Review of
`
`Organic Functional Groups
`
`Introduction to Medicinal Organic Chemistry
`
`THOMAS L. LEMKE
`
`University of Houston
`College of Pharmacy
`Houston, Texas
`
`Second Edition
`
`@ L
`
`EA & FEBIGER
`
`a
`
`Philadelphia
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 001
`
`

`
`Lea 8: Febiger
`600 Washington Square
`Philadelphia. PA 19106
`U.S.A.
`
`[215] 922-1330
`
`Library of Cflngmss Cataloging-in-Publication Data
`
`Lemke. Thomas 1...
`Review of organic functional groups.
`
`includes index.
`2. Chemistry. Organic.
`1. Chemistry. Pharmaceutical.
`[. Title.
`[DNLM:
`1. Chemistry. Organic.
`2. Chemistry. Pharmaceutical. QV ‘F44 L554r}
`RS4U3.L397
`1938
`515'.3
`ISBN 0-3121-1128-1
`
`87-22310
`
`
`
`Copyright © 1983 by Lea & Febiger. Copyright under the International Copyright
`Union. All Rights Reserved. This book is protected by copyright. No part ofit may be
`reproduced in any manner or by any means without written permission from the
`publisher.
`
`PRINTED [N THE UNITED 'STATES OF AMERICA
`
`Print ND.
`
`3 2
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 002
`
`

`
`16
`
`Predicting Water Solubility
`
`1. EMPIRIC METHOD
`
`We have now reviewed the major functional groups that might be
`expected in drug molecules. It will soon become obvious to you that
`the majority of the drugs discussed are not simple monofunctional
`molecules but instead are polyfunctional molecules. Most drugs will
`be found to contain two. three. four. or more of the organic func-
`tional groups within a single chemical entity. How then does one
`predict physical and chemical properties of these more complex
`molecules? As mentioned throughout the book. one must recognize
`the individual functional groups within the more complex struc-
`tures. Once this is done. the chemical properties. namely, in vitro
`stability and in vivo stability. are easily predicted. The chemical
`properties of a functional group are usually not affected by the pres-
`ence of another functional group within the molecule. Therefore,
`each functional group can be treated independently of the other
`functional groups present.
`If we consider the important physical property of water solubility.
`it is found that polyfunctional molecules behave somewhat differ-
`ently than monofunctional molecules. A simple summation of the
`water-solubilizing properties of each functional group will usually
`not lead to a successful prediction of water solubility for the more
`complex systems. When one looks at the water-solubilizing property
`ofa single functional group. there is no possibility of intramolecular
`bonding, that is. bonding within the molecule, because no second
`functional group is present. On the other hand. with polyfunctional
`molecules.
`intramolecular bonding may become a significant in-
`teraction. With the individual functional groups, the solubilizing
`potential of the groups took into consideration intermolecular bond-
`ing. As an example, an alcohol functional group in a molecule such
`as hexanol binds to a second molecule of hexane] through dipole-
`
`113
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 003
`
`

