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Hoveyda-­‐‑Grubbs  Second  Generation  Catalyst  for  Cross  Metathesis  of  Eugenol  with  cis-­‐‑2-­‐‑Butene-­‐‑1,4-­‐‑diol  

Thomas  Kelly        

                   

               

Abstract     In  order  to  synthesis  the  natural  product  (E)-­‐‑4-­‐‑(4-­‐‑Hydroxy-­‐‑3-­‐‑methoxyphenyl)but-­‐‑2-­‐‑enol,  the  starting  materials  were  chosen  to  be  Eugenol  and  cis-­‐‑2-­‐‑butene-­‐‑1,4-­‐‑diol.  A  cross  metathesis  reaction  was  then  carried  out  with  a  2nd  generation  Hoveyda-­‐‑Grubbs  catalyst.  The  reaction  product  was  then  isolated  and  purified  before  characterization  using  multiple  techniques.  While  due  to  issues  in  crystallization,  no  purified  product  was  isolated  for  yield  calculations,  yet  the  reaction  product  was  confirmed  using  a  variety  of  techniques.  

 

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Introduction     The  Metathesis  Reaction  being  investigated  here  has  wide  applications  within  the  realm  of  synthetic  organic  chemistry.  As  with  any  novel  tool,  new  applications  and  export  will  be  found  for  the  chemistry  being  illustrated  in  the  following  experiment,  and  therefore  I  shall  leave  the  potential  applications  of  this  work  to  others  such  as  J.C.  Mol1  and  merely  remark  on  the  breath  of  potential  that  metathesis  reactions  as  a  whole  contain.     The  2005  Nobel  Prize  in  Chemistry  was  awarded  to  Yves  Chauvin,  Richard  Schrock  and  Robert  Grubbs  for  their  achievements  in  metathesis  mechanics  and  catalysis.  With  more  than  30  special  made  catalysts  available  from  Sigma-­‐‑Aldrich  alone†,  the  range  of  chemistry  available  for  synthesis  is  extensive.  This  fact  is  established  by  the  extensive  reviews  which  have  been  published  summarizing  a  few  of  the  applications  of  metathesis  in  Pharmaceutical  and  Natural  Product  research2.  

In  this  protocol,  Eugenol  was  reacted  with  cis-­‐‑2-­‐‑butene-­‐‑1,4-­‐‑diol,  1,  with  an  expectation  of  forming  (E)-­‐‑4-­‐‑(4-­‐‑Hydroxy-­‐‑3-­‐‑methoxyphenyl)but-­‐‑2-­‐‑enol,  2.  Eugenol  is  a  substituted  phenyl  which  was  originally  isolated  from  oil  of  clove3.  Compound  1  is  a  simple  unsaturated  glycol  of  butane.  Compound  2  is  a  natural  product  originally  isolated  from  the  root  of  the  Zingiber  cassumunar  plant  and  notable  for  its  anti-­‐‑inflammatory  properties  and  subsequent  medicinal  implications4.  The  primary  objective  of  this  experiment  was  to  correctly  synthesize  and  isolate  the  product  and  verify  its  identity  as  Compound  2.  

The  catalyst  used  to  run  the  cross  metathesis  reaction  was  a  second  generation  Hoveyda-­‐‑Grubbs  rubidium  complex  (Figure  1).  This  catalyst  was  prepared  a  week  before  the  reaction,  reference  the  Experimental  Procedure  for  details.  

 

Experimental  Procedure  All  methods  and  procedures  were  followed  as  

recorded  in  the  Laboratory  Manual5.  In  addition  to  protocols,  observations  and  qualitative  measurements  were  recorded  therein  as  well.  Below  is  the  overall  reaction  (Figure  2).  

 

                                                                                                               †  A  first  order  approximation  based  on  general  search  of  reagents  available  at  <http://sigmaaldrich.com/>.  

