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Unit One Part 8:stereochemistry    the lecture everyone      (but me) hates...
‘...How would you like to live inLooking-glass House, Kitty? Iwonder if theyd give you milk inthere? Perhaps Looking-glass...
‘...How would you like to live inLooking-glass House, Kitty? Ithere? Perhaps Looking-glass                                ...
Unit OnePart    8stereoisomersshape & chirality
isomers                       happy with isomers                        having the same                            atoms.....
isomersstructural isomers                 ...and structural                       isomers have these                      ...
structural isomers                             OH  all these have thesame formula but are  obviously (!) very        diffe...
isomers     stereoisomers have     the same atoms andstructural     the same bonds...so     same number of C–        stere...
isomers    ...they only differ by how these      bonds are arranged in space        (how they are orientated         relat...
stereoisomerismor configurational isomerism     A     C                        A             D     B     D                 ...
stereoisomerismor configurational isomerism     A       C                      A        D     B       D                    ...
stereoisomerismor configurational isomerism        A     C       A     D        B     D                  ≠   B      C   bre...
stereoisomerismor configurational isomerism        A     C                 A          D                            ...rotat...
stereoisomerismor configurational isomerism        A     C                 A    D        B     D                     ≠     ...
diastereoisomers MeO2C      H        MeO2C                   CO2Me     H      CO2Me               H            H dimethyl ...
cyclic molecules & diastereoisomers               cyclic molecules can exist as               diastereoisomers depending  ...
change the relativestereochemistry to give new      diastereoisomers
Cl                   Cl             Cl                     Cl      cis-1,2-            trans-1,2-dichlorocylohexane   dich...
Cl                          Cl             Cl                            Cl      cis-1,2-                   trans-1,2-dich...
Cl                               Cl             Cl                                Cl      cis-1,2-                       t...
what will the favouredconformation be?
ax     ax         Cl1               ax eq                    eq                 eq               eq                    eq ...
Cl1                                                           Cl2          ax     ax                  up         up       ...
Cl1                                                                              Cl2          ax     ax                   ...
Cl1                                  Cl2         Cl 1               Cl1              H                  H            eq   ...
Cl1           randomly place a substituent in an        upwards position. In this case I’ve chosen         axial but I cou...
Cl1                                        Cl2                             Cl 1                                    H      ...
Cl1                                 Cl2   ax                 up              Cl 1              Cl 1        eq           do...
Cl1                                                       Cl2   ax                                        up              ...
Cl1                 Cl2Cl2          Cl 1  H      H
cis                                Cl1                                Cl2      Cl1                      Cl2            2  ...
cis                                                    Cl1                                                    Cl2      Cl1...
cis                                               Cl1                                               Cl2      Cl1          ...
ax     ax         Cl1               ax eq                    eq                 eq               eq                    eq ...
Cl1                                   Cl2          Cl 1              Cl 1              H                  H            eq ...
Cl1              Cl2  Cl1          H      HCl2
Cl1                                 Cl2   ax                 up              Cl 1              Cl 1        eq           do...
Cl1                 Cl2H          Cl 1Cl2      H
trans                                                      Cl                                                           Cl...
trans                               Cl                                    Cl                            2Cl               ...
H                                        H         tBu                                                H       H           ...
this one favoured as big tert-butyl  group is equatorial...minimises 1,3-          diaxial interactions               H   ...
H     Me              tBu                       Me                H                                             H     tBu ...
Draw the twoconformations of:                                             Ph        following the guidelines above you    ...
Ph can go in any                                           Phdown position:          ax     ax                  up        ...
Ph can go in any                                    Phdown position:         up           H                         H     ...
Ph can go in any                 Phdown position:                     H                         Ph          Hnow methyl ca...
second conformation                                        Phhas Ph in axial downposition:          ax     ax             ...
second conformation                               Phhas Ph in axial downposition:       up                    up         u...
second conformation              Phhas Ph in axial downposition:        H                        H                   Phnow...
