2-Iodoxybenzoic acid, oxidations

IBX acid or 2-iodoxybenzoic acid is an organic compound used in organic synthesis as an oxidizing agent. This periodinane is especially suited to oxidize alcohols to aldehydes. The IBX acid is prepared from 2-iodobenzoic acid, potassium bromate and sulfuric acid.[1]

2-Iodoxybenzoic acid

The reaction mechanism for an oxidation of an alcohol to an aldehyde according the so-called hypervalent twisting mechanism[4] involves a ligand exchange reaction replacing the hydroxyl group by the alcohol followed by a twist and a elimination reaction.

The hypervalent twisting mechanism during conversion of methanol to formaldehyde: a) ligand exchange reaction (activation energy 9.1 kcal/mol (38 kJ/mol), b) hypervalent twist 12.1 kcal/mol (51 kJ/mol), c) elimination 4.7 kcal/mol (20 kJ/mol)). There is steric repulsion between protons in red.
Oxidative cleavage of vicinal diols: mechanism
The reaction mechanism for this glycol cleavage is based on initial formation of an adduct between 10-I-4 IBX and DMSO to an 12-I-5 intermediate 3 in which DMSO acts as a leaving group for incoming alcohol 4 to intermediate 5. One equivalent of water is split off forming 12-I-5 spirobicyclic periodinane 6 setting the stage for fragmentation to 7. With hydroxyl alpha protons presents oxidation to the acyloin competes. Trifluoroacetic acid is found to facilitate the overall reaction.
IBX is also available as silica gel or polystyrene bound IBX. In many application IBX acid is replaced by Dess-Martin periodinane which is more soluble in common organic solvents. A sample reaction is a IBX oxidation used in the total synthesis of eicosanoid:[6]

IBX acid oxidation of alcohol to aldehyde key data: a) IBX, DMSO, THF, 4h, 94% chemical yield (Mohapatra, 2005)

References

  1. Boeckman, R. K. Jr., Shao, P.; Mullins, J. J. (2000), “Dess-Martin periodinane: 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one”, Org. Synth. 77: 141; Coll. Vol. 10: 696
  2. Frigerio, M.; Santagostino, M.; Sputore, S. (1999). “A User-Friendly Entry to 2-Iodoxybenzoic Acid (IBX)”. Journal of Organic Chemistry 64 (12): 4537–4538. doi:10.1021/jo9824596.
  3. Dess, D. B.; Martin, J. C. (1991). “A Useful 12-I-5 Triacetoxyperiodinane (the Dess-Martin Periodinane) for the Selective Oxidation of Primary or Secondary Alcohols and a Variety of Related 12-I-5 Species”. Journal of the American Chemical Society 113 (19): 7277–7287. doi:10.1021/ja00019a027.
  4. Su, J. T.; Goddard, W. A. III (2005). “Enhancing 2-Iodoxybenzoic Acid Reactivity by Exploiting a Hypervalent Twist”. Journal of the American Chemical Society 127 (41): 14146–14147. doi:10.1021/ja054446x. PMID 16218584.
  5. Gallen, M. J.; Goumont, R.; Clark, T.; Terrier, F.; Williams, C. M. (2006). “o-Iodoxybenzoic Acid (IBX): pKa and Proton-Affinity Analysis”. Angewandte Chemie International Edition 45 (18): 2929–2934. doi:10.1002/anie.200504156. PMID 16566050.
  6. Mohapatra, D. K.; Yellol, G. S. (2005). “Asymmetric Total Synthesis of Eicosanoid” (pdf). Arkivoc 2005 (3): 144–155.

thanks to DR WILL WATSON OF SCIENTIFIC UPDATE ON A WARNING

Beware, IBX can explode, see C&E News, 1990, vol 68, issue 29 page 3. A stabilised non-explosive formulation of IBX mixed with benzoic acid and phthalic acid is available from Simafex, see Org. Lett., 2003, 5, 2903.

EFFICIENT CONVERSION OF CARBONYL TO METHYLENE GROUP

 

anicheck.gif (1995 bytes)TEBBE reagent exhibits carbenoid behavior after the addition of a catalytic amout of pyridine.

anicheck.gif (1995 bytes)mechanism:

anicheck.gif (1995 bytes)remarks:

  • The Tebbe’s reagent transfers a methylene group (CH2) efficiently to various carbonyl compounds to afford olefins 

anicheck.gif (1995 bytes)references:

J. Org. Chem. 200671, 5457.
J. Am. Chem. Soc. 1997119, 7483.
J. Am. Chem. Soc. 1993115, 10400.
J. Org. Chem. 198550, 1212.
J. Am. Chem. Soc. 1978100, 3611.

anicheck.gif (1995 bytes)DR A.M. CRASTO

amcrasto@gmail.com

NMR spectroscopy of stereoisomers

NMR spectroscopy techniques can determine the absolute configuration of stereoisomers such as cis or trans alkenesR or Senantiomers, and R,R or R,S diastereomers.[1][2]

In a mixture of enantiomers, these methods can help quantify the optical purity by integrating the area under the NMR peak corresponding to each stereoisomer. Accuracy of integration can be improved by inserting a chiral derivatizing agent with a nucleus other than hydrogen or carbon, then reading the heteronuclear NMR spectrum: for example fluorine-19 NMR or phosphorus-31 NMR.Mosher’s acid contains a -CF3 group, so if the adduct has no other fluorine atoms, the 19F NMR of a racemic mixture shows just two peaks, one for each stereoisomer.

As with NMR spectroscopy in general, good resolution requires a high signal-to-noise ratio, clear separation between peaks for each stereoisomer, and narrow line width for each peak. Chiral lanthanide shift reagents cause a clear separation of chemical shift, but they must be used in low concentrations to avoid line broadening.

References

  1. David Parker. “NMR determination of enantiomeric purity.” Chem. Rev. 199191, 1441–1457. [1]
  2. Frank J. Hollis. “NMR Through the Looking Glass: Uses of NMR Spectroscopy in the Analysis and Synthesis of Chiral Pharmaceuticals.” 1994. [2]

S442. NMR Project

CLOPIDOGREL ENANTIOMER ENRICHMENT

Abstract Image

 

The recently discovered technique of deracemization by means of attrition-induced grinding of a solid conglomerate in contact with a solution wherein racemization occurs has been used with a derivative of 2-chlorophenyl glycine, the key chiral component in the synthesis of Clopidogrel (Plavix). Deracemization of the racemate proceeds to a single enantiomer and in essentially absolute enantiomeric excess. Further conversion of enantiomerically pure material to Clopidogrel was achieved in 88% yield.

Attrition-Enhanced Deracemization in the Synthesis of Clopidogrel – A Practical Application of a New Discovery

Org. Process Res. Dev., 2009, 13 (6), pp 1195–1198
DOI: 10.1021/op900243c