Figure  2.  Overall  Reaction  

Figure  1.  Hoveyda-­‐Grubbs  Catalyst  

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Results  &  Discussion     The  final,  un-­‐‑crystalized  product  mass  and  the  masses  of  the  starting  materials  were  unmeasured  and  as  indicated  in  the  procedure,  respectively.  The  product  obtained  was  in  a  solvated  form  which  precluded  the  possibility  of  recording  a  final,  purified  mass;  and  therefore,  there  are  no  yield  calculations  to  present.  Although  a  representatively  small  sample  size,  we  expect  a  yield  of  2%  -­‐‑  5%  based  data  from  colleagues‡.  

A  melting  point  analysis  was  planned  for  the  final,  purified  product,  but  due  to  unknown  causes,  the  final  product  was  not  isolated.  After  a  week,  the  end  solution  was  observed  to  have  high  clarity  and  the  first  signs  of  a  crystalized  product.  In  order  to  force  further  product  from  solution,  the  mixture  was  heated  and  a  maximal  quantity  of  the  solvent  was  evaporated  to  concentrate  the  compound.  Next,  the  solution  was  rapidly  cooled  in  an  ice  bath  in  the  hope  of  having  the  purified  compound  to  ‘crash  out’  and  crystalize.  The  only  observed  product  was  marginal  crystallization  along  the  bottom  of  the  flash  along  with  a  dark,  oily  residue.  

Thin  Layer  Chromatography     Since  an  important  aspect  of  synthesis  is  by  providing  adequate  time  for  product  formation,  thin  layer  chromatography  was  used  to  gauge  the  reaction  progress.  By  blotting  the  reaction  crude  product  along  with  the  starting  material,  a  qualitative  assessment  of  completion  was  determined.  The  reaction  was  deemed  complete  once  the  starting  material  ‘spot’  had  disappeared.     Thin  Layer  Chromatography  was  also  utilized  to  identify  the  column  fractions  which  contained  the  crude  product.  This  was  an  efficient  method  for  rapidly  determining  where  our  product  compound  was.  The  presence  or  absence  of  the  reaction  product  was  clear  and  obvious,  as  can  be  seen  in  the  laboratory  notebook.  Only  the  fractions  which  lacked  a  Eugenol  spot  (high,  Rf  >  0.9,  brown  spot)  and  contained  a  product  spot§  were  kept  and  concentrated.  

Infrared  Spectroscopy     As  one  of  three  spectrographic  techniques  used  to  verify  the  structure  of  the  reaction  product,  IR  was  able  to  assist  primarily  in  identifying  the  presence  and  absence  of  certain  functional  groups.  Since  no  IR  spec  was  taken  for  the  reaction  product,  we  are  restricted  to  speaking  generally  of  anticipated  results.     A  significant  change  in  the  IR  spectrum  outside  the  “fingerprint”  region  is  the  new  hydroxyl  absorption  band  seen  only  in  the  product.  Like  many  

                                                                                                               ‡  See  Table  A1  for  data  and  Formula  1a  for  yield  definition.  §  A  green  band  at  Rf  ≅  0.8  as  reproduced  in  the  appendix  figure  A1.  

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hydroxyls,  the  absorption  is  broad,  and  it  overlaps  with  the  aromatic  hydroxyl  present  in  both  the  product  and  the  starting  materials.  Since  the  new  hydroxyl  on  the  product  is  relatively  electron  poor  relative  to  the  phenol,  its  absorption  band  is  shifted  down  to  lower  frequencies.  

Nuclear  Magnetic  Resonance**     NMR  was  utilized  in  coordination  with  the  other  verification  methods  to  determine  the  carbon  structure  and  placement  of  functional  groups  within  the  purified  product.  The  appearance  of  two  new  signals  at  δ  of  3.65  ppm  and  4.18  ppm  indicate  the  addition  of  an  alcohol  and  methylene  modality,  respectively,  to  compound  2  relative  to  Eugenol.  One  of  the  characteristics  indicative  of  the  transformation  from  Eugenol  to  Compound  2  is  a  relative  shift  downfield  due  to  the  additional  electronegative  hydroxyl  group.  This  is  seen  in  Spectrum  2  as  the  ethylene  hydrogens  are  shifted  from  a  δ  of  5.00  ppm  to  5.60  ppm.  This  lends  support  to  the  successful  synthesis  of  Compound  2.  

