Chem 2411 Lecture 08 Stereochemistry

7/23/2019 Chem 2411 Lecture 08 Stereochemistry

http://slidepdf.com/reader/full/chem-2411-lecture-08-stereochemistry 1/60

Stereochemistry at Tetrahedral Centers



Diferent Types o IsomerismDiferent Types o Isomerism



• Diferent order o connections gives diferent

carbon backbone and/or diferent unctionalgroups

Constitutional IsomersConstitutional Isomers



StereochemistryStereochemistry

• For pharmaceuticals, slight diferences in 3D

spatial arrangement can make the diferencebeteen targeted treatment and undesired side!efects"

• #somers that have the same connectivity beteenatoms but diferent 3D, spatial arrangement otheir atoms are called STEREOisomers



Stereochemistry o Organic CompoundsStereochemistry o Organic Compounds

Seager S$, Slabaugh %&, Chemistry or Today' (eneral, )rganic and *iochemistry, +th dition, -.0

Stereoisomers:

•Same molecular ormula

•Same seuence o bonded atoms 4constitution5,

•Diferent 3!D orientations o their atoms in space"Enantiomers: Stereoisomers that are mirror images o each other"

Diastereomers: Stereoisomers that difer at chiral centers, but no every chiral center"

enantiomers



Stereochemistry o Organic CompoundsStereochemistry o Organic Compounds

Seager S$, Slabaugh %&, Chemistry or Today' (eneral, )rganic and *iochemistry, +th dition, -.

Chiral Carbon: Carbon in organic compound that has our diferent groupsattached to it"

Chirality: 67andedness8" &eers to compounds that cannot be superimposed onmirror image"

!De9ned relative to central, chiral atom 4carbon5

enantiomers

)7C

7

C )7

C7-)7

C7)

7

C7)

C7-)7)7C C

)7

C7-)

7

C7)C

7)

C7-)

7

Chiralcarbon

CHOindicatesaldehyde



Cis-trans IsomersCis-trans Isomers• C!C bonds that are constrained in a cyclic structure can not reely rotate

• To maintain orbital overlap in the pi bond, C:C double bonds can not reely rotate"



Cis-trans IsomersCis-trans Isomers

• ;ith rings and ith C:C double bonds, cis!

trans notation is used to distinguish beteenstereoisomers

• Cis < identical groups are positioned on the

S=% side o a ring• Trans < identical groups are positioned on

)>>)S#T sides o a ring

Copyright ? -.@ Aohn;iley B Sons, #nc" =ll lein, )rganic Chemistry -e@!



• #dentiy the olloing pairs as either

constitutional isomers, stereoisomers, oridentical"

"

-"

3"

IsomersIsomers

E"

@"



StereoisomersStereoisomers

• *eyond cis-trans isomers, there are many other

important stereoisomers• To identiy such stereoisomers, e must be able to

identiy chiral molecules

• = chiral ob1ect is )T identical to its mirror image

•

Gou are a chiral ob1ect" $ook in a mirror and raiseyour right hand" Gour mirror image raises his or herlet hand"

• Gou can test hether to ob1ects are identical byseeing i they are superimposable"

• Chirality is important in molecules" – *ecause to chiral molecules are mirror images, they ill

have many identical properties, but because they are notidentical, their pharmacology may be very diferent



• Some ob1ects are notthe same as theirmirror images4technically, they haveno plane o symmetry5

–

= right!hand glove isdiferent roma let!hand glove" Theproperty iscommonly called6handedness8

• )rganic molecules4including many drugs5have handedness thatresults romsubstitution patterns onsp3 hybridiHed carbon

StereochemistryStereochemistry




• Chirality most oten results hen a carbon

atom is bonded to E uniue groups o atoms"



• Same connections, diferent spatial arrangement o atoms – nantiomers 4nonsuperimposable mirror images5

– Diastereomers 4all other stereoisomers5

• #ncludes cis, trans, con9gurational




• = point in a molecule here our diferent groups 4oratoms5 are attached to carbon is called a chirality

center stereocenter!"• There are to nonsuperimposable ays that E diferent

diferent groups 4or atoms5 can be attached to onecarbon atom

• = chiral molecule usually has at least one chirality center

Chirality CentersChirality Centers



Chirality CentersChirality Centers




• #dentiy all o the chirality centers 4i any5 in

the olloing molecules



• %olecules that have one carbon ith E diferent

substituents have a nonsuperimposable mirrorimage < enantiomer

• *uild molecular models to see this

E#amples o EnantiomersE#amples o Enantiomers



• %olecules that are not superimposableith their mirror images are chiral 4havehandedness5

•

= plane o symmetry divides an entiremolecule into to pieces that are eIactmirror images

• = molecule ith a plane o symmetry is

the same as its mirror image and is said tobe achiral"

The Reason or $andedness: ChiralityThe Reason or $andedness: Chirality



• The plane has thesame thing on bothsides or the Jask

• There is no mirror

plane or a hand

%lane o Symmetry%lane o Symmetry



• (roups are considered 6diferent8 i there is anystructural variation 4i the groups could not besuperimposed i detached, they are diferent5