`
`114
`
`Review of Organic Functional Groups
`
`dipole bonding. This bonding must be broken in order to dissolve
`the hexanol in water. When one states that an alcohol functional
`
`group solubilizes approximately six carbon atoms. this statement
`took into consideration intermolecular bonding of this type. But
`what about the polyfunctional molecules? The intermolecular bond-
`ing between like functional groups can still occur. but now a new
`type of bonding is possible. the intramolecular bond. Bonding may
`occur between dissimilar functional groups. and these types of
`intermolecular and intramolecular bonding may be quite strong. In
`order for a molecule to dissolve in water. the intramolecular and
`
`intermolecular bonding must first be broken so that the water mole-
`cules can bond to the functional groups.
`
`Ix; Carboxyt
`CHé— CH‘—CO0H
`
`I N
`
`H2
`
`\
`
`10
`
`amine
`
`Phenol /’
`
`H0
`
`Tyrosine
`
`Solubility in water
`
`0.45 g/1000 ml
`
`(5 25°C
`
`An excellent example of the importance of intramolecular bond-
`ing is seen with the amino acid tyrosine. This molecule has three
`functional groups present. a phenol. an amine. and a carboxylic acid.
`By a simple summation of the water-solubilizing potential of each
`functional group. one would predict that the phenol would sol~
`ubilize 6 to 7 carbon atoms, the amine 6 to 7 carbon atoms, and the
`
`carboxyl 5 to 6 carbon atoms. giving a total solubilizing potential of
`17 to 20 carbon atoms. Tyrosine contains 9 carbons. yet the molecule
`is soluble to the extent of 0.5%. The explanation for this lack of water
`solubility can be understood if one recognizes the possibility of
`intramolecular bonding. The amino acid can exist as a zwitterion
`[Fig. 16~—1}. The charged molecule exhibits intramolecular ion-ion
`bonding. As a result. this destroys the ability of these two functional
`groups to bond to water. The phenol is not capable by itself of dis-
`solving the molecule. If the intramolecular bonding is destroyed by
`either adding sodium hydroxide or hydrochloric acid to the amino
`acid, the resulting compound becomes quite water soluble.
`Although less dramatic. most functional groups are capable of
`showing some intra- and intermolecular hydrogen bonding. which
`decreases the potential for promoting water solubility. How much
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 004
`
`

`
`Predicting Water Solubility
`Zwitterionit: Form
`
`115
`
`NaDH
`
`H 0
`
`Hfl
`
`H U
`
`0
`CH2-CH-C-0‘
`2
`Ill-I
`
`Na+
`
`_
`
`0
`
`+Na
`
`0
`an -cu-E-nH
`2 ill-t
`* 3
`
`:1
`
`'
`
`Ho
`
`Very Soluble
`
`Very Soluble
`
`Fig. 15-1. Solubilization of tyrosine in aqueous base or aqueous acid
`
`weight should be given to each such interaction for individual func-
`tional groups? This is a difficult question to answer. but as a general
`rule. if one is conservative in the amount of soluhilizing potential
`that is given to each functional group. one will find that fairly accu-
`rate predictions can be made for polyfunctional molecules.
`In Table 16-1. the various functional groups that have been dis—
`cussed are listed with the solubilizing potential of each group when
`present in a monofunctional molecule and the solubilizing potential
`when present in a polyfunctional molecule. This latter value will be
`the more useful value, since most of the molecules that we discuss
`will be polyfunctional.
`Several examples will help demonstrate this method of predicting
`water solubility. In the first molecule (Fig. 16-2]. one should recog-
`nize the presence of two tertiary amines. If the more liberal solubiliz-
`ing potential for an amine is used, it might be expected that each
`amine would have the capability of solubilizing up to 7 carbon
`atoms. leading to a total potential of dissolving 14 carbon atoms in
`the molecule. Since the molecule contains 13 carbon atoms. one
`would predict that the molecule would be soluble. Using the more
`conservative estimate and allowing 3 carbons worth of solubility to
`each amine. a prediction of insoluble would result. It turns out that
`the molecule is water soluble. The use of the more liberal estimate in
`order to obtain the correct results is acceptable in this case since the
`molecule contains only amines that act alike, not creating any new
`inter- and intramolecular bonds.
`With porn-dimethylaminobenzaldehyde (Fig. 16-2}. a nine»
`carbon molecule. the liberal estimate would predict solubility. since
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 005
`
`