Mass  Spectrometry     Mass  spectrometry  was  not  conducted  since  the  resulting  product  was  not  isolatable.  In  an  attempt  to  crystalize  a  purified  product  out  of  solution,  the  mixture  was  first  heated  to  evaporate  the  solvent.  Once  concentrated,  the  solution  was  quickly  chilled  in  an  effort  to  have  the  final  compound  ‘crash  out’,  but  little  to  no  precipitate  was  observed.  Therefore,  we  have  chosen  to  present  here  a  representative  spectrum  in  order  to  describe  the  features  that  are  expected  of  Compound  2.     The  calculated  molecular  mass  of  Compound  2  is  193.2  g  mol-­‐‑1.  The  mass  spectrum  indicates  a  strong  peak  at  177.1  and  194.1  indicative  of  a  protonated,  condensation  fragment  and  the  protonated  product,  respectively.  The  last  peak  observed  occurs  as  mass  to  charge  ratio  of  212.1:  suspected  to  be  an  ammonium  complex  of  Compound  2.  

Conclusion     Although  the  final,  purified  product  did  not  crystalize  properly,  we  are  confident  that  our  product  was  the  expected:  Compound  2.  This  conclusion  was  drawn  using  a  variety  of  source  including  NMR,  IR  spectroscopy,  Mass  spectrometry,  and  qualitative  observations.  

                                                                                                               **  As  noted  in  the  Appendix  under  Spectrum  1  and  Spectrum  2,  since  1H-­‐NMR  data  was  not  accessible  for  the  reaction  product,  calculated  spectra  have  been  included  instead.  Consider  this  as  a  tutorial  of  how  results  would  have  been  treated  instead.  

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  The  unfortunate  difficulty  in  crystallization  of  the  final  product  precludes  the  possibility  of  reaching  much  of  a  conclusion;  therefore,  following  are  several  possible  sources  of  error  from  the  experimental  procedure  followed.  The  flash  chromatography  column  is  a  critical  step  in  the  purification  of  the  final  product.  But  as  the  only  columns  available  with  the  proper  radius  were  24”  in  length,  considerable  trouble  was  found  when  attempting  to  pack  and  run  such  a  long  column  with  so  little  reaction  material.  Alternatively,  an  auto-­‐‑column  would  have  worked  well  in  running  and  collecting  the  proper  fractions.  Contamination  by  water  or  another  solvent  may  have  denied  the  final  solution  from  being  able  to  crystalize.  These  oversights  will  be  properly  addressed  for  the  next  experiment.  

To  end  this  report  with  a  nod  to  basic  research,  provided  below  is  a  brief  quote  by  Richard  Schrock  who  was  awarded  a  Nobel  in  Chemistry  for  his  metathesis  research.    

“…what   we   accomplished…   came   through   basic   research  without   really  knowing  exactly  how  we  were  proceeding;  we  ultimately   came   to   realize,  step   by   step,   that   our   basic   research   was   leading   to   something   really  useful.  And  that  is  very,  very  pleasing  to  me;  and  I  think  that’s  what  the  Nobel  Prize  is  all  about:  to  do  work  that  turns  out  to  be  useful  to  society  in  some  way  and  certainly  other  fields  in  science.”6  

   

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Appendices    Formula  1a.  Yield  Calculations     Yield,  Y,  is  defined  here  as  the  ratio  of  the  product,  P,  to  the  starting  materials,  SM,  as  measured  by  number  of  atoms  (or  equivalently,  in  mols).  

𝑌 =𝑃𝑆𝑀  ≡

[𝑚𝑜𝑙]![𝑚𝑜𝑙]!"

