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Chapter 2: Water: The Solvent for Biochemical Reactions

Electronegativity and Bonding


 When two atoms with the same electronegativity form a bond, the electrons are shared equally b/w the two atoms
o The polar nature of water largely determines its solvent properties.
 Know the definition for electronegativity and how to recognize an electronegative element
o Electronegativity – the force of an atom’s attraction for shared electrons in a chemical bond
 Oxygen and nitrogen are more electronegative than carbon and hydrogen
 This relates to chemical reactivity, classifying nucleophiles or electrophiles.
 Understand the concept of a polar bond and how to recognize it
o Because of electronegativity, polar bonds result in an unequal sharing of electrons
 The more electronegative atom has a greater attraction for the electrons, carrying a more negative charge
 This generates a partial dipole
 Know the concept of a dipole moment and what it measures
o Dipole moment – measure of polarity of chemical bond
 The arrow points to the center of electronegativity – similar to a magnet strength
 Know the concept of the van der Waals radius
o Van der Waals radius – the distance between the nucleus of an atom and its effective electronic surface
 If each element is a magnet, van der Waals radius is the limit of the magnet’s ability to attract
 Any bonds formed between atoms result from an overlap of van der Waal’s radii
o The greater the overlap, the shorter the bond distance, the stronger the bond
 Covalent bonds > Hydrogen bonds due to greater overlap of Van der Waal’s radii
 Know the difference between a polar bond and a polar molecule
o CO2 contains polar bonds due to the difference in polarity b/w oxygen and carbon
 BUT, because the alignment of the atoms is linear and symmetrical, CO 2 is nonpolar overall
 The net effect of the polar dipole moment cancels out with the oxygens on opposite ends of the C.
o This makes the molecule nonpolar: O=C=O
 Recognize and distinguish between:
o Ionic bonds – (ionic solids) held together by the attraction of opposite charges (+) and (-)
 Holds sodium chloride crystals together: NaCl
 Intermediate in strength to covalent bonds and hydrogen bonds.
o Salt bridges – occurs between charged functional groups
 Functional groups that carry opposite charges attract each other via electrostatic attraction
 Positively charged amine group (NH3+ ) forms a salt bridge with a negatively charged carboxyl
group (COO--)
 Noncovalent interaction between two ionized sites.
 Two components: hydrogen bond and electrostatic interaction
 A proton migrates from a carboxylic acid to a primary amine or the guanidine group in arg.
o Ion-dipole interactions – when ions in solution interact with molecules that have dipoles
 When potassium chloride is dissolved in water, water molecules surround the ion: KCl in H2O
 The (+) charged K ions interact with (-) dipoles on oxygen
 The (-) chloride ions interact with the (+) dipoles on the hydrogens
 Electrostatic interaction between a charged ion and a molecule that has a dipole.
 It’s an attractive force found in solutions, especially ionic compounds dissolved in polar liquid.

Review Exercises Recommended: 1, 6, 7

van der Waals Forces


 Understand the nature and principles of van der Waals forces
o Van Der Waal’s forces is a noncovalent association that results from weak attractions of dipoles
 B/c there is no net charge, they are not electrostatic in nature
 Thus, these bonds occur b/w particles that are polar but not actually charged.
 EX: two carbonyl groups: RC=O ------RC=O
 They’re weaker than hydrogen bonds
 Know the 3 types of van der Waals interactions
o Dipole-dipole – attractive interactions b/w molecules that carry permanent dipoles i.e. two strongly polar groups
 The partial + dipole on one molecule attractive the partial – dipole on another
 Water + alcohol VS water + ketone
o Dipole-induced dipole – permanent dipole in one molecule can induce the formation of a transient dipole in another
 Causes a momentary distortion of electron clouds
 These interactions are weak and not generally soluble in water
 The dipole of water induces a dipole in O2 by distorting the O2 electron cloud

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Chapter 2: Water: The Solvent for Biochemical Reactions
o Induced dipole-induced dipole (London dispersion forces) – two molecules induce dipoles in each other
 Weakest of the three forces
 London dispersion force – Occur between nonpolar molecules as a result of small fluctuations in their
distribution of electrons that create a temporary separation of charge.
 The attraction b/w transient induced dipoles; nonpolar groups such as methyl experience some
 Know the relative strengths of biochemical bonds and which play the most vital role
o Weaker forces play a vital role in biological systems and structures
 Covalent (C-H) > covalent (O-H) > ionic > ion-dipole > Hydrogen bonds > Van der Waal
o Alone they are weak; together they are strong as seen in drug molecules.
 Weaker forces only act when the groups are very close together
o But if the groups approach too closely, van der Waal’s radii collide and a strong repulsive force overcomes the
attractive force.
 Know how to rank melting or boiling points of compounds
o Based on nature and strength of intermolecular forces