H           Ph         H                                  HH                           Phfavoured conformation has large  ...
decalins    fused ring system found in           many natural products (such       H   as steroids) can exist as two      ...
trans-decalins        H                     H         H                  H   trans-decalin   equatorial, equatorial       ...
cis-decalins       H               H                  H        H   cis-decalin   equatorial, axial                   ring ...
the one you all hate...
isomersstructural     stereoisomers isomers       diastereomers    enantiomers samebond pattern
isomersstructural      stereoisomers isomers                a special kind of (pain)                stereosiomer...a pair ...
...an object that isnonsuperposable onits mirror image...
chirality in naturechiralityin nature
chirality in naturechirality     our hands are    mirror images...in nature
chiralityin nature
chirality   they look identicalin nature            (barring scars etc)
chirality    but can never   occupy the same   space...they arein nature        chiral
chirality                         snail shells are                       either clockwise or                              ...
chirality                           ...and clockwise snails                              will only mate with              ...
chiral                          objects    windmills and propellers are left orright handed as are...
chiralobjects   corkscrews
molecules can be left             or right handedchiral molecules
Achiral compounds                           Mirror                           plane   if we take a molecule          and it...
Achiral compounds                           Mirror                           plane   ...mirror image...and     we then sta...
Achiral compounds       Mirror       plane                                rotate                ...rotate that molecule
Achiral compounds       Mirror       plane
Achiral compounds       Mirror       plane                rotate
Achiral compounds                             Mirror                             plane  ...we can get to a point  were the...
Achiral compounds       Mirror       plane
Achiral compounds       Mirror       plane                superposed upon each                  other...then those        ...
Chiral compounds                              Mirror                              plane                                   ...
Chiral compounds       Mirror       plane                it can never be                 superposed...
the two isomers are called           enantiomerssuch mirror images   are called...
they are identical in all ways...
physical properties         NMR (see lecture 9) identical for        both enantiomers as is the melting         points and...
but they do differ                        under certain                        circumstances                    (otherwise...
physical properties                                                                             α light     light (λ)     ...
physical properties                                                                                     α          each en...
other chiral objects
other chiral objects   ...how they interact with other chiralobjects is very different (imagine trying toput your left foo...
we are chiral
we are chiral        so chiral molecules will          interact with us in            different ways...
smell      CH3        CH3        H       H       CH3     H3C(S)-limonene (R)-limonene   lemons      oranges
taste                             CH3            CH3                                   O   O                              ...
taste                                                   CH3            CH3                                                ...
chirality and drugs        Me                   MeMe2N                               NMe2       Ph O              O Ph    ...
chirality and drugs        Me                                  MeMe2N                                                 NMe2...
drugs that target bacterial                          alanine won’t hurt us (but                           cause bacteria t...
chirality and drugs           O                                O           H                                H             ...
www.massey.ac.nz/~gjrowlan/teaching.html    more information about chirality    can be found on my web site (if      you’r...
why does nature onlyproduce one enantiomer?     not part of the      course but a       wonderful      philosophical      ...
Me     CO2H               a molecule with one carbon                 atom with four different              groups coming o...
O   H2N              N      CO2CH3              H                      a molecule with two carbon  HO2C               atom...
if it has three atoms              (stereocentres) with 4 different         OH      groups then it can have 8             ...
insulin                                        (monomer) has 51 stereocentres so it can exist as a large number of stereoi...
insulin                               (monomer) we have seen the problems   with just a 50:50 choice (does it smell of lem...
insulin                                          (monomer)  so we must have a single form of insulin so it always does the...
DNA               polymerase                   this number is                 meaningless to me!         342>2342 = >8.96 ...
DNA               polymerase         342                    but it gets                 worse...consider                  ...
46   46 chromosomes      comprising of...
and each base pair istwo molecules with three  stereocentres...so we  have a possibility of...                         OH ...
Benny Herudek 3D Hifi - High Fidelity 3d Graphics Solutions                 29,000,000,000 =                            ∞st...
Benny Herudek 3D Hifi - High Fidelity 3d Graphics Solutions                                                             if ...
