15 min presentation for 407 2006 by 8d7gUqg

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									The Three “R’s” of Green Chemistry
   Recovery
     Isolation of solvents and reagents following the
      completion of reaction


   Reuse/Recycling
     Beneficial both environmentally and economically


   Regeneration
     Able to be regenerated with high efficiency

                    K. M. Doxsee, J.E. Hutchison, Green Organic
                                 Chemistry, 2004                  2
    Principles of Green Chemistry
   Prevent waste
     Better to prevent waste than to dispose of it


   Less hazardous reaction conditions
     More amenable to undergraduate instruction
     More focus on the reaction and products than
      complex procedures


   Safer solvents

                                                      3
                   HMBI vs. HTIB
               O
                                                     O
HO   I     O   S                                 S        O

               O                                     O

                                                 I

                                                     OH


Hydroxy(tosyloxy)iodobenzene       1H-1-hydroxy-5-methyl-1,2,3-
      Koser’s Reagent              benziodoxathiole 3,3-Dioxide
            HTIB                              HMBI

A mild and useful oxidant that   Should be a compact heterocyclic
  mimics elemental bromine                  equivalent

         277 publications                 3 publications

         MW 392.22 g/mol                MW 314.10 g/mol

                                                                    4
Typical reaction of HTIB                                            removed by
                                                                  aqueous workup
       O                                                                                  OH
HO I O S                  O                                     O                                         I
                                                                                     O S O
       O                              H 2O                              OH
                 +                                                               +                  +
                                    DMSO, rt

    HTIB                                               -hydroxyketone

                     Xie, Y.Y. and Z.C. Chen, Synth. Comm. 2002, 32, 1875-1879
                                                                                                 removed by
                                                                                               chromatography




            O              O                                        O                                    O
           S O                           H2O                                 OH                         S O
?          I
             O   +                                                                    +                   OH
                                                                                                        I
            OH
                                                          -hydroxyketone                        removed by
                                                                                               aqueous workup

                     can it be r ecover ed, recycled and r eused?




                                                                                                                5
Goals of the Projects
   We wish to investigate if HMBI is a true
    analog of HTIB using a simple model
    reactions

   Demonstrate of the generality of any
    reactions through exploration of substrates

   To employ more modern, microscale work-up
    procedures to reduce waste and ease
    purification

   Demonstrate the recovery and recycling of
    the reagent

                                                  6
Experimental Procedure
   With our new NMR – only
    small scale (0.5 mmol)
    reactions need to be run to
    probe these reactions




                                  7
Experimental Procedure
   Small scale extraction
    techniques are used to
    maximize yield

   Specialized glassware is also
    used for filtration and drying
    operations




                                     8
Experimental Procedure
   Preparative TLC allows a full
    analysis of all reaction products
    – we only need 1-5 mg to
    acquire a good 1H NMR!




                                        9
Experimental Procedure
Can the reagent be recycled and reused?

If the aqueous layer from the extraction technique is allowed to evaporate
reduced HMBI could be recovered quantitatively (95%+)




                                                                             10
Organic Syntheses - Multistep
 II. Synthetic Efficiency
      We need some benchmarks by which to evaluate comparable
     syntheses:

    Five criteria for evaluating synthetic efficiency:
            1. Number of Steps – should be minimized
            2. Yield for each step – should be maximized
            3. Reaction Conditions
            4. Ease of Purification
            5. Cost


                                                   H
                                      O            N
                                                       CH3


                       F3C




                           Fluoxetine (Prozac, Eli Lily)
                      Seratonin Specific Reuptake Inhibitor
Organic Syntheses - Multistep
 II. Synthetic Efficiency
     A. The first and second criteria are closely related:
         1. Number of steps – Should be minimized

        2. Yield per step – Should be maximized

             •   The overall or synthetic yield is the amount of final product (by
                 moles, of course) after a multistep synthesis over the moles of
                 limiting reagent for the first step

             •   Number of steps is reduced through careful orchestration
                 and ordering of steps

