Property Relationships Acid-Base Chemistry W

109, Structure & Properties, Acid-Base

CHEM 109, Lecture 1 Structure – Property Relationships Acid-Base Chemistry  McMurry & Begley (M&B) Chapter 1.1-1.2 (posted on CHEM 109 website)

CONCEPT MAP: CHEMICAL STRUCTURE & PROPERTY RELATIONSHIPS WHAT DO WE KNOW WELL & WHAT COULD WE KNOW BETTER?

The intention of this exercise is to figure out your current knowledge of the relationship between chemical structures and properties. Perhaps more importantly, we want to identify misconceptions or gaps in knowledge. Learning that you don’t understand something as well as you thought is actually a good thing!

This will be based on your knowledge and, eventually, that of your peers. No outside resources such as cell phones, notebooks, textbooks, etc. are necessary.

Before Class: Cut out each term on page E1-3 to create a set of cards. Begin to categorize and relate the fundamental general chemistry terms to each other by moving the term cards around. Brainstorm your current understanding of each term on a separate sheet of paper. Draw structures and/or figures to exemplify the term where appropriate (this is appropriate for most terms).

Create a concept map (example on next page) with these terms – use the cards, write the terms by hand, or use a digital format such as ThinkSpace or Mindmeister. Add terms and links as necessary to complete your map. There are many, many ways to organize and describe these terms. Do what make sense to you!

I can’t stop you from looking up terms on your own, but I’d recommend avoiding this as much as possible. Searching for and reproducing someone else’s definition is not nearly as useful as creating your own. If there’s anything you don’t know – that’s ok! Leave the card blank. Maybe you’ll remember it tomorrow or when you get to class.

In Class: Instructors will facilitate rotations for you to discuss parts of your concept map and collaborate with your peers to build a new one. Think about how you’ll share your ideas to your classmates on the first day of class.

Quick reference to the terms: Intramolecular Lewis structure Boiling Polar Forces Skeletal structure Ionic Bond Melting Non-polar Hybridization Covalent Bond Dissolve Nucleophile Intermolecular Molecular Geometry Dissociate Electrophile Forces Bond Polarity Hydrogen bond Salt Mechanism

Molecular Polarity London Dispersion Hydrocarbon Arrow Pushing Dipole Dipole-Dipole Solubility Chemical Reaction Electronegativity Ion-Dipole Alcohol Physical Change

L1-1 109, Structure & Properties, Acid-Base

L1-2 109, Structure & Properties, Acid-Base

Pre-class assignment: Color each column (see title), cut into cards, make concept map Column 1 - Blue Column 2 - Red Column 3 – Green Column 4 - Yellow

Intramolecular Lewis structure Boiling Polar Forces

Skeletal Ionic Bond Melting Non-polar structure

Hybridization Covalent Bond Dissolve Nucleophile

Molecular Intermolecular Dissociate Electrophile Geometry Forces

Bond Polarity Hydrogen bond Salt Mechanism

Molecular London Hydrocarbon Arrow Pushing Polarity Dispersion

Chemical Dipole Dipole-Dipole Solubility Reaction

Electronegativity Ion-Dipole Alcohol Physical Change

L1-3 109, Structure & Properties, Acid-Base

L1-4 109, Structure & Properties, Acid-Base

ACID-BASE CHEMISTRY

Rulz to Live By Bronsted-Lowry Lewis (BL) Acid Base

 pKa = - log Ka = AFFINITY OF AN ACID FOR ITS PROTON

 eqm favors the weaker acid

Acid Dissociation Equation: HA 

Ka = pKa =

What does it mean if Ka > 1? If Ka < 1? If Ka = 1?

ARROW-PUSHING = the language / symbology of this class!

What do arrows push? What are the possible outcomes of arrow pushing?

ELECTRON RICH TO ELECTRON POOR

Identify the acid, base, conjugate base, conj. acid, and direction of equilibrium (eqm)

Draw proper Lewis structures & mechanism for the reaction above

L1-5 109, Structure & Properties, Acid-Base

Organic Acid-Base Reactions

Amino acid residues = acids & bases in enzyme active sites:

pKa’s to Memorize

Approximating pKa’s: Into which pKa family does each compound belong?