?of course, why we have one enantiomer and  not its mirror image is another questionentirely...one which I will not commen...
what have  ....we learnt?                   •t h e  shape                       of molecules                   •   chirali...
9readpart   ©[auro]@flickr
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Lecture8: 123.101

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  1. 1. Unit One Part 8:stereochemistry the lecture everyone (but me) hates...
  2. 2. ‘...How would you like to live inLooking-glass House, Kitty? Iwonder if theyd give you milk inthere? Perhaps Looking-glassmilk isnt good to drink?Alices Adventures in Wonderland - Lew" Carroll
  3. 3. ‘...How would you like to live inLooking-glass House, Kitty? Ithere? Perhaps Looking-glass glass its a good question...and itwonder if theyd give you milk inturnsmilk’ ‘looking- out would not be good for Kitty...but why?milk isnt good to drink?Alices Adventures in Wonderland - Lew" Carroll
  4. 4. Unit OnePart 8stereoisomersshape & chirality
  5. 5. isomers happy with isomers having the same atoms...structural isomers differentbond pattern
  6. 6. isomersstructural isomers ...and structural isomers have these atoms arranged differently (different bonding)... differentbond pattern
  7. 7. structural isomers OH all these have thesame formula but are obviously (!) very different cyclopentanol C5H10O OH O (E)-pent-3-en-1-ol 4-methoxybut-1-ene C5H10O C5H10O O HO H3-methylbutan-2-one (S)-pent-1-en-3-ol C5H10O C5H10O
  8. 8. isomers stereoisomers have the same atoms andstructural the same bonds...so same number of C– stereoisomers isomers C, C–H etc bonds diastereomers samebond pattern
  9. 9. isomers ...they only differ by how these bonds are arranged in space (how they are orientated relative to each other)structural stereoisomers isomers diastereomers samebond pattern
  10. 10. stereoisomerismor configurational isomerism A C A D B D ≠ B C alkenes are the easiest to understand...these two have all the same bonds but differ because D & C are on different sides of the molecule
  11. 11. stereoisomerismor configurational isomerism A C A D B D ≠ B C these are NOT different conformations...to change between the two stereoisomers we have to break a bond...
  12. 12. stereoisomerismor configurational isomerism A C A D B D ≠ B C breakdouble bond remember: we cannot rotate double bonds...so we must break the π A C bond, then... B D
  13. 13. stereoisomerismor configurational isomerism A C A D ...rotate central C–C B D ≠ B bond... C breakdouble bond A C A D B D B C rotate single bond
  14. 14. stereoisomerismor configurational isomerism A C A D B D ≠ B C break reformdouble bond double bond A C A D B D B C rotate single bond
  15. 15. diastereoisomers MeO2C H MeO2C CO2Me H CO2Me H H dimethyl fumarate dimethyl maleate trans (E) cis (Z) mp 103°C mp –19°C bp 193°C bp 202°C diastereoisomers are different compounds with different chemical and physical properties
  16. 16. cyclic molecules & diastereoisomers cyclic molecules can exist as diastereoisomers depending on the relative orientation of substituents... Cl Clrelative stereochemistry
  17. 17. change the relativestereochemistry to give new diastereoisomers
  18. 18. Cl Cl Cl Cl cis-1,2- trans-1,2-dichlorocylohexane dichlorocylohexane (syn) (anti) Cl Cl Cl Cl trans-1,2- cis-1,2-dichlorocylohexane dichlorocylohexane (anti) (syn)
  19. 19. Cl Cl Cl Cl cis-1,2- trans-1,2-dichlorocylohexane dichlorocylohexane (syn) (anti) Cl Cl Cl Cl trans-1,2- TWO diastereoisomers... cis-1,2- here we have dichlorocylohexanedichlorocylohexaneare on the same side either both the chlorines (anti) are on opposite sides or they (syn)
  20. 20. Cl Cl Cl Cl cis-1,2- trans-1,2-dichlorocylohexane dichlorocylohexane (syn) (anti) Cl Cl Cl Cl cis-1,2- trans-1,2- two questions arise from this slide...which conformation of each diastereoisomer is dichlorocylohexanedichlorocylohexane (easy)...and, why have I draw four preferred (anti) (syn) molecules (hard)?