             •   Yield per step is increased by careful selection of reactions that
                 are specific and produce few by-products (which also will ease
                 the purification of the product, the fourth criterion)

             Synthetic yield is defined as the product of the percentages
                 (converted to their decimal equivalents) of all steps of a
                 synthesis times 100%
Organic Syntheses - Multistep
 II. Synthetic Efficiency
     A. The first and second criteria
       The combination of these first two criteria is illustrated in the table below:


                   # OF                   Yield/Step %
                   STEPS             90         75          50

                         1           90          75         50
                         2           81          56         25
                         3           73          42         12
                         4           66          32          6
                         5           53          18          3


         For example a two-step synthesis with a 50% yield per step is not as
         efficient as a five-step synthesis with a 90% yield per step based on the
         first two criteria
There are ways of modifying synthetic efficiency:
Two types of syntheses:
Linear Synthesis:


       50%                50%            50%              50%             50%
A                  B             C                  D              E               F
Synthetic yield:                 25%             12.5%            6.25%         3.1%

333g starting material*                                                10g product


Convergent Synthesis:
                           50%             50%
    40g                    A              B                   C
                                                        50%
                                                              G   10g product
                           50%             50%
    40g                    D              E                   F

80 g starting material*                                              10g product

          * Assuming molecular weights between steps roughly equal
Organic Syntheses - Multistep
 II. Synthetic Efficiency
     B. The Third Criterion: Reaction Conditions

        •   Reactions should be as close to ambient conditions as possible

        •   Reactions requiring high pressure, temperature or inert atmospheres
            are not desirable (but remember, sometimes necessary!)

        •   Reactions that require intricate reaction equipment are also less
            desirable

        •   Reactions that require toxic materials that are difficult to remove
            (pharmaceuticals, food additives, etc.) are also not desirable
Organic Syntheses - Multistep
 II. Synthetic Efficiency
     C. The Fourth Criterion: Ease of Purification
         •   Reactions with simple work-up procedures that can be performed on
             a large scale (read: industrial) are preferred: distillation,
             crystallization, sublimation

        •   Reactions requiring intricate work-up procedures that are not easily
            scaled up are not preferred: chromatography (GC, HPLC, column) or
            inert atmospheres

    D. The Fifth Criterion: Cost – related to the four previous steps
        •   Starting materials – should be cheap and easily handled

        •   Reagents – should be common and easily handled

        •   Personnel time – better if the labor required can be automated or
            performed by personnel of lower skill

        •   Waste disposal – becoming more important and more expensive
Success with HMBI here at Behrend
Oxidative rearrangements of arylalkanones to alkyl 2-
arylesters
  ○   The conversion of arylalkanones, 1, to alkyl 2-arylesters, 2, by oxidative
      rearrangement and subsequent hydrolysis to the corresponding 2-arylacids is a
      facile and useful transformation


                      O                                  O
                                  oxidative
                              r earrang ement   Ar
                          R                                  O
                 Ar                R'OH
                                                     R
                      1                                  2

  ○   Many 2-arylacids are known for their anti-inflammatory, anti-pyretic and analgesic
      properties. Early methods used for this conversion utilized thallium(III), silver or
      lead salts – highly toxic materials with high disposal costs

  ○   Subsequently, due to the inherent toxicity and cost of these materials, alternative
      methods were developed which included the use of iodine, iodine monochloride,
      iodine trichloride
Success with HMBI here at Behrend
Oxidative rearrangements of arylalkanones to alkyl 2-
arylesters
  ○   When HMBI is applied to this conversion:
      ○  Identical products are observed
      ○  The use of toxic lead or thallium salts are avoided – good for drugs!
      ○  The reduced reagent can be recycled and reused with high efficiency


          O                                                                      O
                                 O          oxidative             O
         S O                             rearrangement                          S O
                   +                 R                   Ar                +
           O                                                          O           OH
                            Ar               R'OH
         I                                                    R                 I
          OH