`
`116
`
`Review of Organic Functional Groups
`
`Table 15-1.
`
`Water-Solubilizing Potential of Organic Functional Groups
`When Present in a Mono- or Polyfunctional Molecule.
`Water Solubility Is Defined As >10/o Solubility.
`
`Functional Group
`
`Monofunctional Molecule
`
`Polyfunctional Molecule
`
`Alcohol
`
`Phenol
`
`Ether
`
`Aldehyde
`
`Ketone
`
`Amine
`
`5 to 6 carbons
`
`6 to ? carbons
`
`4 to 5 carbons
`
`4 to 5 carbons
`
`5 to 6 carbons
`
`6 to T carbons
`
`Carboxylic Acid
`
`5 to 6 carbons
`
`Ester
`
`Amide
`
`6 carbons
`
`6 carbons
`
`3 to 4 carbons
`
`3 to 4 carbons
`
`2 carbons
`
`2 carbons
`
`2 carbons
`
`3 carbons
`
`3 carbons
`
`3 carbons
`
`2 to 3 carbons
`
`Urea. Carbonate.
`Carbamate
`
`
`2 carbons
`
`H0
`
`CH
`911
`
`N0
`
`7+5
`
`12
`
`3+2
`
`Il-
`
`5
`
`“"--J + ""-J
`
`II
`
`I-3 -11‘-
`
`Nater Soluble
`
`Slightly
`
`Prediction of water solubility of organic molecules using
`Fig. 15-2.
`polyfunctional estimates for [he fu notional groups
`
`Soluble
`rnono-and
`
`Par Pharm., Inc.
`Exhmfl1008
`Page 006
`
`

`
`Predicting Water Solubility
`
`117
`
`the amine is capable of solubilizing up to seven carbon atoms and an
`aldehyde could solubilize up to five carbon atoms. On the other
`hand. the conservative estimate would predict insolubility with the
`amine worth three and the aldehyde worth two carbon atoms. This
`molecule is listed as slightly soluble. a result that falls between the
`two estimates. This simply shows that
`these are only predictions
`and, with borderline compounds. may lead to inaccurate results. The
`next examples (Fig. 16—3] lead to a more accurate prediction. In the
`first compound [Fig. 16-3). one should recognize the presence of
`
`Hi]
`
`DCH3
`
`<” 00
`
`—~-- 0
`
`N
`.
`cs?‘
`
`°19"19“°4
`5 + 5 + 5 + 1 + f = 29
`
`2+2+2+3+.1=13
`
`Hater Inso1ub1e
`
`I
`
`/
`
`0
`
`CH3C-U
`
`v
`
`CH i5-0
`3
`
`c21H23"°5
`6 + 5 + 5 + ? = 24
`
`3+3+2+3=11
`
`Hater Insoluble
`
`Fig. _‘l5—3. Prediction of water solubility of organic molecules using mono- and
`polytunctiona] estimates for the functional groups
`
`three ethers. a phenol. and a tertiary amine. Using the mono-
`functional solubilizing potential. one would expect enough sol-
`ubility from these groups to dissolve this 19-carbon compound.
`since each ether would be assigned 5 carbons, the phenol 7 carbons.
`and the amine 7 carbons worth of solubilizing potential. If one uses
`the more conservative estimate, which takes into consideration the
`
`intra~ and intermolecular bonding. however. each ether contributes
`two carbons worth of solubility. while the phenol and amine con-
`tribute three and four carbons worth of solubilizing potential. re-
`spectively. The prediction now is that the molecule is insoluble in
`Water. and this turns out to be the case.
`
`The next two examples use the same approach. The first com-
`pound [Fig. 16-4] has two ethers. two alcohols. and an ester. Using
`the liberal Inonofunctional estimates for water solubility would pre-
`dict a soluble compound, while the conservative estimate would
`predict only 15 carbons worth of solubility. Since the compound
`possesses I5 carbons, one would predict solubility by either approach
`and the compound is soluble. In the last compound we should rec-
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 007
`
`

