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					Myths and legends in Ozonolysis

      Dr Peter J. Haslam



                                          1
                       Uquifa Company Presentation
                               Myth No 1
• All ozonides are explosive
   Not true
• Some are quite stable however low
  molecular weight ozonides are unstable.
• As professor Carl Dietrich Harries (1866-
  1923) at the University of Kiel found out
  when he transferred ethylene ozonide from
  one vessel to another.


                                 Uquifa Company Presentation
                                              Myth No 1


                                      O       O
                  O       -78oC                   H      warm up a bit
                                  H
H2C   CH2 +
              O       O                   O
                                  H               H




                          kerpow


                                                  Uquifa Company Presentation
                                  Myth No 1


              tNPh                           F       tNPh
      H   F                           H
                          O       O
H2C
                 CO2CH3                                   CO2CH3
                              O


                              Stable with DMS at
                              room temperature




                                          Uquifa Company Presentation
                           Myth No 2
• You have to use smelly compounds like
  dimethyl sulphide during the work –up
  Only if you want to

• You can use any reducing agent you like
  e.g. bisulphite, thiourea, iodine……
• Industrially hydrogenation tends to be
  chosen for ease of work up procedure.


                               Uquifa Company Presentation
                              Myth No 2
• The DMS is used to neutralise the hydrogen
  peroxide formed in the reaction otherwise
  the aldehyde formed would be oxidised to
  formic acid.
• Ethylene ozonide on straight hydrolytic
  cleavage gives one mole of hydrogen peroxide
  and two moles of formaldehyde.
• Consequently one mole each of formic acid,
  formaldehyde and water are formed


                                   Uquifa Company Presentation
                                                 Myth No 2


    O       O
H               H
                    +   H2O            H2C   O + H2C       O + H2O2
H       O       H



                                  O

                                      OH     +    H2C    O    +     H2O
                              H



                                                    Uquifa Company Presentation
             It’s all in the work up!


•If you want the acid do the reaction in
acetic acid and add zinc at the end.
•If you want the alcohol add borohydride
•If you want the ester use the appropriate
alcohol and borohydride



                                Uquifa Company Presentation
                             Myth No 3
• You can only react small amounts of
  substrate.
• Not true
  With low molecular weight compounds
  it’s safer to use smaller quantities. This
  can be overcome by;
  a) using a continuous flow reactor.
  b) linking a series of flasks together so
  the ozone passes from one to the other.
                                 Uquifa Company Presentation
                                                        Myth No 4
• You can avoid the formation of dangerous
  products by addition of methanol?
• True
                      O                                 H3C           OH

                  O       O     Primary ozonide                   O         Hydroperoxide
            H3C               CH3                                     CH3
                                                        H3C   O

            H3C               CH3
                                                                            H3C
                                                                                        O
                                                                            H3C     +
H3C   CH3                                H3C
                                                        O
                                               C    O                         H3C       OH
H3C   CH3                                H3C                                        +
                                                                                  H2O
                                       zwitterion


                                                                  Uquifa Company Presentation
 What happens when
you don’t add alcohols ?



                   Uquifa Company Presentation
                              Myth No 4
• The first step is the addition to the double
  bond in the formation of the primary ozonide
  (molozonide).
• These (1,2,3-trioxolanes) are unstable above
  –120°C. They can decompose to give a carbonyl
  compounds and oxygen via a cyclic peroxide
  (scary) and not the secondary ozonide.
• Or the zwitterions form polymeric peroxides
  that can act like detonators.

                                   Uquifa Company Presentation
                                                                         Myth No 4
                                           O

                                       O       O
H3C              CH3             H3C                 CH3                                  O    O
                                                                                  H3C                CH3

H3C              CH3             H3C                 CH3                          H3C                CH3
                                                                                          O    O

                                 1ary ozonide                                    dimeric peroxide
                                                           H3C
                                                                         O
                                                                 C   O
                                                           H3C

                                                           Carbonyl oxide

      H3C                                                                        H3C
                       O     O     O           O     O
            C     O                                                                       O + O2
                             CH3
      H3C                                                                        H3C
                       H3C                     CH3
                                                                                        Oxygen !
                                H3C

                Polymeric peroxide

                                                                             Uquifa Company Presentation
                              Myth No 4
• The polymeric peroxides can precipitate out
  of the reaction mixture!
• Break down of the peroxide still yields a
  carbonyl compound. However oxygen is
  liberated!
• The addition of methanol helps prevent this.
• The respective rate constants govern what is
  formed.