                       Reoxidation with peracetic acid or sodium percarbonate
Success with HMBI here at Behrend
Oxidative rearrangements of arylalkanones to alkyl 2-
arylesters
  ○   How is this important – Why should I be interested in alkyl 2-arylesters?
      ○   Let’s look at the current industrial synthesis of ibuprofen

                         O                        O                                  OH

                             Cl                            NaBH 4
                         AlCl3                             ethanol


                                                                                  PBr3

                  O
                                                   C N                                   Br
                  C OH
                         1) NaOH
                         2) H3 O+                           NaCN
                                                          acetonitrile

      Ibuprofen



       Total of five steps from isobutylbenzene, using toxic or harmful
                   reagents in two steps, and recycling none
Success with HMBI here at Behrend
Oxidative rearrangements of arylalkanones to alkyl 2-
arylesters
  ○     Now the synthesis of ibuprofen can be completed more succinctly!


                         O                  O
                                                                               OCH 3
                             Cl                     HMBI
                         AlCl3                     methanol                O




                  O
                  C OH
                          H2 O, H3 O+



      Ibuprofen




          Total of five steps from isobutylbenzene, using toxic or harmful
                      reagents in two steps, and recycling none
Success with HMBI here at Behrend
Oxidative rearrangements of arylalkanones to alkyl 2-
arylesters
  ○    This synthesis can be extended to other drugs of this type:

                                     O
                      OH                            OH
                                                                                    OH
                  O                             O
                                                                                O
                                                               O
      Ibuprofen                    Ketoprofen                        Naproxen
Future Project 1:
Oxidative rearrangements of arylalkenes to arylalkanones
  ○   The purpose of this project is to make this known reaction “green” in two ways. First,
      replacing the original reagent [hydroxyl(tosyloxy)iodo]benzene (HTIB) with an analog
      that allows the reduced by-product to be separated from the reaction mixture by simple
      aqueous extraction for re-oxidation and reuse. Second, because iodobenzene is no
      longer contaminating the organic by-products of the reaction, column chromatography
      can either be simplified or eliminated altogether.


        Before:
                                       R2                             R2                         I
                                                                                O

        PhI(OH)OTs         +           R1                                               +            +       TsOH
                                            95% MeOH, RT                            1
                                   n                                       n    R




         Proposed:

                      OH                    R2                                 R2

                      I                                                                 O                    I
                          O    +                1                                                                OH
                                            R                                                +
                      S                             95% MeOH, RT                                             S
                                        n                                           n   R1
                  O       O                                                                              O       O

                                            recover, recycle, reuse
Future Project 2:
Oxidative Rearrangement of alkynes with CHTIB
 ○   HTIB can oxidize terminal and internal alkynes (terminal shown) in various solvents; one
     of the more interesting “oxidative rearrangements” is observed when terminal alkynes
     are treated in an alcohol, to afford alkyl esters



        Equation 1:

                                                                                       I
                                                               O
         PhI(OH)OTs +   Ph          H                      R               Ph   +
                                               ROH                 O


         Equation 2:

                                  reoxidize within the reaciton mixture or

                OH
                I                                                      O                       I
                  O     +    Ph          H                         R            Ph +               OH
                S                                                          O                   S
               O O                                                                         O       O

                                             recover, recycle, reuse
Future Project 3:
Synthesis of Isoflavones – Currently underway
  ○   Isoflavones are recognized as potent anti-oxidants and
      phytoestrogens. Most syntheses in the literature rely on
      toxic thallium(III) compounds

  ○   We have developed a synthesis of isoflavones that is
      basically one step from easily prepared
      2-hydroxychalcones:

             O                                          O
                                  HMBI
      R                                          R                   R'
                            MeOH, reflux 20 hr
             OH                                          O
                       R'
                                                     an Isoflavone
Questions?
   If you want any further information feel
    free to stop by anytime

   The first publication using this reagent is
    also available

   Through this month and next we will be
    finishing the work on the second
ng this reagent is
    also available

   Through this month and next we will be
    finishing the work on the second

								
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