Estimation of the Enthalpies of Formation of Organic Componds in the

Chapter 5

Downloaded by STANFORD UNIV GREEN LIBR on September 30, 2012 | http://pubs.acs.org Publication Date: February 1, 1998 | doi: 10.1021/bk-1998-0677.ch005

Estimation of the Enthalpies of Formation of Organic Componds in the Solid Phase The Study of 2-Acetoxybenzoic Acid (Aspirin) and Its Isomers Hussein Y . Afeefy and Joel F . Liebman Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, M D 21250

Recent experiment shows that the archival value for the enthalpy o f formation o f solid 2-acetoxybenzoic acid is seriously in error. Although the source o f error is relatively easy to find and to correct, this observation documents the importance o f being able to estimate enthalpies o f formation o f solid phase species. Estimations o f the enthalpies o f formation o f solid phase 2-, 3- and 4-acetoxybenzoic acids are offered and the first and last values favorably compared with those from experiment; the middle value is offered as a prediction to encourage its measurement.

W e start with the observation that there are over ten million known organic compounds, o f which enthalpies o f formation are known for under ten thousand {1-4). Accordingly, it is usually necessary to estimate an enthalpy o f formation when a value is desired, whether for industrial, academic, or theoretical reasons. This is a fortiori true for a new compound because it is regrettably unlikely that the compound will be o f adequate quantity, purity and interest to excite the experimental calorimetrist to perform the necessary measurement. For relatively simple, i.e. unsubstituted or monofunctional, unstrained compounds found in the gas phase, calculation by Benson's group increments (5) is usually adequate to provide the missing number. However, when a group increment contribution is absent, other methods o f estimation become imperative. Very often, the compound o f interest is solely found in the condensed (liquid and/or solid) phase. Sometimes enthalpies o f vaporization and/or sublimation can not be measured because o f the low thermal stability o f the compounds. Sometimes, the gas phase —so important and interesting for the theoretically inclined student o f molecules — lacks relevance for the bench chemist. Parametrization o f either the enthalpy o f formation group increments (6) and/or o f the phase change enthalpies (7,8) is thus essential.

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© 1998 American Chemical Society

In Computational Thermochemistry; Irikura, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1905.

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A F E E F Y & LIEBMAN

Enthalpies of Formation of Solid-Phase Species

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Group Additivity, Isodesmic and Macroincrementation Reactions Regardless o f the desired phase o f the compound, when there is more than one substituent and/or the molecule is strained, it is necessary to include correction terms in group additivity approaches (5) to account for otherwise ignored interactions. Many correction terms have been developed but they customarily lack generality, e.g. the ring correction (cf. strain energy) term for cyclopropane is not directly applicable to either its unsaturated or monooxygen derivative, cyclopropene or oxirane, respectively (5). Most often, the correction terms are derived from the enthalpy o f formation o f a single species. What is to be done when the desired correction term is absent? It is important to note that our analysis is not limited to making predictions o f the values o f enthalpies o f formation. It is not uncommon to find conflicting measurements o f this quantity. Even more commonly, there may be reason for suspect the single value available for analysis. For examples o f this last type o f problem, it is desirable to emphasize that agreement between group additivity and experiment is not adequate because the value for the group may arise uniquely from the compound o f interest. A n approach we have found most useful is that o f isodesmic reactions (?) in which the various groups and interactions appear in equal number and type on both sides o f the reaction. Numerous cancellations arise because large structural features such as benzene rings are common to both reactant and product. M o r e properly, what the authors prefer are "macroincrementation reactions" (10) which are isodesmic reactions with some ancillary "verbal correction" included such as equating strain energies o f comparably substituted cyclopropanes and cyclobutanes. A s o f now, no expert system or computer code exists to make these corrections. The power and weakness o f "macroincrementation reactions" is the inherent subjectivity in its applications and assumptions. Experimental Studies of the Energetics of 2-Acetoxybenzoic Acid To demonstrate our reasoning, we will discuss the energetics o f acetylsalicylic acid (77). COOH

This compound is more properly named 2-acetoxybenzoic acid and is generally and colloquially called "aspirin". This compound is o f considerable medicinal, and additionally o f commercial, importance. It is a relatively low molecular weight (under 200), multifunctional species with pronounced nonpolar and polar parts (the benzene