  21. 21. what will the favouredconformation be?
  22. 22. ax ax Cl1 ax eq eq eq eq eq Cl2 eq ax ax axneed to map skeletal representation onto 3D representation
  23. 23. Cl1 Cl2 ax ax up up eq up up ax eq eq down downeq eq up up eq ax down down ax ax down down bold is up dashed is down
  24. 24. Cl1 Cl2 ax ax up up eq up up ax eq eq down downeq eq up up eq ax down down ax ax down down Please remember that up and down refers to which face of the molecule the bold is up substituent is whilst equatorial and axial refer to their orientation dashed is down
  25. 25. Cl1 Cl2 Cl 1 Cl1 H H eq up ax down once the first substituent is inplace the other’s position is fixed
  26. 26. Cl1 randomly place a substituent in an upwards position. In this case I’ve chosen axial but I could have had an equatorial Cl2 upward substituent... Cl 1 Cl1 H H eq up ax down once the first substituent is inplace the other’s position is fixed
  27. 27. Cl1 Cl2 Cl 1 H Cl 2 Hthe second substituentmust be in an upwards position
  28. 28. Cl1 Cl2 ax up Cl 1 Cl 1 eq down H Hthe other conformation starts with Cl1 equatorial
  29. 29. Cl1 Cl2 ax up Cl 1 Cl 1 eq down H H if I had started with the firstthe other conformation starts with upward substituent equatorial we would end up with the same Cl1 equatorial answer
  30. 30. Cl1 Cl2Cl2 Cl 1 H H
  31. 31. cis Cl1 Cl2 Cl1 Cl2 2 H Cl1 Cl H H H always axial one substituent
  32. 32. cis Cl1 Cl2 Cl1 Cl2 2 H Cl1 Cl H H H always axial in this example...both one conformations of the cis diastereoisomer are identical...both have one axial & one equatorial substituent substituent
  33. 33. cis Cl1 Cl2 Cl1 Cl2 2 H Cl1 Cl H H H always axial one BUT REMEMBER THIS IS ONLY TRUE FOR 1,2-DISUBSTITUTED SYSTEMS!!!! substituent
  34. 34. ax ax Cl1 ax eq eq eq eq eq Cl2 eq ax ax axneed to map skeletal representation onto 3D representation
  35. 35. Cl1 Cl2 Cl 1 Cl 1 H H eq up ax down once the first substituent is inplace the other’s position is fixed
  36. 36. Cl1 Cl2 Cl1 H HCl2
  37. 37. Cl1 Cl2 ax up Cl 1 Cl 1 eq down H Hthe other conformation starts with Cl1 equatorial
  38. 38. Cl1 Cl2H Cl 1Cl2 H
  39. 39. trans Cl Cl 2Cl H 2Cl H H 1Cl H 1Cl for the trans diastereomer the two conformations are very different...one has two axial substituents and the other has two equatorial substituents...which is preferred?
  40. 40. trans Cl Cl 2Cl X H 2Cl H H 1Cl H 1Cl equatorialfavoured
  41. 41. H H tBu H H HO t BuOH what happens if we have twodifferent substituents (two different groups on the ring)?