 

 Formula  1b.  Yield  calculation  from  Mass     In  order  to  calculate  Yield  based  on  weights  the  following  equation  was  used  where  mass  and  molar  mass  are  m  and  M,  respectively.  

𝑌 =𝑚!

𝑚!"

𝑀!"

𝑀!  

Example:     Consider  the  following  reaction  where  2.0  g  of  benzene  is  sulfonated  to  form  1.9  g  of  product.  

𝐵𝑒𝑛𝑧𝑒𝑛𝑒  !!!!! 𝐵𝑒𝑛𝑧𝑒𝑛𝑒𝑠𝑢𝑙𝑓𝑜𝑛𝑖𝑐  𝐴𝑐𝑖𝑑  

Therefore;  

𝑌 =1.9  𝑔2.0  𝑔

78.1  𝑔/𝑚𝑜𝑙158  𝑔/𝑚𝑜𝑙 = 47  %  

   Table  A1.  Collaboration  Data     Peers  working  in  other  groups  provided  this  data.  Since  their  protocols  are  similar  to  ours,  we  are  confident  that  their  results  are  indicative  of  a  probable  outcome  for  our  product.    

Group   Yield   Melting  Pt.  (oC)  

1  (AJA)   2.47%   93.5-­‐‑96.5  2  (DH)   4.81%   88.5-­‐‑94.0  

 Table  A2.  Compound  Data    

Compound   Molecular  Mass  Eugenol   164.2  

Compound  1   88.1  Compound  2   193.2  

 

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 Spectrum  1.  Eugenol  1H-­‐‑NMR     Provided  below  is  a  calculated  spectrum  for  Eugenol  as  a  means  of  comparison  between  the  starting  material  and  product.  The  spectrum  was  calculated  using  ChemBioDraw  Ultra  version  12.0.3.1216  by  CambridgeSoft.

Spectrum  2.  Compound  2  1H-­‐‑NMR     Provided  below  is  the  theoretical  spectrum  for  the  expected  product,  Compound  2.  The  spectrum  was  calculated  using  ChemBioDraw  Ultra  version  12.0.3.1216  by  CambridgeSoft.  

           

ChemNMR 1H Estimation

6.72

6.62

6.84

5.35

3.83

3.21

5.92

5.00

4.98

OH

O

H

H

H

Estimation quality is indicated by color: good, medium, rough

01234567PPM

Protocol of the H-1 NMR Prediction:

Node Shift Base + Inc. Comment (ppm rel. to TMS)

OH 5.35 5.00 aromatic C-OH 0.35 general correctionsCH 6.84 7.26 1-benzene -0.49 1 -O-C -0.17 1 -O -0.20 1 -C 0.44 general correctionsCH 6.72 7.26 1-benzene -0.11 1 -O-C -0.53 1 -O -0.12 1 -C 0.22 general correctionsCH 6.62 7.26 1-benzene -0.44 1 -O-C -0.17 1 -O -0.20 1 -C 0.17 general correctionsCH3 3.83 0.86 methyl 2.87 1 alpha -O-1:C*C*C*C*C*C*1 0.10 general correctionsCH2 3.21 1.37 methylene 1.22 1 alpha -1:C*C*C*C*C*C*1 0.63 1 alpha -C=C -0.01 general correctionsH 5.92 5.25 1-ethylene 1.05 1 -C-1:C*C*C*C*C*C*1 gem -0.38 general correctionsH 5.00 5.25 1-ethylene -0.29 1 -C-1:C*C*C*C*C*C*1 cis 0.04 general correctionsH 4.98 5.25 1-ethylene -0.32 1 -C-1:C*C*C*C*C*C*1 trans 0.05 general corrections