Review Exercises Recommended: 8

Hydrophobic Effect
 Know the difference between hydrophilic and hydrophobic tendencies
o Hydrophilic – tending to dissolve in water; ionic (or charged substances) and (un/charged) polar substances
o Hydrophobic – tending to not dissolve in water
 Hydrophobic interactions – attractions b/w nonpolar molecules; examples include hexanes and alkanes.
 Associate with each other – not with water
 Understand the nature of amphipathic molecules
o Amphipathic – molecules that contain both hydrophilic and hydrophobic regions
 EX: sodium palmitate is polar via the charged carboxyl group and nonpolar via its long hydrocarbon tail
 Considered water insoluble b/c its mostly nonpolar
o There are degrees of both polarity and non-polarity
 The greater the nonpolar surface area, the more nonpolar the compound
o How lipids can associate as micelles or membranes and what determines the nature of their association in an
aqueous environment
 An amphipathic molecule that is mostly hydrophobic in surface area tends to aggregate together in various
ways depending on the molecule’s geometry
 Fatty acids associate to form spherical arrangement via micelles – nonpolar tails aggregate and are
buried inside away from water while the polar head groups associate on the head surface in direct
contact w/ water’s solvent molecules.
o As a result, amphiphiles can form spherical micelle, a particle w/ solvated surface and
hydrophobic core.
o They may also form a sheet such as lipid bilayers- hydrophobic core sandwiched b/w
hydrated polar surfaces.
o One-tailed lipids tend to form micelles while two-tailed lipids form bilayers.
 Formation shape depends on the attraction between temporary and induced dipoles
 Nonpolar regions are involved in interactions due to induced dipoles
o The interaction of biomolecules is related highly to the hydrophobic effect.
o Benefits of lipid associations into membranes
 Know how to recognize classes of molecules based on hydrophobicity (polarity)
 Recognize that the hydrophobic effect is based mainly on changes in entropy – spontaneous associations
o In order to mix oil and water, free energy must be added to the system
 The free energy barrier to the solvation process depends on the entropy term (∆𝑆) b/c when a hydrophobic
molecule is hydrated, it become surrounded by a layer of waters molecule that cannot participate in normal
hydrogen bonding. Instead, they must align themselves so that their polar heads are not oriented towards
the nonpolar solute.
 This constraint on the structure of water represents a loss of entropy in the system b/c now the
highly mobile water molecules have lost some of their freedom to rapidly form, break, and reform
hydrogen bonds with other water molecules.
o The aggregation of nonpolar molecules in water –
 The individual hydration of nonpolar molecules decreases the entropy b/c the hydrating water molecules
are not free to form hydrogen bonds
 Aggregation of the nonpolar molecules increases the entropy of the (polar) water molecules b/c the # of
water molecules required to hydrate the aggregate solutes is less than the # of water molecules required to
hydrate the dispersed solute molecules.

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Chapter 2: Water: The Solvent for Biochemical Reactions
 This increase in entropy accounts for the spontaneous aggregation of nonpolar substances in water.
 The hydrophobic effect – the exclusion of nonpolar substances from an aqueous solution
o The nonpolar molecules do not experience any additional attractive force among themselves; they aggregate only b/c
they are driven out of the aqueous phase by the unfavorable entropy cost of individually hydrating them.

Hydrogen Bonding
 Water has unique properties for a molecule its size such as a very high boiling point and melting point.
 Understand the basic principles of hydrogen bonds
o Hydrogen bonds – result from noncovalent attractions between dipoles w/ one dipole as a donor & one as an
acceptor
 The (+) dipole is a H atom covalently bonded to a highly electronegative donor (hydrogen bond donor)
 The (-) end of the other dipole is also electronegative and contains a lone pair of electrons (hydrogen bond
acceptor)