`
`118
`
`Review of Organic Functional Groups
`
`J\‘ OCH3 3
`
`/\
`
`CISHIBOG
`
`5+5+5+6+6=28
`
`2+2+i+4+3=15
`
`water Soiuhte
`
`':23"22°i
`
`5x5=25+5+7=3s
`
`5x2=1o+2+a=1e
`
`Hater Insoluble
`
`Fig. 16-4. Prediction of water solubility of organic molecules using mono- and
`polyfnnctional estimates for the functional groups
`
`ognize the presence of five ethers. a ketone, and a phenol. The liberal
`estimate would result in a prediction of water solubility for this
`23-carbon compound. but using the conservative estimate the more
`accurate prediction of water insolubility would result.
`
`2. ANALYTIC METHOD
`
`Throughout this presentation. emphasis has been placed on the
`water-solubilizing properties of the common organic functional
`groups. This was recapitulated in Table 16-1 with carbon-
`solubilizing potentials for each functional group. and the use of
`these values was demonstrated by the examples shown in Figures
`16-2 through 16——4. While this approach is empiric, others have
`attempted to derive an analytic method for calculation of water sol-
`ubility. One such mathematical approach recently reported by L. A.
`Cates (Am. ]. Pharm. Ed.. 45. 11. 1931] is now presented. This ap~
`proach is based upon the partitioning of a drug between octanol [a
`
`109 P = Cone. of Drug in Octane‘!
`
`Cone. of Drug in water-
`
`standard for lipophilic media) and water. The base-ten logarithm of
`the partition coefficients is defined as log P. While the measured log
`P values are a measure of the solubility Characteristics of the whole
`molecule. one can use fragments of the whole molecule and assign a
`specific hydrophilic-lipophilic value [defined as 11- value] to each of
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 008
`
`

`
`Predicting Water Solubility
`
`119
`
`these fragments. Thus. a calculated log P can be obtained by the sum
`of the hydrophilic-lipophilic fragments:
`
`109 F‘
`
`calc.
`
`.= X T1‘
`
`(fragments)
`
`To use this procedure, the student must fragment the molecule into
`basic units and assign an appropriate rr value corresponding to the
`atoms or groups of atoms present. Table 16-2 lists the common
`fragments found in organic molecules and their arr values. Positive
`values for 1r mean that the fragment. relative to hydrogen, is lipo-
`philic or favors solubility in octanol. A negative value indicates a
`hydrophilic group and thus an affinity for water. While the envi-
`ronment of the substituent can influence the 71- value. such changes
`are small. and for our purposes this factor can be neglected.
`Through the examination of a large number of experimentally ob-
`tained log P and solubility values. an arbitrary standard has been
`
`Table 16-2.
`
`Hydrophilic-lipophilic Values [1-r Values) for
`Organic Fragments
`
`Fragments
`
`‘JT Vaiue
`
`C(a11'phat1'c) . . . .
`
`. . . . . . . . . . . .
`
`.
`
`.
`
`. . .
`
`. . . ..
`
`+ 0.5
`
`Phenyi . . . . . .
`
`.
`
`.
`
`. . .
`
`. . . . . . . .
`
`. . . . . . . . . . . ..
`
`+ 2.0
`
`Ci . . .
`
`.
`
`.
`
`. . .
`
`. . . . . . . . .
`
`. . . . . . . .
`
`. . . . . . .
`
`. . ..
`
`+ 0 5
`
`. . . . . .
`.
`.
`.
`.
`.
`.
`. . . . . .
`02M} . .
`IMHB .
`. . .
`. . . . . . . . . . . .
`. . .
`.
`
`. . . . . . . . .
`.
`. . . . .
`. . .
`
`. . . ..
`.
`.
`. ..
`
`+ 0.2
`+ 0.65
`
`S . . . . . .
`
`. . .
`
`.
`
`. . .
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`. . .
`
`. . . .
`
`. . ..
`
`0.0
`
`. . .
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`. . ..
`
`— 0.7
`
`0=C-0 .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`. . . . .
`
`. . .
`
`0=C-N (other than amine) . .
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`. . . ..
`
`- 0.7
`
`0 (hydroxyl, phenol, ether) . . .
`
`. . .
`
`. . . ..
`
`- 1.0
`
`N (amine) .
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`. . .
`
`. . . . . . . .
`
`.
`
`.
`
`. ..
`
`- 1.0
`
`02N (aliphatic) .
`
`. . .
`
`. . .
`
`.
`
`.
`
`. . .
`
`. . . . .
`
`. _ .
`
`. ..
`
`— 0.85
`
`02N (aromatic) . . . . .
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`. . ..
`
`- 0.28
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 009
`
`