HO NH2

Norepinephrine

L1 & L2 HW “due” in discussion next week (quiz directly from HW) – assignment online

Next time: Electrophilic Add’n & Substitution Reaction Mechanisms

L1-6 109, Binder E-philic Add’n / SN1 & SN2 CHEM 109, Lecture 2 Mechanism Review 1. Electrophilic Addition (E-philic Add’n) 2. Nucleophilic Substitution (SN1 & SN2) * Given starting materials and either product(s) or name of mechanism, you should be able to complete the mechanism and/or draw the product(s).

MECHANISM REVIEW

1. Electrophilic Addition to Alkenes

E-philic Add’n in Synthesis: Acid-Catalyzed Hydration of Alkenes

E-philic Add’n in Biology: Biosynthesis of -terpineol

OP O 3- 2 6 PP i Intramolecular Electrophilic Addition

Linalyl diphosphate

Carbocation Rearrangement H2O H2O

O H H OH -Terpineol

L2-1

109, Binder E-philic Add’n / SN1 & SN2 2. Nucleophilic Substitution

SN1 or SN2

2A. Unimolecular Nucleophilic Substitution (SN1) Mechanism

SN1 in Synthesis (8L Lab Practical):

SN1 in Biology: Biosynthesis of geraniol, rose oil component

L2-2

109, Binder E-philic Add’n / SN1 & SN2

2B. Bimolecular Nucleophilic Substitution (SN2) Mechanism

SN2 in Williamson ether synthesis (McMurry Chapter 18)

SN2 in Biology: Synthesis of Adrenaline Hint: the most basic atom is also the best nucleophile!

Next time…  Carbonyl Mechanisms: McMurry & Begley (M&B) Chapter 1.5-1.7

Next week in discussion…  Open notebook quiz directly from week 1 HW (posted online) o Take a few days or at least sleep on it before checking the solutions online! L2-3

109, Binder E-philic Add’n / SN1 & SN2

L2-4

109, Binder Nuc Add’n to Ald / Ket CHEM 109, Lecture 3 3. Nucleophilic Addition Reactions to Aldehydes & Ketones (Nuc Add’n) A. Alcohol Formation B. Imine (Schiff Base) Formation C. Acetal Formation D. Conjugate (Michael) Addition * Given starting materials and either product(s) or name of mechanism, you should be able to complete the mechanism and/or draw the product(s).

CARBONYL MECHANISM REVIEW

The New Guy: Michael Addition (AKA conjugate addition, AAKA 1,4-addition)

Another new guy: Claisen condensation (lecture 4)

L3-1 109, Binder Nuc Add’n to Ald / Ket 3. Nuc Add’n Rxns to Aldehydes & Ketones

3A. Alcohol Formation… Synthesis: Sodium borohydride reduction of acetone

1. NaBH + O 4 2. H2O, H

alkoxide

Synthesis: Grignard addition to acetone

+ O 1. CH3MgBr 2. H2O, H

alkoxide

Nuc Add’n in Biology: Fatty acid synthesis

3B. Imine (Schiff Base) Formation

Synthesis: Treatment of acetone with ammonia

L3-2 109, Binder Nuc Add’n to Ald / Ket 3B. Imine (Schiff Base) Formation (cont’d)

Biosynthesis of Amino Acids:

2- O3PO

- N CO2 HN OH

3C. (Hemi)Acetal Formation

Synthesis: Treatment of acetone with ethanol

+ H+ H H O O :B H2O hemiacetal

H O O O

Hemiacetals in Nature: Carbohydrates

L3-3 109, Binder Nuc Add’n to Ald / Ket 3D. Conjugate 1,4 (Michael) Addition

Synthesis

O R2CuLi O R

enolate

Biology: Citric Acid Cycle

Apply the template mechanism from page 1 and keep track of those protons!

Next time… Nucleophilic Acyl Substitution & Carbonyl Condensation Reactions (aldol & Claisen) - M&B Chapter 1.6-1.7

L3-4 109, Binder Nuc Add’n to Ald / Ket

L3-5 109, Binder NAS / aldol & Claisen Condensation CHEM 109, Lecture 4 4. Nucleophilic Acyl Substitution (NAS) 5. Carbonyl Condensation A. Aldol Condensation B. Claisen Condensation * Given starting materials and either product(s) or name of mechanism, you should be able to complete the mechanism and/or draw the product(s).