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ring and ester linkage, and the carboxylic acid group respectively). 2-acetoxybenzoic acid is normally found as a solid although since its enthalpy o f fusion is known, knowledge o f its enthalpy o f formation as a solid is immediately accompanied by the knowledge o f enthalpy o f formation as a liquid. However, no measured enthalpy o f sublimation has been reported and so its gas phase energetics remain unavailable from experiment. The standard thermochemical archive by Pedley (7) o f the enthalpy o f formation o f organic compounds reports a solid phase value o f -815.6 U m o l ' as determined from analysis o f cited enthalpy o f hydrolysis measurements. B y contrast, Kirklin (77) recently reported the very dissonant value o f -758.6 kJ mol* from direct enthalpy o f combustion measurements; we note that Kirklin also gives us the value o f -739.3 kJ mol" for the liquid by the use o f his enthalpy o f fusion results. W e might ask which o f these values is more plausible. Kirklin documented errors in Pedley's analysis that will be chronicled below. Nonetheless, we ask what theory would have predicted to help us decide. I f our analysis is admittedly a posteriori, nonetheless, it gives us a chance to expand and expound on our thought processes and associated decisions about the interplay o f structure and energetics.


1

1

1

Why are Pedley's and Kirklin's numbers are so different? Pedley, in his earlier edition (72), chronicles the literature hydrolysis reaction o f 2-acetoxybenzoic acid to form salicylic (2-hydroxybenzoic) and acetic acids to be endothermic by 27 k J mol" , 1

6

COOH

COOH

.OCOCH3

+

^ i / O H

H 0(lq) 2

•

J

J

+ CH COOH(lq) 3

(1)

(s) (s) where we emphasize that this endothermicity does not refer to the reaction COOH

COOH

I ^ / O C O C H

r ^ V ^

3

0

H

+ CH COOH(aq) 3

fi

J

+

H 0(lq)

(2)

||

2

dq)

dq)

Upon careful reading o f the original paper, Kirklin noted that the hydrolysis is exothermic by 27 kJ mol' and thus there is a discrepancy or 27 -(-27) = 54 kJ m o l ' between the reported experimental value and that given by Pedley. Following our customary prejudice and preference we use the latest study for the desired data and the enthalpy o f formation o f salicylic acid (73). Using the archival values for acetic acid (14) and water (75), we find a revised value o f the enthalpy o f formation o f solid 2-acetoxybenzoic acid o f -766 kJ mol' . 1

1

1


5.



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1

Within a range o f 7 kJ mol* the values from enthalpy o f combustion and enthalpy o f reaction are equal; the discrepancy has thus effectively vanished. While this 7 kJ mol" difference is not insignificant and its consequences should not be ignored, the difference tells us that we should not be disappointed i f theoretically deduced and experimentally measured values o f an enthalpy o f formation o f some solid phase organic compound fail to agree better than, say, 10 kJ mol" . M o r e honestly and properly said, discrepancies o f this magnitude are reasonable to expect because they may well be unavoidable in the absence o f some new measurements. Indeed, had there not been a new value for the enthalpy o f formation o f 2-acetoxybenzoic acid, would we have had any reason to challenge the hydrolysis data and its subsequent analysis? That is, we find that we generally do not go back to the original source when we use compilations. Corresponding to customary practice as to the use o f archival references, as research scientists, we generally assume that published numbers are valid unless there is reason for suspicion. We could now turn to theoretical considerations, estimation techniques, and excruciating details as applied to the enthalpy o f formation o f solid and liquid 2-acetoxybenzoic acid. Rather, we commence by explaining how we could have known to challenge Pedley's archived value for the endothermicity o f the hydrolysis o f aspirin. In the current case, it is really quite easy. Bottles o f aspirin that have sat in the cabinet too long often smell o f vinegar, a household "compound" that we recognize as the common name for a dilute aqueous solution o f acetic acid. This observation suggests that the hydrolysis o f 2-acetoxybenzoic acid is thermodynamically favorable and indeed, this process must be facile i f atmospheric moisture is enough to allow it to happen. Reactions solely in the condensed phase generally have rather small entropic contributions: we note the hydrolysis reaction takes us from two "particles" to two "particles" and so the entropy change would be expected to be small in the gas phase as well. The above analysis suggests we should expect the hydrolysis reaction of 2-acetoxybenzoic acid to be exothermic ( A H < 0) as well as exergic.(AG < 0) Equivalently, an ester hydrolysis enthalpy o f +27 kJ mol" appears not to be particularly plausible while a result o f -27 kJ mol" is consistent with other things we know. 1