  42. 42. this one favoured as big tert-butyl group is equatorial...minimises 1,3- diaxial interactions H H tBu H H HO t Bu OH equatoriallargest groupfavours
  43. 43. H Me tBu Me H H tBu H true for all substitution patterns (it doesn’t matter where you put the big group it will be equatorial equatoriallargest groupfavours
  44. 44. Draw the twoconformations of: Ph following the guidelines above you should be able to deduce the orientation of any substituent and hence draw the conformations
  45. 45. Ph can go in any Phdown position: ax ax up up ax eq up up eq eq down downeq eq up up eq ax down down ax ax down down
  46. 46. Ph can go in any Phdown position: up H H up up down Ph Phup up up down down down down downnow methyl can only go in one place
  47. 47. Ph can go in any Phdown position: H Ph Hnow methyl can only go in one place
  48. 48. second conformation Phhas Ph in axial downposition: ax ax up up ax eq up up eq eq down downeq eq up up eq ax down down ax ax down down
  49. 49. second conformation Phhas Ph in axial downposition: up up up up updown down down H up H down down Ph down Phnow methyl can only go in one place
  50. 50. second conformation Phhas Ph in axial downposition: H H Phnow methyl can only go in one place
  51. 51. H Ph H HH Phfavoured conformation has large group equatorial
  52. 52. decalins fused ring system found in many natural products (such H as steroids) can exist as two diastereoisomers...2 H stereoisomers
  53. 53. trans-decalins H H H H trans-decalin equatorial, equatorial ring fusion they cannot undergo ring flip so they are stuck in these conformations
  54. 54. cis-decalins H H H H cis-decalin equatorial, axial ring fusion
  55. 55. the one you all hate...
  56. 56. isomersstructural stereoisomers isomers diastereomers enantiomers samebond pattern
  57. 57. isomersstructural stereoisomers isomers a special kind of (pain) stereosiomer...a pair of enantiomers are identical in always except... diastereomers enantiomers samebond pattern
  58. 58. ...an object that isnonsuperposable onits mirror image...
  59. 59. chirality in naturechiralityin nature
  60. 60. chirality in naturechirality our hands are mirror images...in nature
  61. 61. chiralityin nature
  62. 62. chirality they look identicalin nature (barring scars etc)
  63. 63. chirality but can never occupy the same space...they arein nature chiral
  64. 64. chirality snail shells are either clockwise or in nature anti-clockwise...photograph: Willi Rolfes
  65. 65. chirality ...and clockwise snails will only mate with in nature clockwise snails....photograph: Willi Rolfes
  66. 66. chiral objects windmills and propellers are left orright handed as are...
  67. 67. chiralobjects corkscrews
  68. 68. molecules can be left or right handedchiral molecules
  69. 69. Achiral compounds Mirror plane if we take a molecule and its...
  70. 70. Achiral compounds Mirror plane ...mirror image...and we then start to...
  71. 71. Achiral compounds Mirror plane rotate ...rotate that molecule
  72. 72. Achiral compounds Mirror plane
  73. 73. Achiral compounds Mirror plane rotate
  74. 74. Achiral compounds Mirror plane ...we can get to a point were the molecules are identical and can be...
  75. 75. Achiral compounds Mirror plane
  76. 76. Achiral compounds Mirror plane superposed upon each other...then those molecules are achiral
  77. 77. Chiral compounds Mirror plane rotate ...it doesn’t matter how many times and directions you rotate a chiral object...
  78. 78. Chiral compounds Mirror plane it can never be superposed...
  79. 79. the two isomers are called enantiomerssuch mirror images are called...
  80. 80. they are identical in all ways...
  81. 81. physical properties NMR (see lecture 9) identical for both enantiomers as is the melting points and all standard chemicalE-300 180 160 reactions 140 120 100 80 60 40 H OH Ph CO2H (R)-(-)-mandelic acid mp 131-133°C HO H Ph CO2H (S)-(+)-mandelic acid mp 130-132°C 9 8 7 6 5 4 3 2
  82. 82. but they do differ under certain circumstances (otherwise why would we care...)excepttwo properties...
  83. 83. physical properties α light light (λ) polariser plane sample readingsource polarised light cell length l (dm) H OH HO H Ph CO2H Ph CO2H (R)-(-)-mandelic acid (S)-(+)-mandelic acid [α]23 –153 D [α]23 +153 D
  84. 84. physical properties α each enantiomer rotates plane polarised light in a different direction and more importantly... light light (λ) polariser plane sample readingsource polarised light cell length l (dm) H OH HO H Ph CO2H Ph CO2H (R)-(-)-mandelic acid (S)-(+)-mandelic acid [α]23 –153 D [α]23 +153 D
  85. 85. other chiral objects
  86. 86. other chiral objects ...how they interact with other chiralobjects is very different (imagine trying toput your left foot in your right shoe...its a tad more difficult than putting the right foot in the right shoe)
  87. 87. we are chiral
  88. 88. we are chiral so chiral molecules will interact with us in different ways...
