Word of the week…Racemate

The definition of racemate, an equimolar mixture of enantiomers, is old hat to most of us having learned it in our introductory organic chemistry courses. And so it was for me until recently.

Being a synthetic chemist, I don’t have much time or energy to gain a deep understanding of physicochemical properties. Therefore, I was not surprised to find that I was ignorant of the fact that in the solid state racemates come in two flavors and that the IUPAC has developed specefic nomenclature to define each. There is a “racemic compound” where the two enantiomers are co-crystallized homogenously into a single crystal. However, racemates can also exist as “racemic conglomerates” which describes the situation where the two enantiomers crystallize separately but still might be occluded in a single particle.

Tangentially related to this topic is Wallach’s rule which states that racemic crystals (ie. racemic compounds) are more dense than the crystals of the pure enantiomers. Which makes me think…since increased crystalline density is generally associated with increased stability and increased crystalline stability can be correlated with reduced aqueous solubility, one would expect that racemates would be less soluble than their pure enantiomers. I did a search of the literature see if this was the case and come up with the examples below..there appears to be a  slight trend.

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7 Responses to “Word of the week…Racemate”

  1. kinasepro Says:

    slight trend?

    Hmm… so are the single enantiomers more or less soluble?

  2. walkerma Says:

    Good question…I don’t know if I am going too far out on a limb in proposing that Wallach’s rule would predict that single enantiomers are more thermodynamically soluble than their racemic compund. Other than those shown, I have not been able to find a large number of cases in the literature where all three forms were prepared and analyzed. Two of the examples appear to be consistent with the assumption however the sulfonamide example shows the opposite trend. The fluoxetine case shows that the racemate-solid is more stable than the single enantiomer, but the solubility for the single enantiomer is missing.

    There also appears to be some controversy surrounding Wallach’s rule. For an interesting discusion on this topic see the paper. Jack Dunitz published a paper in 1991 DOI: dx.doi.org/10.1021/ja00026a015 where he surveyed the Cambridge Structural.

  3. milkshake Says:

    The answer my friend, is blowin’ in the wind – but you can find it in:
    “Enantiomers, racemates, and resolutions” Jean Jacques, André Collet, Samuel H Wilen 1981 ISBN 0-471-08058-6

    The general tendency is that racemates tend to be more stable in crystalline form because the crystal structure formed from 1:1 R+S elements has usually higher symmetry and density – but there are flukes.

    The entropic contribution to racemate deltaG is -RTln2
    So weakly interacting molecules (molecular crystals of non-polar molecules) tend to almost always form more stable racemate (the exceptions are less than 2% of cases) – whereas with strongly polar molecules forming ionic bonds like aminoacids where the delta H difference can sometimes over-rule the entropic factor so you get up to 5% of exceptions. By exceptions I mean more stable enantiomer than racemate. If this is so then instead of racemate a mixture (“conglomerate”) of enantiomericaly enriched crystals forms. In such case you can separate the racemate by purely physical means, by alternating inoculation of the oversaturated racemate solution with seeds of one and then another enantiomer.
    This seeding technique is pretty labor-intensive but it has been used in industry because it does not need any resolving agent, just repetitive seeding/heating/cooling. It has been applied for separating enantiomers of aminoacids and also chloramphenicol base. But again, this technique is applicable only with compounds that form conglomerate = the enantiomers crystallize separately. A famous example is sodium-ammonium tartarate that crystallizes slowly by evaporation from cold solution as conglomerate and Pasteur was first to separate the crystals by hand and show they were optically active.

    So, to make it shorte, you have >95% chance that a racemate will be less soluble and have higher melting point. This is even more likely with non-polar compounds.

  4. milkshake Says:

    I should add that the sulfone-sulfonamide compound in upper right is most likely the “exception”, the conglomerate – because if the racemate crystallizes as a mixture of enantiomericaly-pure crystals you would expect the racemate to be about twice as much soluble as the pure enantiomer.

  5. weirdo Says:

    Racemates can be more stable in solution as “dimers” compared to pure enantiomer dimers. Most known cases of positive non-linearity in enantioselective catalysis rely upon this very phenomenon.

  6. nearlynothingbutnovels Says:

    I’ve mentioned this briefly elsewhere (well, my comments always seem brief to me), but the place to go for detailed analysis that explains theory and practice of this area is “Enantiomers, Racemates and Resolutions” by Jean Jacques (Author) Hardcover Publisher: Krieger Pub Co (August 1991)
    Language: English ISBN-10: 0894646184 ISBN-13: 978-0894646188. I used an earlier edition of this book in grad school in the early 1980’s and it was very helpful. It was particularly illuminating on spontaneously resolutions and the formation of physical mixtures of chiral crystals from a racemic solution. Magic? It may seem like it, but it is sound chemistry (we did it successfully in my group). Jim http://greenchemistry.wordpress.com/

  7. nearlynothingbutnovels Says:

    I just stopped back to have a look at this page. The post and discussion are fascinating. One thing that confuses me, though, is the issue of density vs. solubility. How (or why) are these supposed to be related? What am I missing?

    Here is the reference I mentioned above:

    A new route to chiral bis-tertiary phosphine ligands: synthesis, resolution, and crystal structure of trans-bis-1,2-(diphenylphosphino)cyclopentane and the nickel adduct [trans-1,2-(PPh2)2C5H8]NiBr2. Allen, David L. et al. Journal of the Chemical Society, Chemical Communications (1983), (16), 895-6. CODEN: JCCCAT ISSN: 0022-4936. Journal written in English. CAN 100:34631 AN 1984:34631 CAPLUS

    Abstract

    Grignard reaction of PhMgBr with diphosphinocyclopentane I (R = Cl), prepd. by heating white P, PCl3 and cyclopentene at 200, gave I (R = Ph) (II). II with NiBr2 in 95% aq. EtOH gave the II.NiBr2 complex (III). Crystn. of III from CH2Cl2 gave crystals of (+)- and (-)-III.CH2Cl2, which were sepd. by hand picking. Treatment of (+)-III.CH2Cl2 with NaCN gave (-)-II. (-)-II with [RhLCl]2 (L = 1,4-cyclooctadiene) catalyzed the hydrogenation of methyl(N-benzoyl)- and (N-benzoyl)dehydrophenylalanine to give hydrogenated products of .apprx.100% optical purity. The crystal structures of II and III.CH2Cl2 are reported.

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