1

1

1

Evaluation of the Energetics of 2-Acetoxybenzoic Acid Suppose we did not have olfactory or other sensory information, after all, we generally dissuade our students and junior colleagues from smelling a sample o f an arbitrary new organic compound. What could we then deduce? A s said above, 2-acetoxybenzoic acid is a polyfiinctional molecule. W e recognize an ester functionality and, in turn, refine this realization to a carboxylic acid ester, an aryl ester and a hindered one at that (cf. the two rather large groups ortho or adjacent to each other). What do we expect about the sign o f its enthalpy o f hydrolysis? For a simple example, consider methyl acetate and its hydrolysis reaction;


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CH COOCH (lq) + H 0(lq) 3

3

-

2

CH OH(lq) + CH COOH(lq) 3

(3)

3

Is this reaction exothermic? From literature (14J5) enthalpies o f formation we find that it is endothermic by 8 kJ mol" . Is that a surprise? W e know ester hydrolysis reactions proceed in acid and basic solutions. If so, reaction rate aside, why does it not proceed spontaneously (in a thermodynamic sense) in essentially neutral media as well? W e are not surprised that alkyl esters o f strong oxy (i.e., hydroxylic) acids readily hydrolyze. dimethyl sulfate readily methylates numerous nucleophiles including water, cf. equation 4.


1

(CH 0) S0 (lq) + 2H 0(lq) 3

2

2

-

2

2CH OH(aq) + H S0 (ai) 3

2

(4)

4

where the "aq" is in aqueous media and the " a i " tells us that the acid product is in aqueous media and ionized. This reaction is exothermic by 93 kJ mol" . Then we remember that concentrated sulfuric acid reacts violently with water because o f its high exothermicity o f solution and so the relevant reaction (equation 5) has not been considered so far. 1

(CH 0) S0 (lq) + 2H 0(lq) 3

2

2

2CH OH(lq) + H S0 (lq)

2

3

2

(5)

4

1

In fact, it is also endothermic, in this case by ca. 15 kJ mol" . B y contrast, alkyl esters o f weak hydroxylic acids often hydrolyze exothermically. For example, the following, conventionally unobserved, reaction is exothermic (16) by 6.5 kJ mol" 1

C H OC H (lq) + H 0(lq) 2

5

2

5

2C H OH(lq)

2

2

(6)

5

Interpolating, the exothermicity o f the hydrolysis o f intermediate strength acid esters is hard to appraise. Let's now change the alcohol. Acid anhydrides hydrolyze more readily, as well as exothermically, than ethers. For example, consider acetic anhydride which is formally the ester o f acetic acid and "acetyl alcohol". We find the following reaction CH COOCOCH (lq) + H 0(lq) 3

3

-

2

2CH COOH(lq) 3

(7)

1

is exothermic by almost 60 kJ mol" . What about phenols? Consider the reaction C H OOCCH (lq) + H 0(lq) 6

5

3

2

-

C H O H + CH COOH(lq) 6

5

3

(8)

which is the same as the hydrolysis reaction (equation 1) except for the ortho or 2-carboxylic acid substituent. This reaction is also exothermic, here by nearly 29 kJ mol'^when phenol is taken to be in its standard solid state. However, we should be considering phenol as a liquid — or more properly said, our experience has shown predictions to be the most reliable when all o f the species are in the same phase. W e have also found that predictions are most reliable for gases, then liquids, then solids.


5.



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Lacking enthalpy o f fusion data, we would still expect the enthalpy o f fusion o f phenol to be relatively low — or at least low enough to not reverse the energetics and make this last reaction endothermic. Why would we assume this? A simple response notes that 3-methylphenol is a liquid under standard conditions and thus suggests that the crystal energy in the parent species phenol is not that large. W e also note the melting point o f phenol is "only a few degrees" above 298 K (313 K)and so it is "almost a liquid". Alternatively, we can estimate the enthalpy o f formation o f liquid phenol by assuming that the following reaction is thermoneutral: C H CH (lq) + 3-CH C H40H(lq) 6

5

3

3

l,3-C H4(CH ) (lq) + C H O H ( l q )

6

6

3

2

6

5

(9)

We make herein the simplest assumption that conservation o f groups always results in thermoneutrality. The enthalpy o f formation o f liquid phenol, -156 kJ mol" , is found while assuming thermoneutrality for the related reaction 1

Oq)

(lq)

(lq)

0

Estimation of the Enthalpies of Formation of Organic Componds in the

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