o What contributes to a strong H-bond versus a weak one?
 A linear alignment results in a greater overlap of Van der Waal’s radii = shorter bond length which is
stronger by definition
 Nonlinear – weaker bond
o Electronegative element covalently bonded to H atom and electrostatically attracted to 2 nd H atom
 Understand the molecular structure of water
o What makes it a polar molecule?
 Polar solute (such as alcohol, carbonyl, amine) can serve as a donor or acceptor of H bonds
 They can form H bonds with water and participate in nonspecific dipole-dipole ineractions
 Acceptor to alcohol, donor to ketone, or an acceptor to an amine group.
o Hydrogen fluoride and ammonia can form hydrogen bonds
 Each of their structures contains the required donor and acceptor atoms
 HFl – one H donor (as a H bond) and 3 (lone pair) acceptors on fluorine
 NH3 – three H donors (i.e. hydrogen bonds) and one acceptor (lone pair) on nitrogen
o Water is optimized for H bonding w/ 2 acceptors via the two lone pairs on Oxygen and 2 donors via the 2 H bonds
 This optimum arrangement makes it the universal solvent
o The tetrahedral arrangement around Oxygen contributes to the unique bonding properties of water
 Due to the two lone pairs around Oxygen, the bond angles are 104.3 degrees
 Ice or solid water has a lower density as water as a liquid
 Thus, the H bonding network is more restricted, leading to a more opened and less densely packed
arrangement of H bonds than liquid water
o Unique: water’s solid form is less dense than its liquid form letting ice float
 Understand the formation of H-bonds in water in liquid and solid form
o What contributes to the surface tension of water?
o Why is solid water less dense than the liquid form?
 Be able to recognize H-bond donors and acceptors
 Know the significance of hydrogen bonds in biomolecules
o Hydrogen bonds are weaker than covalent bonds but still have strong effect on physical properties
 Compared to molecules of similar size like CH4 or NH3, water has a super high boiling and melting point
o H bonding stabilizes 3D structures of molecules such as proteins, DNA, and RNA

 Hydrogen bonds are usually bonded to electronegative elements – N, O, or S atoms – which function as hydrogen acceptors.
o Thus, water can form hydrogen bonds not just with other water molecules but with a wide variety of other
compounds that bear N-, O-, or S- containing functional groups.
 These functional groups can form hydrogen bonds among themselves such as in base pairing DNA.
Review Exercises Recommended: 11, 13, 15, 17, 18

Acid, Bases and pH


 pH is a measure of the acidity of a solution – a solution with a lower pH is more acidic.
 Know the definition of a Bronsted acid/base
o Bronsted Acid – molecule that behaves as a proton donor
o Bronsted Base – molecule that accepts a proton
 Know the concept of acid strength and how to quantify it
o Acids are compounds that dissociate to release H ions (or protons) and its
conjugate base (A--) when dissolved in aqueous solution.
 Acid strength is characterized by the acid dissociation constant
(KA)

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Chapter 2: Water: The Solvent for Biochemical Reactions
 KA describes the ratio of dissociated to undissociated forms
o As KA increases, acid strength increases; high K A = low pKa
 This equation shows the participation of water – water accepts the proton to form hydronium ion

 Principles of spontaneous dissociation of water


o Ionization constant of water – KW
 Water is considered a weak acid: it can dissociate into H ion + OH
 The molar concentration of pure water is 55.5 M
 Be able to use ionization constant of water to determine concentration of either H + or OH-
o KW – a measure of the tendency of water to dissociate into ions
 The concentration of un-ionized water multiplied by KA = KW
 Represents the product of the concentrations of the ionized species: [H] x [OH] = KW
 KW is determined by measuring [H] of pure water
 Water is a monoprotic acid; thus, [H] = [OH]
 Understand principles of pH scale and how to determine pH from [H +] and vice versa
o pH = -log10[H]
 An increase of pH by 1 unit means a 10-fold increase (10x) in hydrogen ion concentration [H]
 Neutral = 7
 The tendency for a proton to dissociate from an acid is expressed as a pK value.
 Understand concept of acid dissociation constant and pK value
o pH at which group is ½ ionized
o Be able to calculate pKa from Ka and vice versa
 pKa = -log10 KA
 A greater KA = stronger acid; as KA increases pKa decreases
o The lowest pKa indicates the strongest acid.
 Calculate the hydrogen ion concentration, [H+], for saliva (pH 6.5). Express answer in scientific notation.
o [H+] = 10-pH = 10-6.5 = 3.2 x 10-7 M
 Calculate the hydroxide ion concentration, [OH-], for saliva (pH 6.5). Express answer in scientific notation.
o KW = 1 x 10-14 M = [H+] x [OH-] = (3.2 x 10-7) x [OH-]
 [OH-] = 3.2 x 10-8 M
 What is the pH of a solution of 1.0 x 10-9 M HCl? Express answer as a whole number (no decimals).
 The HCl is a strong acid and dissociates completely. This means that the concentration of hydrogen ions contributed by the
HCl is 1.0 x 10-9 M. But the concentration of the hydrogen ions contributed by the dissociation of water is 100-fold greater
than this: 1.0 x 10-7 M. The concentration of the hydrogen ions contributed by the HCl is negligible in comparison.
Therefore, the pH of the solution is equal to 7.0. Note that this demonstrates that water, itself, is a buffer!
o From H2O: 1 x 10-7 M
o From HCl: 1 x 10-9 M or 0.01 x 10-7 M
o Sum: 1.01 x 10-7 M
o pH = - log (1.01 x 10-7 M) = 6.9957  7.0

