Note 2). Carbon tetrachloride (350 mL, (Note 3)) is added, the Ilask is connected to
a clean rotatory evaporator (Note 4) and the apparatus is Ilushed with argon. The Ilask is cooled, while
being rotated, by means oI a water bath and is irradiated with two 150-W tungsten lamps (Note 5) Ior 1
hr. The colorless solution becomes dark red and a precipitate Iorms. The suspension is Iiltered through a
Schlenk tube and the carbon tetrachloride (CCl
4
) is evaporated under reduced pressure. The remaining
yellowish oil is employed in the next step without puriIication (Note 6).
B. tert-Butvl [1-(tert-butoxvcarbonvl)-3-oxo-4-pentenvl]carbamate. The crude bromination product
Irom the previous step is taken up in 240 mL oI dry tetrahydroIuran (THF) (Note 7) and transIerred to a
1000-mL Ilask equipped with a stirrer, thermometer, dropping Iunnel, and argon inlet. The solution is
cooled to 78C and a solution oI 42 g (0.20 mol) oI dichlorodiethoxytitanium |TiCl
2
(OEt)
2
| in 80 mL
oI dry THF (Note 8) is added at such a rate that the internal temperature does not exceed 72C. When
the addition is complete, the reaction mixture is stirred at 78C Ior 10 min and then 24 g (0.170 mol)
oI 2-trimethylsiloxybutadiene (Note 9) in 100 mL oI THF is added dropwise, causing only a slight
increase in temperature (72C). The reaction mixture is allowed to warm to room temperature
overnight and poured into 700 mL oI ice-cooled, saturated sodium bicarbonate solution. AIter Iiltration
through Celite, the aqueous phase is extracted with three 200-mL portions oI ether. The combined
organic layers are washed twice with water, dried over magnesium sulIate (MgSO
4
), Iiltered, and
concentrated. The remaining dark oil (29 g) is subjected to Ilash chromatography (20-cm column
diameter, ether/hexane 1:3); 8.448.73 g (3336) (Note 10) oI the product is obtained as a slightly
yellowish oil (Note 11).
DOI:10.15227/orgsyn.071.0200
Allyllc bromlnauon
31
Org. Svnth. 2012, 89, 55-65 55
Published on the Web 9/1/2011
2012 Organic Syntheses, Inc.
Dibenzoa,e]cyclooctene: Multi-gram Synthesis of a Bidentate
Ligand

Br
Br
Li
THF, reflux
NBS
CCl
4
, reflux
Br
Br
!
" !
Br
Br
"
#
KO!Bu
THF, 0 C to rt
A.
B.
C.



Submitted by Geraldine Franck, Marcel Brill and Gnter Helmchen.
1

Checked by Tohru Fukuyama and Takuya Nishimura.

Caution' Once ,-dibromo-o-xvlene is dissolved in an organic solvent it
becomes lachrvmatorv. The use of granular lithium on a larger scale
requires special care due to the exothermic formation of lithium bromide.

1. Procedure

A. 5,6,11,12-Tetrahvdrodiben:o[a,e]cvclooctene (1). A 1-L, three-
necked round-bottomed Ilask, equipped with a 4-cm egg-shaped magnetic
stirring bar, a reIlux condenser, an internal thermometer and a 250-mL
pressure-equalizing dropping Iunnel (capped with a rubber septum), is
Ilame-dried and purged with argon. Degassed THF (200 mL) (Note 1) is
added and subsequently granular lithium (6.63 g, 956 mmol, 2.5 equiv)
(Note 2). The dropping Iunnel is charged with a solution oI Ireshly sublimed
,`-dibromo-o-xylene (101 g, 382 mmol) in degassed THF (150 mL)
DOI:10.15227/orgsyn.089.0055
:;<<-=47/*%*-:;>;<<;<,-6(6/?'3@/*@47(5A*B?;(C-+3+2**+6(5( (6)" under an aLmosphere of argon ln a
ame-drled, 300-mL, Lhree-necked round-bouomed ask, equlpped wlLh a reux condensor and a 4-
cm egg- shaped magneuc surrlng bar, 7 (19.2 g, 92.3 mmol) ls dlssolved ln carbon LeLrachlorlde (200
mL). n8S (33.3 g, 198.4 mmol, 2.13 equlv) ls added, and Lhe surred mlxLure ls Lhen reuxed aL 83 C
(oll baLh LemperaLure). Aer 2 h nM8 analysls lndlcaLes compleLe consumpuon of Lhe sLarung
maLerlal 7. 1he hoL suspenslon (63 C) ls lLered Lhrough a frlued glass funnel (8.0 cm dlameLer,
poroslLy 3), and Lhe remalnlng succlnlmlde ls washed wlLh carbon LeLrachlorlde (400 mL). 1he
solvenL of Lhe lLraLe ls evaporaLed under gradually reduced pressure (40 C, 223 Lo 18 mmPg). A
pale yellow resldue remalns, whlch ls scraped o Lhe lnner wall of Lhe ask, poured lnLo a frlued
glass funnel (7.0 cm dlameLer, poroslLy 3), washed wlLh dlsulled waLer (300 mL) and drled overnlghL
under vacuum (23 C, 0.3 mmPg) Lo glve 33.4 g of crude 6 as a pale yellow solld.

Ceraldlne lranck, Marcel 8rlll, and CunLer Pelmchen, Crganlsch-Chemlsches lnsuLuL der unlverslLaL
Peldelberg