• #n cyclic molecules, e compare by olloing in

each direction in a ring

Chirality Centers in ChiralChirality Centers in Chiral

&olecules&olecules



Designating Con'gurationsDesignating Con'gurations

• nantiomers are )T identical, so they must

not have identical names

• Their names must be diferent, so e use theCahn!#ngold!>relog system to designate eachmolecule as either R or S"




• The Cahn, #ngold and >relog system

" Ksing atomic numbers, prioritiHe the E groupsattached to the chirality center

-" =rrange the molecule in space so the loestpriority group aces aay rom you

3" Count the group priorities L-L3 to determinehether the order progresses in a clockise orcounterclockise direction

E" Clockise : R and Counterclockise : S




" Ksing atomic numbers, prioritiHe the E groupsattached to the chirality center" The higher theatomic number, the higher the priority

– >rioritiHe the groups on this molecule






-" =rrange the molecule in space so the loestpriority group aces aay rom you

– This is the step here it is most helpul to have ahandheld model



•

# a decision cannot be reached by ranking the 9rstatoms in the substituents, look at the second,third, or ourth atoms until diference is ound






3" Counting the other group priorities, L-L3,determine hether the order progresses in aclockise or counterclockise direction

E" Clockise : R and Counterclockise : S




• Designate each chirality center belo as

either R or S"




• ;hen the groups attached to a chirality

center are similar, it can be tricky toprioritiHe them

• =nalyHe the atomic numbers one layer oatoms at a time

First layer

Second layer

E

Tie

- 3

• #s this moleculeR or SM



• =nalyHe the atomic numbers one layer o

atoms at a time• First layer

• Second layer


E

Tie

- 3

• The priority is based on the 9rstpoint o diference, (OT thesum o the atomic numbers

• #s this molecule R or SM




• ;hen prioritiHing or the Cahn, #ngold and

>relog system, double bonds count as tosingle bonds

• Determine R or S or the olloing molecule




• 7andheld molecular models can be very

helpul hen arranging the molecule inspace so the loest priority group acesaay rom you

• 7ere are some other tricks that can use

– Sitching to groups on a chirality center illproduce its opposite con9guration




• Sitching to groups on a chirality center ill

produce its opposite con9guration• Gou can use this trick to ad1ust a molecule so

that the loest priority group aces aayrom you

•

;ith the Eth

priority group acing aay, youcan designate the con9guration as R

• ;ork backards to sho ho the originalstructureNs con9guration is also R







• The R or S con9guration is used in the #K>=C

name or a molecule to distinguish it romits stereoisomer4s5

Copyright ? -.@ Aohn;iley B Sons, #nc" =ll lein, )rganic Chemistry -e@!3E



• $ight restricted to pass through a plane is plane- polarized

• >lane!polariHed light that passes throughsolutions o achiral compounds retains its originalplane o polariHation

• Solutions o chiral compounds rotate plane!polariHed light and the molecules are said to beoptically active

• >henomenon discovered by Aean!*aptiste *iot in

the early Oth century

Optical )cti*ityOptical )cti*ity



• $ight passes through a plane polariHer

• >lane polariHed light is rotated in solutions ooptically active compounds

• %easured ith polarimeter

• &otation, in degrees, is PαQ

• Clockise rotation is called de#trorotatory

• =nti!clockise is le*orotatory




• = polarimeter measures the rotation o plane!polariHed light that has passed through a solution

• The source passes through a polari+er and thenis detected at a second polariHer

• The angle beteen the entrance and eIit planesis the optical rotation"

&easurement o Optical Rotation&easurement o Optical Rotation

O ti l ) ti itO ti l ) ti it




• nantiomers ill rotate the plane o the light to

eual degrees but in opposite directions• The degree to hich light is rotated depends on the

sample concentration and the pathlength o thelight

•

Standard optical rotation measurements are takenith gram o compound dissolved in m$ osolution, and ith a pathlength o dm or the light

• Temperature and the avelength o light can alsoafect rotation and must be reported ithmeasurements that are taken




• Consider the enantiomers o -!bromobutane

• R and S reer to the con9guration o thechirality center

•

4R5 and 4!5 signs reer to the direction that theplane o light is rotated

• The speci9c rotation o the enantiomer iseual in magnitude but opposite in sign




• There is no relationship beteen the R/S con9gurationand the direction o light rotation 4R/!5

• The magnitude and direction o optical rotation can notbe predicted rom a chiral moleculeNs structure orcon9guration" #t can )$G be determined eIperimentally

• =s long as its bonds are not rearranged, its con9guration

C=)T change

• &acemic %iItures 4samples ith eual amounts o toenantiomers5 eIhibit no optical activity




• For uneual amounts o enantiomers, the

enantiomeric e#cess , ee! can bedetermined rom the optical rotation

• For a miIture o +. 4R5 and 3. 4S5, hat

is the eeM

Copyright ? -.@ Aohn;iley B Sons, #nc" =ll lein, )rganic Chemistry -e@!E

O ti l ) ti itOptical )cti*ity




• # the miIture has an optical rotation oRE", use the ormula to calculate the eeand the ratio o R/S