Review Exercises Recommended: 19, 21, 22, 23, 25


Titration Curves of Acids – pg 40
 Be able to use Henderson-Hasselbalch equation in acid-base chemistry problems
 Understand the concept of an equivalence point and how to interpret a titration curve
o Titration – measured amounts of base added to acid
 Equivalence point (EP) – point in titration at which enough based is added to neutralize the acid
 pKa – halfway point in acid-base titration in which ½ the solution is ionized:
 At the halfway point, pH = pKa, which means that [HA] = [A--]; the acid is ½ protonated
 pH < pKa – the acid is more protonated; [HA] > [A--]
 pH > pKa – the acid is more deprotonated; [A--] > [HA]
o Be able to recognize the point on the curve related to the equivalence points and to pKa
 Understand the concept of polyprotic acids and how to recognize them
o Know the general trend of pKa values and the reason for that trend
 Henderson-Hasselbalch equation relates the pH of a solution to the pK of an acid and the concentration of
the acid and its conjugate base.
 When the pH of a solution is equal to the pK of an acid, the acid is ½ dissociated.
 Be able to determine if group will be charged or uncharged at given pH
o Based on pK value

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Chapter 2: Water: The Solvent for Biochemical Reactions
 At the start point (before base is added), the acid is present mainly in its CH 3COOH form. As small amounts of base are
added, protons dissociate until, at the midpoint of the titration (where pH 5 pK ), [CH3COOH] 5 [CH3COO2].
o The addition of more base causes more protons to dissociate until nearly all the acid is in the CH 3COO2 form (the
end point).
o Within one pH unit of the pK, additions of acid or base do not greatly perturb the pH of the solution

Groups of Acids
 Understand the principles and properties of polyprotic acids
o Monoprotic acid – release 1 H+ ion and have 1 Ka and pKa
o Diprotic acids – release 2 H+ ion and have 2 Ka and pKa
o Polyprotic acids – release more than two H+ ion
 Phosphoric acid is a polyprotic acid, with 3 protons to donate
o As each proton is released, the corresponding pKa
values increase because the ionized form becomes
more and more negative.
 Thus, it becomes harder and harder to
stabilize the additional negative charges.
 For each of the 3 pKa values, there is a corresponding acid and conjugate based pair.
 Influence of pH on enzymatic activity –
o Each enzyme – pepsin, trypsin, lysozyme – have a pH range of activity
 Protein activity can rapidly change as pH changes; pH range is critical in biological systems.
 Know the general trend of pKa values for a polyprotic acid and why

Buffers: Solution and Mechanism


 Buffers function based on the nature of weak acids and their conjugate bases that compose buffer.
o If a source of extra hydrogen or hydroxide ion is added to a buffer solution, it reacts with buffer components and is
neutralized. This keeps the pH much more stable than if the same acid or base had been added to an unbuffered
system.
 Understand principles of buffers
o Buffers resist change in pH when a strong acid or base is added BUT only if added in small to moderate amounts
o Buffer always contain and weak acid/conjugate base pair
 [Buffer] = [HA] + [A]
 EX: acetic acid (CH3COOH) + acetate (CH3COONa)
o Carbonic Acid (H2CO3) + bicarbonate (NAHCO3)
o Dihydrogen phosphate (NaH2PO4) + hydrogen phosphate (Na2HPO4)
 The acid and conjugate base in each pair differ only by one proton (minus 1H +)
 Be able to recognize a weak acid/conjugate base pair and distinguish between them
 Le Chatelier’s principle – if stress is applied to a system at equilibrium, the system will shift to relieve stress
o When H is added (strong acid) to a buffer system, stress is added to a reaction: HA <-> H + A
 The released protons of the added strong acid react with the conjugate base.
 This forces the equilibrium towards the formation of HA or the weak acid
o Equilibrium shifts towards the weak acid and NOT the conjugate base.
o Buffers can neutralize the addition of a strong acid or strong base in limited amounts – partial dissociation
 Understand effect of adding strong to weak acid and strong to weak base
o Know how to calculate changes in pH when strong acid/base added to buffer (3m 44s)
 A phosphate buffer is prepared with KH2PO4 at 0.02 M and K2HPO4 at 0.03M. What is the concentration of phosphate
buffer? Express answer to two decimal places.
o The simple solution is that the total concentration of buffer is equal to the sum of the concentrations of acid
and conjugate base, hence:
 [buffer] = 0.02 + 0.03 = 0.05 M
 If you have 100 mL of a 0.10 TRIS buffer (pKa 8.3) at pH 8.3 and you add 3.0 mL of 1.0 M HCl, what will be the new pH?
Express answer to one decimal place.
o Moles of buffer: 0.1 L x 0.1 M (mol/L) = 0.01 moles
o pH = pKa, so moles A- = moles HA
o moles A- = 0.005 = moles HA
o Moles of acid added: 0.003 L x 1.0 M HCl = 0.003 moles H +
 H + A-  HA
+