                                   Uquifa Company Presentation
                                                                          Myth No 4
      • Example
                                                                                                  CH3
                              CH3
                                                                                          H3C
                      H3C
                                                                                            O
                        O                                                                               F
                                                  1) ozone / DCM
                                    F                                                 H                         F
                  H                     F
                                                                    H3C               N
H3C               N
                                                                                                                        O
                                                                                                  H
                              H                                                                   N
                              N             CH2                                                                             O

                                                     2) DMS
                                                                          CH3   O                       O   O
      CH3   O                       O
                                                                                    H3C     CH3
                H3C     CH3                                                                                         O




                                                                                                  CH3
                              CH3
                                                                                          H3C
                      H3C
                                                                                            O
                        O                                                                               F
                                                                                                                F
                                                  1) ozone / MeOH
                                    F                                                 H
                  H                     F
                                                                    H3C               N
H3C               N                                                                                                     O
                                                                                                  H
                              H                                                                   N
                              N             CH2
                                                                          CH3   O                       O
      CH3   O
                H3C     CH3
                                    O
                                                     2) DMS                         H3C     CH3
                                                                                                                H




                                                                                    Uquifa Company Presentation
                                                                                                Myth No 4
                                CH3

                      H3C                                                                                            F         F
                        O                                                  F       F
                                          F                                                                      R
                  H                                  F                                                                                 O
                                                                     R
H3C               N
                                H                                                                                    O                 O
                                N                        CH2               O       O           O
      CH3   O                             O                                                O                                   O   H
                H3C       CH3                                                                                            H3C
                                                     O
                                                O         O



                                                                                                      CH3

                                                                                               H3C
                          F           F                                                          O
                                                                                                            F
                                          O                                            H                         F
                      R                                        H3C                     N                             H
                                                OH
                                                                                                      H
                          O           O                                                               N
                                          CH3                            CH3   O                            O    O
                                                                                   H3C          CH3




                                                                                                            Uquifa Company Presentation
                                                           Myth No 5
  • It’s not very selective
        Not true
  • Here are just a few
    examples    R'                                                         R''

                                 1) O3 MeOH / DMS


                                  2) NH4OH                                       N

                       R''
                                                                           R'

                                 CH3                                                        CH3
         CH3                 O
                                       O3 / MeOH -78°C           CH3                    O
EtOOC          S                                         EtOOC         S

        HC     CHCH3
                                                                 CHO


                                                                   Uquifa Company Presentation
                                                                                      Myth No 5
                                                Cortisone precursor
                                                         H3C         CH3
                                                                                                                                          O

                                                                                                                       H3C21          22
                                 H3C21              22          24         CH3                                                                H
                                                                                                                                20
                                          20               23
                                                                                                                       18 CH3
                                 18 CH3                                                                                                   H
                                                                                                                  12
                            12
                                                    H                                                                           17
                                          17                                                                 11         13

                                                                O3 / DCM / Pyridine
                       11         13                                                              19   CH3        H                  16
            19   CH3        H                  16
                                                                                              1              9          14
        1              9          14                                                                                            15
                                          15                                              2            10         8
    2            10         8                                                                                H           H
                       H           H
                                                                     95%                  3            5          7
    3            5          7                                                         O       4              6
O       4              6




    The pyridine allows the Carbon 4-5 bond to stay intact.
    The use of moderators in ozonolysis reactions provides
    greater flexibility.

                                                                                                  Uquifa Company Presentation
                                                   Myth No 6
• It’s all about double bonds
   Not true
• This comes from the polymer industry where
  ozone is used frequently.
               CO2CH3                                   CO2CH3
                              ozone

                SnBu2                                     O
    O                                          O


        P. Gilbert et al., Tetrahedron Lett., 1993, 34, 1111

                                                          Uquifa Company Presentation
                                                                   Myth No 6
          O                                                            O
                    O                                                              O       H
                            H
Ph                                              Ozone / pyridine
     Se

                                          Br       -78 - -25°C                                           Br
               H        O           O                                          H       O           O


                        Overman et al., J. Org. Chem., 1993, 58, 2468

                                O         1) NaOMe / MeOH                                      O


 H3C                                CH3
                                               2) Ozone -78°C
                                                                 H3C                               CH3
              NO2
                                                3) Me2S                    O


                        McMurray et al., J. Org. Chem., 1974, 39, 259.