  89. 89. smell CH3 CH3 H H CH3 H3C(S)-limonene (R)-limonene lemons oranges
  90. 90. taste CH3 CH3 O O H H CH3 H3C (R)-carvone (S)-carvone©Patrick J. Lynch 2006 spearmint caraway
  91. 91. taste CH3 CH3 O O H H ...but these differences are trivial compared to... CH3 H3C (R)-carvone (S)-carvone©Patrick J. Lynch 2006 spearmint caraway
  92. 92. chirality and drugs Me MeMe2N NMe2 Ph O O Ph O O Et Et darvon novrad painkiller cough-suppressant
  93. 93. chirality and drugs Me MeMe2N NMe2 Ph O O Ph O O Et Et darvon novrad painkiller cough-suppressant both are commercially available and look what those comical chemists have done with the names!
  94. 94. drugs that target bacterial alanine won’t hurt us (but cause bacteria to burst!) Me CO2H Me CO2H NH2 NH2 L-alanine D-alaninemammalian amino acid bacterial cell wall
  95. 95. chirality and drugs O O H H N N O O O N O O N O H H (R)-thalidomide (S)-thalidomide (morning sickness) (teratogenic) but we have to be very careful otherwise we can have horrific problems such as the limbless children born because of the use of thalidomide
  96. 96. www.massey.ac.nz/~gjrowlan/teaching.html more information about chirality can be found on my web site (if you’re sad or sick of mind)
  97. 97. why does nature onlyproduce one enantiomer? not part of the course but a wonderful philosophical question...
  98. 98. Me CO2H a molecule with one carbon atom with four different groups coming off it can exist NH2 as 2 enantiomers 21=2stereoisomers
  99. 99. O H2N N CO2CH3 H a molecule with two carbon HO2C atoms each with four different aspartame 22=4 groups coming off them can exist as 4 stereoisomersstereoisomers
  100. 100. if it has three atoms (stereocentres) with 4 different OH groups then it can have 8 stereoisomers... CHO HO OH OH 23=8stereoisomers
  101. 101. insulin (monomer) has 51 stereocentres so it can exist as a large number of stereoisomers 251 = 2.25 x 1015stereoisomers
  102. 102. insulin (monomer) we have seen the problems with just a 50:50 choice (does it smell of lemons or oranges?) 251 = 2.25 x 1015stereoisomers
  103. 103. insulin (monomer) so we must have a single form of insulin so it always does the same thing...but insulin ain’t particularly big... 251 = 2.25 x 1015stereoisomers
  104. 104. DNA polymerase this number is meaningless to me! 342>2342 = >8.96 x 10102stereoisomers
  105. 105. DNA polymerase 342 but it gets worse...consider our genes...>2342 = >8.96 x 10102stereoisomers
  106. 106. 46 46 chromosomes comprising of...
  107. 107. and each base pair istwo molecules with three stereocentres...so we have a possibility of... OH N O O N NH N HO NH2 >3 billion base pairs
  108. 108. Benny Herudek 3D Hifi - High Fidelity 3d Graphics Solutions 29,000,000,000 = ∞stereoisomers
  109. 109. Benny Herudek 3D Hifi - High Fidelity 3d Graphics Solutions if we produce just one isomer then we don’t have this problem... 29,000,000,000 = ∞stereoisomers
  110. 110. ?of course, why we have one enantiomer and not its mirror image is another questionentirely...one which I will not comment on in order to avoid offending the religious amongst you...
  111. 111. what have ....we learnt? •t h e shape of molecules • chirality©bioneural.net
  112. 112. 9readpart ©[auro]@flickr
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