 Because of the stoichiometry, the moles of acid added will decrease the amount of conjugate base and increase the
amount of weak acid to the same extent
o New moles A- = 0.005 – 0.003 = 0.002
o New moles of HA = 0.005 + 0.003 = 0.008

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Chapter 2: Water: The Solvent for Biochemical Reactions
[A− ] 𝟎. 𝟎𝟎𝟐
pH = p𝑲a + 𝐥𝐨𝐠 = 𝟖. 𝟑 + 𝐥𝐨𝐠 ( ) = 𝟕. 𝟕
[HA] 𝟎. 𝟎𝟎𝟖
Review Exercises Recommended: 30, 31, 33, 35, 37, 41, 43, 44, 47, 51
Buffer Selection
 Understand the principles of buffering capacity
o Effective buffering range – how much strong acid or base can be added without significantly altering pH
 The midpoint – or inflection point – is reached when ½ of the acid had been titrated or converted to
conjugate base.
 At the inflection point, the concentration of acid and conjugate base are equal: [HA]=[A --]
 There is small pH changes in the vicinity of the inflection point of the titration curve.
 Little change in relative abundance if the buffering capacity holds true for pH = pKa +/- 1
o Know that capacity increases with concentration of components
 1 pH unit represents a 10-fold change in hydrogen ion concentration
 If the pH changes by 2 units, the concentration changes by 100: 10 2 = 100
 Know the criteria for buffer selection
o Find a buffer solution who’s pKa value is the closest match to the target pH
 Buffer solutions maintain an about constant pH value at values near the pKa of the acid
o Buffer capacity = measure of the amount of acid or base that can be absorbed by a buffer w/ little changes in pH.
 The buffering capacity increases with greater concentrations of weak acid and conjugate base.
o In summary, favorable criteria for selecting a buffer include –
 Suitable pKa and suitable concentration of the buffer
 No interference with reaction or with experimental assay
 Suitable ionic strength of buffer
 No precipitation of reactants or products
 Nonbiological nature of buffer

Review Exercises Recommended: 53, 55

Buffer Capacity and Application


 Know the general method of buffer preparation in the lab
o Start with the weak acid, [HA] and add a strong base (NaOH) until target pH is reached
o May also begin with a conjugate base [A] and add strong acid (HCl) until target pH is reached
 Know the two main buffer systems in living organisms – in vivo (inside living body)
o Phosphate buffer is the principle system within cells
 H2PO4--/HPO42—has a pKa of 7.20.
o Carbonate buffer is the principle system in blood – based on the dissociation of carbonic acid
 H2CO3 has a pKa of 6.37
o Principles of buffering with bicarbonate and CO2
 Carbon dioxide is the waste product associated in aerobic metabolism.
 It can dissolve in water to give carbonic acid
o pKa of carbonic acid is about 6.4 while blood pH is 7.4; this means that carbonic acid
will readily dissociate to its conjugate base form, bicarbonate.
 Despite being a spontaneous reaction, the conversion of CO2 to bicarbonate is enhanced by the
catalyst, carbonic anhydrase.
o Buffer systems in vitro – outside the living body
 EX: buffer system based on tris (hydroxymethyl) aminomethane (TRIS).
 Know the concept of zwitterions
o Nonbiological buffers are often zwitterions – or compounds that have both (+) and (-) charge.
 Beneficial b/c they are less likely to interfere in biochemical reactions than other naturally-occurring
buffers.
o ALL living systems operate within a narrow pH range
 Therefore, they must all be buffered in some way: pH always matters.
 Must apply principles related to pH and pKa to almost all biological molecules and systems.

Review Exercises Recommended: 60