`
`120
`
`Review of Organic Functional Groups
`
`U=C-UH
`
`OH
`
`Solubility 0.2%
`
`Calc.
`
`log P without
`
`IMHB
`
`Calc.
`
`log P with IMHB
`
`Phenyl .
`
`OH .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . . .
`
`.
`
`. . .
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. ..
`
`. ..
`
`+ 2.0
`
`— 1.0
`
`Phenyl .
`
`0H .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`. ..
`
`+ 2.0
`
`. . . . . . . ..
`
`-
`
`1 0
`
`- 0.?
`
`0=C-0 .
`
`.
`
`. .
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`. ....
`
`- 0.7
`
`+ 0.3
`
`Prediction:
`
`Soluble
`
`0=C-0 .
`
`IMHB . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . . .
`
`. . . . .
`
`.
`
`.
`
`.
`
`.
`
`. . . . ..
`
`.
`
`.
`
`.
`
`. ..
`
`+ 0.65
`
`+ 0.95
`
`Prediction:
`
`Insoluble
`
`Calculation of water solubility of salicylic acid without and with the
`flg.15—5
`intramolecular hydrogen bonding [l=\/IHB] factor
`
`adopted whereby those chemicals with a positive log P value over
`+0.5 are considered waterinsoluble{i.e.,solubilityisless than 3.3‘/oin
`wate.-r—a definition for solubility used by the USP}. Log P values less
`than +0.5 are considered to be water soluble.
`
`U
`
`Procaine
`
`C H
`
`C2H5
`
`6—C@+U.5... . . .
`
`. . . .
`
`. . ..+3.0
`
`Phenyl . . . . .... . . . .
`
`. . . .
`
`. .... + 2.0
`
`2—N@-1.U...... . . .
`
`. . . . ..-2.0
`
`0=C-0- . . . . . .
`
`.
`
`. . .
`
`. . . .
`
`- 0.?
`
`+ 2.3
`
`Prediction:
`
`Insoluble
`
`Hg.t5—&
`
`Calculation of water solubility of procaine
`
`ParPhann”|nc
`Exhibit 1008
`Page010
`
`

`
`Predicting Water Solubility
`
`121
`
`This method of calculating water solubility has proved quite effec-
`tive with a large number of organic molecules containing C. Cl. N.
`and 0. but several additional factors may have to be considered for
`specific drugs. A complicating factor is the influence of intra-
`molecular hydrogen bonding [IMHB] on rr values. As discussed in
`the previous empiric approach to predicting water solubility. IMHB
`would be expected to decrease water solubility. and. therefore.
`where IMHB exists. a nr value of +0.65 is added to the calculations.
`
`An example of using this factor is shown for salicylic acid
`[Fig. 15-5].
`The log P values of a drug with acid or base character are influ-
`enced by the pH of the media in which the drug is placed. This is not
`surprising. since acid or base groups will become ionic under ap-
`propriate conditions. Although the rr values given in Table 16-2
`were obtained under conditions in which the amine. phenol, or car-
`boxylic acid are un-ionized. which would allow an accurate predic-
`tion of log P. observed log Ps at various pH values may not be accu-
`rate for water prediction. The experimental log Ps found for procaine
`are -0.32 [pH 7] and 0.14 {pH 6). both of which would lead to the
`prediction that procaine is water soluble. In fact. procaine is soluble
`to the extent of 0.5% at pH 7. The calculated log P = +2.3 [Fig 16-6]
`correctly predicts that procaine is water insoluble.
`
`Par Pharm., Inc.
`Exhibit 1008
`Page 011