• %olecules ith more than one chirality center

usually have mirror image stereoisomers that areenantiomers

• #n addition they can have stereoisomeric orms

that are not mirror images, calleddiastereomers

DiastereomersDiastereomers

Stereoisomeric RelationshipsStereoisomeric Relationships



Stereoisomeric RelationshipsStereoisomeric Relationships

• The number o possible stereoisomers or a

compound depends on the number ochirality centers 4n5 in the compound

• ;hat is the maIimum number o possiblecholesterol isomersM

Symmetry and ChiralitySymmetry and Chirality




• =ny compound ith only ) chirality center ill be chiraland have an optical rotation

• 7oever, compounds ith an even number 4-,E,, etc"5 ochirality centers may or may not be chiral

• # a molecule has a plane o symmetry, it ill be achiral

• 7al o the molecule reJects the other hal

• #ts optical activity ill be canceled out ithin the molecule,similar to ho a pair or mirror image enantiomers cancel outeach others optical rotation




• Dra the mirror image o the cis isomer and shothat it can be superimposed on its mirror image

• *y de9nition, hen a compound is identical to itsmirror image, it is )T chiral" #t is achiral

• %olecules ith an even number o

chirality centers that have a plane osymmetry are called mesocompounds

• =nother ay to test i a compound is ameso compound is to see i it isidentical to its mirror image

Copyright ? -.@ Aohn;iley B Sons, #nc" =ll lein, )rganic Chemistry -e@!E




• #n another eIample, the plane o symmetry

identi9es it as a meso compound

• meso compounds also have less than the

predicted number o stereoisomers based on the-4n5 ormula

• Dra all our eIpected isomers and sho hoto o them are identical" = handheld modelmight be helpul

Chirality at (itrogen %hosphorus andChirality at (itrogen %hosphorus and



• , >, S commonly ound in organic compounds, and

can have chirality centers• Trivalent nitrogen is tetrahedral

• Does not orm a chirality center since it rapidly Jips

• #ndividual enantiomers cannot be isolated


SulurSulur



• %ay also apply to phosphorus but it Jipsmore sloly


SulurSulur



.ischer %ro/ections.ischer %ro/ections

• Fischer pro1ections can also be used to

represent molecules ith chirality centers• 7oriHontal lines represent attachments

coming out o the page

•

Uertical lines represent attachments goingback into the page




• Fischer pro1ections can be used to uickly

dra molecules ith multiple chiralitycenters




• Fischer pro1ections can also be used to

uickly assess stereoisomeric relationships



Intercon*erting EnantiomersIntercon*erting Enantiomers

• %olecules can rotate around single bonds"

•

&ecall the gauche rotational conormationo butane

• #s the gauche conormation o butanechiralM

• Dra its mirror image" #s it superimposableon its mirror imageM

• ;hy is butaneNs optical rotation eual to

HeroM• To be chiral, a compound cannot be a

rotational conormer o its mirror image




• Compare the 4cis5!,-!dimethylcycloheIane

chair ith the 7aorth pro1ection

• The 7aorth image can be used to uicklyidentiy the compound as an achiral mesocompound"

• 7oever, a plane o symmetry can )T beound in the chair conormation

i i




• The reely interconverting mirror images cancel out their optical rotation, soit is achiral

• This analysis is much easier to do ith a handheld models than in your mind

• # the 7aorth image has a mirror plane, then the chair ill be able tointerconvert ith its enantiomer, and it ill be achiral"

hi li% hi li



• = molecule that is achiral but that can become chiralby a single alteration is a prochiral molecule

%rochirality%rochirality

hi l i i i% hi l Di ti ti .



•

>lanar aces that can become tetrahedral are diferentrom the top or bottom

• = center at the planar ace at a carbon atom isdesignated re i the three groups in priority seuenceare clockise, and si i they are counterclockise

%rochiral Distinctions: .aces%rochiral Distinctions: .aces

% hi l Di i i .% hi l Di ti ti .



• =n sp3 carbon ith to groups that are the sameis a prochirality center

• The to identical groups are distinguished byconsidering either and seeing i it ereincreasedin priority in comparison ith the other

• # the center becomes R the group is pro-R and pro-S i the center becomes S

%rochiral Distinctions: .aces%rochiral Distinctions: .aces

% hi l Di ti ti i ( t% hi l Di ti ti i ( t



• *iological reactions oten involve makingdistinctions beteen prochiral aces or groups

• Chiral entities 4such as enHymes5 can alaysmake such a distinction

•

Iample' addition o ater to umarate

%rochiral Distinctions in (ature%rochiral Distinctions in (ature



• Stereoisomers are readily distinguished bychiral receptors in nature

• >roperties o drugs depend onstereochemistry

• Think o biological recognition as euivalentto 3!point interaction

Chirality in (ature and ChiralChirality in (ature and Chiral

En*ironmentsEn*ironments

Documents

Chem 2411 Lecture 08 Stereochemistry