On the Number of Phthalates
Recently, four cover stories of C&EN magazine were dedicated to the class of molecules called phthalates. Phthalate esters of fatty alcohols are generally used in industry as plasticizers, turning PVC into a more malleable form which comprises many toys for young children. There have been studies of the links between exposure to phthalate plasticizers and antiandrogenic effects in humans (do a PubMed search for phthalates). Reports are coming out about its reproductive effects on females. So, the race is on to develop the next "healthier" plasticizer.
In the article "Regulators And Retailers Raise Pressure On Phthalates", I read the line:
"The number of alcohol-acid combinations that are possible and their resulting properties are as endless as the number of applications."
I understood this line as a (friendly) challenge and took it upon myself to
count the number of phthalates theoretically possible.
My parents always told me I took things too literally.
General
Structure of Industrial Phthalates
The general structure of phthalates appears straightforward: They are
hydrocarbon (limited here to C_{1} to C_{13}) diesters of
phthalic acid.^{1,2} I will only consider linear and branched
alkyl chains here.
Counting Phthalates
Enumerating phthalates begins with enumerating the phthalate
scaffolds, then counting the alcohols that react with the scaffolds and then
finding the combinations of alcohols on a phthalate.
There are three
phthalate scaffolds
There are only three major phthalate scaffolds in use: ortho-, meta-, and
para-phthalic acid--or in other words: phthalic, isophthalic and terephthalic
acids.^{1,2} They are shown below along with SMILES
strings written from the functional perspective.
phthalic acid
isophthalic
acid terephthalic acid c1c2c3ccc1.C2(=O)O.C3(=O)O
c1c2cc3cc1.C2(=O)O.C3(=O)O c1c2ccc3c1.C2(=O)O.C3(=O)O
Counting the alcohol chains is much more difficult. Luckily, it has already been done.
These number of uniquely connected alcohols can be extracted from the set of all C_{n}H_{2n+2}O isomers in SMILES notation^{3-5}(which includes alcohols and ethers) using the regular expression ".*O\\).*|.*O$" (double backslash is the regex escape character for R programming language).^{6} This regular expression extracts the full SMILES strings which represent alcohols.
The same numbers are described by the series of the number of n-carbon
alkyl radicals C_{n}H_{2n+1} ignoring stereoisomers and
can be found at A000598.
If one considers stereochemistry, then the number of unique alcohols increases.
For x chiral centres, there are 2^{x} stereoisomers.
The total number of unique alcohols generated here is described by the series
at this link A000625.
The number of chiral alcohols is another important number to
consider. These numbers have also been described by the series of "chiral
planted trees" found at A005628.
Table 1 shows the numbers.^{7}
Table 1. All
unique alcohols and some subclasses.
Carbon Number |
Number of alcohols |
Total number of |
Number of chiral |
1 |
1 |
1 |
0 |
2 |
1 |
1 |
0 |
3 |
2 |
2 |
0 |
4 |
4 |
5 |
2 |
5 |
8 |
11 |
6 |
6 |
17 |
28 |
20 |
7 |
39 |
74 |
60 |
8 |
89 |
199 |
176 |
9 |
211 |
551 |
510 |
10 |
507 |
1553 |
1484 |
11 |
1235 |
4436 |
4314 |
12 |
3057 |
12832 |
12624 |
13 |
7639 |
37496 |
37126 |
Now we need to see what happens when we take these alcohols and react them with
phthalic acid: how many unique combinations are mathematically possible?
Number of
phthalates with identical alcohol chains
The possible number of molecules in this class will be equivalent to the total
possible number of alcohol chains. There are 57,189 molecules in this class.
This is also the number of possible singly esterified phthalic acids--likely
by-products.
Number of
phthalates with identical length alcohol chains but possibly different identity
The possible number of molecules in this class will be equivalent to the
possible combinations within each alcohol chain carbon number class. This will
be equal to where n equals the number of
alcohols in each carbon number class.
Number of
phthalates with any alcohol side chain
This class of phthalates will contain members, just like the situation
for identical length alcohol chains, but in this case, n = 57,189.
