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4.4: Rules of Thumb for thinking about the relationship between Molecular Structure and Brønsted Acidity and Basicity*

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    282933
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    Because the acidity of a given substance depends on the interplay between the relatively large values of its proton affinity and the energy associated with solvation of an acid's conjugate base it can be sometimes difficult to estimate the strength of an acid in a given solvent in the absence of detailed computations. Nevertheless a variety of simple ideas may be used to roughly estimate the relative strengths of acids. These should never be substituted for a detailed consideration of solvation but can serve as useful aids when thinking about trends and designing new Brønsted acids and bases.

    Four main factors should be considered when thinking about the relationship between Molecular Structure and Brønsted Acidity and Basicity

    Some simple factors that it can be helpful to consider when thinking about the strength of a given acid or base are:

    1. Bond strength effects

    The weaker the bond to the ionizable hydrogen, the stronger the acid. Strongly bonded hydrogen ions are difficult to remove, weakly bonded ones much less so.

    2. Inductive effects

    Inductive effects involve the donation or withdrawal of electrons from an atom by a group connected to it through bonds. Electron donating groups increase the electron density while electron withdrawing groups decrease it. Atoms or groups that withdraw electron density away from a center increase its acidity while those which donate electrons to the center decrease its acidity. The reasons for this follow from the heterolytic bond cleavage of acid ionization:

    \[E-H→E:^-+ H^+\]

    • When a bond to hydrogen is more polarized away from the H (more like\(^{-δ}E-H^{δ+}\)) it is easier to cleave off the hydrogen ion from that E-H bond. This may be seen from how the pKa values of acetic acid and its mono-, di-, and tri-chlorinated derivatives decreases with the extent of chlorination of the methyl group.

    fig7-3-6.png

    • Polarized E-H bonds also make for stronger Brønsted acids because the resulting \(E:^-\) conjugate base is more stable.

    This leads to the third major factor that should be considered when thinking about acid strength.

    3. Electronegativity Effects, Especially as Seen using the Conjugate Base Principle

    The more stable the acid's conjugate base, the stronger the Brønsted acid. All reactions are in theory reversible and so when considering the propensity of an acid to donate hydrogen ions it can be helpful to look at the reverse of hydrogen ion donation, namely protonation of the acid's conjugate base. If deprotonation of the acid gives a very stable conjugate base then deprotonation of the acid will be more favorable.

    Two factors determine the stability of an acid's conjugate base.

    • Conjugate bases in which a small amount of charge is on a large atom, spread over a large number atoms, and on electronegative atoms tend to be more stable. Conjugate bases in which a small amount of charge are spread over a large number of electronegative atoms are especially stable. That is why magic acid, a mixture of HF and \(SbF_5\), is so acidic; the single negative charge on its conjugate base is spread over six F atoms and on Sb in \(SbF_6^- \).
    • Groups which tend to inductively polarize E-H bonds also tend to stabilize the conjugate base formed when that bond ionizes. In general, the more electronegative an atom, the better able it is to bear a negative charge. All other things being equal weaker bases have negative charges on more electronegative atoms; stronger bases have negative charges on less electronegative atoms. This is apparent from how inductive effects lead to an increase in the acidity of E-H bonds as the electronegativity of the element to which the acidic hydrogen is bound increases from left to right across a row of the periodic table. This horizontal periodic trend in acidity and basicity is apparent from the homologous series below:

    Horizontal periodic trend in acidity and basicity

    fig7-3-1.png

    Notice how the inductive polarization of the E-H bond which results in greater acidity contributes to the greater stability of the conjugate base. For the case above look at where the negative charge ends up in each conjugate base. In the conjugate base of ethane, the negative charge is borne by a carbon atom, while on the conjugate base of methylamine and ethanol the negative charge is located on a nitrogen and an oxygen, respectively. Remember that electronegativity also increases as we move from left to right along a row of the periodic table, meaning that oxygen is the most electronegative of the three atoms, and carbon the least.

    Thus, the methoxide anion is the most stable (lowest energy, least basic) of the three conjugate bases, and the ethyl carbanion anion is the least stable (highest energy, most basic). Conversely, ethanol is the strongest acid, and ethane the weakest acid.

    4. Size effects on Bond Strength and Charge Delocalization

    There are two classes of size effects to be considered:

    1. The larger the atom to which a H is bound in an E-H bond, the weaker the bond and the stronger the acid.
    2. Increased charge delocalization with increasing size. Electrostatic charges, whether positive or negative, are more stable when they are ‘spread out’ over a larger area. The greater the volume over which charge is spread in the acid's conjugate base, the more stable that base and the stronger the acid.

    The impact of size effects are readily seen in the increase in acidity of the hydrogen halides, as illustrated by the vertical periodic trend in acidity and basicity below:

    Vertical periodic trend in acidity and basicity

    fig7-3-2.png

    On going vertically down the halogen group from F to I the H-X bond strength decreases in the acid, making it easier to ionize, while the charge becomes more diffuse in the resultant X- ion, making the conjugate base more stable.

    fig7-3-3.png

    The increase in the acidity of the hydrogen halides down a group suggests that size effects are more important than inductive effects. In the case of the hydrogen halides because fluorine is the most electronegative halogen element, we might expect fluoride to also be the least basic halogen ion. But in fact, it is the least stable, and the most basic! It turns out that when moving vertically in the periodic table, the size of the atom trumps its electronegativity with regard to basicity. The atomic radius of iodine is approximately twice that of fluorine, so in an iodide ion, the negative charge is spread out over a significantly larger volume.

    Exercise \(\PageIndex{}\)

    The structure of the amino acids serine and cysteine are shown below. Which do expect will have the more acidic side chain?

    clipboard_ec9a5d8a74531a8692bd49009b35c21c1.png

    Answer

    Cysteine, since the cysteine side chain possesses an ionizable S-H bond while serine's side chain possesses an ionizable O-H bond. Since S is larger than O cysteine's S-H bond will be weaker than serine's O-H bond the and cysteine side chain's thiolate conjugate base more stable than the serine side chian's alkoxide conjugate base. In fact, the side chain \(pK_a\) of cysteine is 8.3 while serine is considered to be nonionizable under physiological conditions.


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