                                                                               Uquifa Company Presentation
                                               Myth No 6

                   P(Ph)3   1) ozone / DCM                      O

Boc       (CH2)5                             Boc       (CH2)5
      N                CN                          N                CN
      H                                            H
              O                                            O



      Wasserman et al., Tetrahedron Lett., 2003, 44, 361




                                                        Uquifa Company Presentation
                                  Myth No 7
• I’ve never come across any stable ozonides-
  they don’t exist!
Not true

• In general alpha substituted electron
  withdrawing groups impart stability.
                                       O       O

       HO           CH2
                             HO            O
            F   F
                                  F    F


                                  Stable

                                           Uquifa Company Presentation
                                                                       Myth No 7
                                                                                        O
            O       O                              O        O
 H3C                                  H3 C                                  H3C                     CH3
                         CH3                                     CH3
                                                                                        O            C7H15
H3C             O                     Ph
                        CH3                            O
                                                                 Ph
                                                                                        O

      mp 133°C                             mp 73°C
                                                                                    O       O


                                                                               mp 75-76°C
            O                             O                                                 O

H3C                     CH3     H3C                        CH3                H3C                     CH3

            O            C2H5             O                            Cl                   O

                O                          O                                                O


        O           O                 O        O                                        O       O


      mp 90-100°C               mp 102-110°C                                      mp > 100°C
                                                                            Uquifa Company Presentation
                               Myth No 8
• You are limited to what solvents you can use.
   True
• Like any other chemical reaction the solvent
  has to be inert to the reaction medium.
• Solvents usually used are pentane, hexane,
  chlorinated hydrocarbons, ethyl acetate,
  alcohols, water, and acetic acid.
• The most common two are methanol and
  dichloromethane or a mixture of the two.

                                    Uquifa Company Presentation
                                    Myth No 9
• You have to do ozonolysis at low
  temperatures.
   Usually
• Reactions have been carried out at –5°C.
•   J. Mann Perkin 1996, 1, 1101. O
           O


                        O3          O
                                            R
           O                        O
                R

                                O       O



• However, in general it is –78°C or below.
                                            Uquifa Company Presentation
                               Myth No 11
• The high oxidation power of ozone at + 2.07 V
  limits its use.
    Not True
• Look at the oxidative power of nitric acid
  (+1.24 V) –sure you will get oxidation if you let
  the temperature rise too high for the
  substrate .
• Impurities in the system pose a greater hazard
  such as inorganic or organics but that is true
  elsewhere.
                                     Uquifa Company Presentation
                            SCALE-UP ?
• Large scale ozonolysis equipment is not
  available
• Not true
• Uquifa use 10,000L vessels with an ozone
  production rate of 15 kg/hr-Italy
• DMS (Chemie Linz)-Austria
• Degussa - Germany
• PPG –Sipsy - France



                                   Uquifa Company Presentation
Thank you very much
  for your attention.


               Uquifa Company Presentation
Frequently Asked Questions




                   Uquifa Company Presentation
                                                                           FAQ’s
1.              Was there some thing called the Criegee
                mechanism?                        R
                                                                                          O
            O                      O                                            C    O
O                O             O       O                                    R
R                R
                           R                   R                                R

                               R       R                                                 O
R                R                                                              R
                                                   O       O
                 R                     R
                                                                   R
        O
                      O
            O    R                         R           O
                                                               R
            C
    R            R

                                                                       Uquifa Company Presentation
                                          FAQ’s
2. Didn’t Pfizer publish something recently on
   the use of Ozone ?
•    J. A. Ragan, et al , Org. Prog. Res. and Dev.,
    2003, 7, 155.

3. Are Ozonides themselves used for anything?
• Yes, ozonides have been used as anti-
   malarial’s
• Mann et al. Perkins 1 1996 1101

                                      Uquifa Company Presentation
                                         FAQ’s
• Why is it not used more?
• Lack of ozone equipment
• Is it worth buying an ozone generator if it is
  only to try out a hunch?
• Maybe but you could get Uquifa to do it for
  you
• Every one thinks it’s dangerous and they are
  waiting for me to prove them right!
• Life is full of risks,with chemistry you can
  minimize them.

                                     Uquifa Company Presentation
                                          FAQ’s
•   However: -
•   Efficient use - 66% of the molecule
•   No heavy metals
•   Clean
•   Cheap
•   Adaptable with moderators
•   Simple to do - turn on the gas, throw the
    switch!


                                      Uquifa Company Presentation

				
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