1H NMR Coupling Constant Prediction

shift atom index coupling partner, constant and vector

5.35! 76.84! 6! 4! 1.5!!H-C*C*C-H6.72! 3! 4! 7.5!!H-C*C-H6.62! 4! 3! 7.5!!H-C*C-H! 6! 1.5!!H-C*C*C-H3.83! 93.21! 10! 13! 6.2!!H-CH-C(sp2)-H! 14! -1.0!!H-CH>CH=CH<H! 15! -1.0!!H-CH>CH=CH>H5.92! 13! 10! 6.2!!H-C(sp2)-CH-H! 14! 16.8!!H>C=CH>H! 15! 10.0!!H>C=CH<H5.00! 14! 15! 2.1!!H-C(sp2)-H! 13! 16.8!!H>CH=C>H! 10! -1.0!!H>CH=CH<CH-H4.98! 15! 14! 2.1!!H-C(sp2)-H! 13! 10.0!!H>CH=C<H! 10! -1.0!!H>CH=CH>CH-H

Spectrum  1.  Eugenol  1H-­‐NMR.  

ChemNMR 1H Estimation

6.72

6.62

6.84

5.35

3.83

3.21

4.18

3.65

5.60

6.29OH

OOH

H

H

Estimation quality is indicated by color: good, medium, rough

01234567PPM

Protocol of the H-1 NMR Prediction:

Node Shift Base + Inc. Comment (ppm rel. to TMS)

OH 5.35 5.00 aromatic C-OH 0.35 general correctionsOH 3.65 2.00 alcohol 1.65 general correctionsCH 6.84 7.26 1-benzene -0.49 1 -O-C -0.17 1 -O -0.20 1 -C 0.44 general correctionsCH 6.72 7.26 1-benzene -0.11 1 -O-C -0.53 1 -O -0.12 1 -C 0.22 general correctionsCH 6.62 7.26 1-benzene -0.44 1 -O-C -0.17 1 -O -0.20 1 -C 0.17 general correctionsCH2 4.18 1.37 methylene 0.63 1 alpha -C=C 2.20 1 alpha -O -0.02 general correctionsCH3 3.83 0.86 methyl 2.87 1 alpha -O-1:C*C*C*C*C*C*1 0.10 general correctionsCH2 3.21 1.37 methylene 1.22 1 alpha -1:C*C*C*C*C*C*1 0.63 1 alpha -C=C -0.01 general correctionsH 5.60 5.25 1-ethylene 0.64 1 -C-O gem -0.29 1 -C-1:C*C*C*C*C*C*1 cisH 6.29 5.25 1-ethylene -0.01 1 -C-O cis 1.05 1 -C-1:C*C*C*C*C*C*1 gem

1H NMR Coupling Constant Prediction

shift atom index coupling partner, constant and vector

5.35! 73.65! 146.84! 6! 4! 1.5!!H-C*C*C-H6.72! 3! 4! 7.5!!H-C*C-H6.62! 4! 3! 7.5!!H-C*C-H! 6! 1.5!!H-C*C*C-H4.18! 13! 15! 6.2!!H-CH-C(sp2)-H! 16! -1.0!!H-CH>CH=C<H3.83! 93.21! 10! 16! 6.2!!H-CH-C(sp2)-H! 15! -1.0!!H-CH>CH=C<H5.60! 15! 13! 6.2!!H-C(sp2)-CH-H! 16! 15.1!!H>C=C>H! 10! -1.0!!H>C=CH<CH-H6.29! 16! 10! 6.2!!H-C(sp2)-CH-H! 15! 15.1!!H>C=C>H! 13! -1.0!!H>C=CH<CH-H

Spectrum  2.  Compound  2  1H-­‐NMR.  

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Figure  A1-­‐‑  TLC  band  of  Product     This  band  was  used  to  determine  which  of  the  column  fractions  to  keep.  All  fractions  showing  this  band  were  collected  and  the  product  was  purified  from  them.        

Rf = 0.80

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References                                                                                                                  1  Mol   J.C.   Industrial  Applications  of  Olefin  Metathesis.   Journal  of  Molecular  Catalysis  

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