Number of
phthalate meso compounds
Because phthalates have a mirror plane which cuts between the ester
linkages, it is possible to have meso compounds of phthalate esters. Meso
compounds of phthalate esters are phthalate esters whose alcohol side chains
bear one or more chiral centres, but the phthalate itself is not chiral. In
other words, a meso compound phthalate ester is actually superposable on its
mirror image, even though there are chiral centres within the molecule. This is
in contrast withenantiomers whose mirror images are not
superposable making them unique compounds.
Meso compounds of phthalate esters are interesting because they will not
contribute much to the optical properties of phthalate mixtures. Therefore,
from the analytical perspective, their presence is particularly important to
consider. Phthalate ester meso compounds must have two of the same alcohol
chains and must have opposite chirality at each chiral centre.
For every chiral alcohol chain, there is a match for opposite chirality.
Therefore, the total number of meso compounds is half the total number of
chiral alcohols. The series of meso compounds with n carbons in each linear or
branched alkyl chain has been submitted by me and has been recently approved at
http://oeis.org/A261336.
Summary - Some
grand totals
It is important to note that even though many of these alcohol chains are
mathematically possible, this does not suggest that these alcohol chain
geometries actually exist! Incorporating a priori knowledge
concerning reactants and products will filter out these numbers to make them
smaller. Therefore, one can interpret the numbers listed here as absolute upper
bounds to the real number of phthalates.
0.0035% of all phthalates with identical length chains are meso compounds.
0.00172% of all possible phthalates with alcohol chains between C_{1} and
C_{13} are meso compounds. Table 2 summarizes
some numbers.
Table 2. Summary of the possible
number of special classes of unique phthalates (stereochemistry included)
Number
of possible phthalates with identical alcohol chains |
57,189 |
Number of possible phthalates with identical length alcohol chains but possibly different identity (isomeric differences, non-identical) |
796,553,474 |
Number of possible phthalates with any alcohol side chain (all combinations) |
1,635,319,455 |
Number of possible phthalate meso compounds |
28,161 |
The number of singly esterified phthalates equals the number of number of
possible phthalates with identical alcohol chains: 57,189.
If you were to store every phthalate as a SMILES string of 50 bytes (which is a
little on the large side), it would take 76 GB of space without any
compression.
I went back to the C&EN article and read the next line,
"Most phthalates, however, never make it into commercial products because of concerns about performance, cost, availability, or toxicity."
I thought two things:
1. "I take things too literally" and
2. "I guess I can reduce these numbers a little"
References
1. "GIF/PNG-Creator for 2D Plots of Chemical Structures". http://cactus.nci.nih.gov/gifcreator/, NCI/CADD Group.
2. J. Chem. Inf. Comput. Sci. (1983) 23, 61-65. http://dx.doi.org/10.1021/ci00038a002
3. M. Shimizu, H. Nagamochi and T. Akutsu, Enumerating tree-like chemical graphs with given upper and lower bounds on path frequencies, BMC Bioinformatics, vol. 12, Suppl 14, S3, 2011. http://dx.doi.org/10.1186/1471-2105-12-S14-S3
4. Y. Ishida, Y. Kato, L. Zhao, H. Nagamochi and T. Akutsu, Branch-and-bound algorithms for enumerating treelike chemical graphs with given path frequency using detachment-cut, Journal of Chemical Information and Modeling, vol. 50, no. 5, pp. 934-946, 2010. http://dx.doi.org/10.1021/ci900447z
5. H. Fujiwara, J. Wang, L. Zhao, H. Nagamochi and T. Akutsu, Enumerating treelike chemical graphs with given path frequency,Journal of Chemical Information and Modeling, vol. 48, no. 7, pp. 1345-1357, 2008.http://dx.doi.org/10.1021/ci700385a
6. R Core Team (2015). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL http://www.R-project.org/.
7. David B. Dahl (2014). xtable: Export tables to LaTeX or HTML. R package version 1.7-4. http://CRAN.R-project.org/package=xtable.
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