4. Nucleophilic Acyl Substitution (NAS)

Synthesis: Fischer Esterification – Fruity Fragrances

BIOREACTIVITY SERIES toward NAS

NAS in Biology: Glycolysis (first step)

CHO H OH HO H H OH ADP H OH 2- CH2OPO3

Glucose-6-phosphate

L4-1 109, Binder NAS / aldol & Claisen Condensation 5. Carbonyl Condensation Reactions

Enolate Ions

5A. Aldol Condensation

Draw that mechanism in one step:

Retro-aldol Reaction

H O O + NaOH H O H O enolate

Retro-aldol: Glycolysis

2- CH2OPO3

C O 2- CH2OPO3 CHO HO H aldolase C O + H OH H OH CH OH CH OPO 2- H OH 2 2 3 Dihydroxyacetone Glyceraldehyde- CH OPO 2- 2 3 phosphate 3-phosphate Fructose-1,6- (DHAP) (GAP) bisphosphate (F1,6P) Re-draw F1,6P below and propose a one-step mechanism…

L4-2 109, Binder NAS / aldol & Claisen Condensation 5B. Claisen Condensation

Draw that mechanism in two steps!

Claisen Condensation in Biology: Lipid Biosynthesis

Retro-Claisen Reaction:

L4-3 109, Binder NAS / aldol & Claisen Condensation Carbonyl Reaction Overview

Nucleophilic Addition Nucleophilic Acyl Substitution (NAS) to Aldehydes & Ketones with Esters, Thioesters, Carboxylic Acids, Amides

Aldol Condensation Claisen Condensation

Next time…Elimination, Redox, pKa and Amino Acids

L4-4 109, Binder Elimination, Redox, Acids & pKa’s CHEM 109, Lecture 5 Mechanism Review 6. Elimination Reactions 7. Oxidation & Reduction Reactions Polyprotic Acids & pKa o Relationship between (pKa of acid) and (pH of solution) o Titration of amino acids ** Know the full structures & abbreviations of the 20 common amino acids (p 7) **

6. Elimination Reactions What is eliminated?

E2 E1 E1cB

Elimination in synthesis…

strong base E2 Br

weak base E1 - Br Br carbocation

H strong base E1cB O Br Br- enolate

Elimination in Biology – Fatty Acid Synthesis

L5-1 109, Binder Elimination, Redox, Acids & pKa’s 7. Oxidation and Reduction (Redox) Reactions

Reduction in Synthesis

Redox in Biology…

REDUCING AGENTS: NADH & NADPH

OXIDIZING AGENTS: NAD+ & NADP+

L5-2 109, Binder Elimination, Redox, Acids & pKa’s Polyprotic Acids & pKa

How does an acid’s pKa relate to the pH of a solution of that acid?

HA  H+ + A- pH = pKa + log [A-] [HA]

pH < pKa pH = pKa pH > pKa

Titration of Phosphoric Acid (pKa1 2.1; pKa2 7.2; pKa3 12.3)

What’s the charge of the dominant ionic phosphate species at pH 1? pH 5? pH 7.4? pH 13?

Amino Acids – which one looks weird to you?

L5-3 109, Binder Elimination, Redox, Acids & pKa’s Titration of a L-Methionine, a neutral amino acid

pI = Isoelectric point – pH at which the molecule is neutral (not necessary neutral @ pH 7) - Calculate by taking the average of the 2 pKa’s on either side of neutral molecule

Titration of L-Glutamic Acid, an acidic amino acid

Titration of L-Histidine, an interesting basic amino acid

L5-4 109, Binder Elimination, Redox, Acids & pKa’s Environmental pH effects the charge of amino acids…

pH 1 pH 3 pH 5 pH 7 pH 9 pH 11

Met

Glu

His

Lys

Tyr

Next time…Biosynthesis of select amino acids

L5-5 109, Binder Elimination, Redox, Acids & pKa’s

The 20 Common Amino Acids – pKa’s and Isoelectric Points (pI)

Name pKa1 pKa2 pKaR pI

Alanine 2.34 9.69 - 6.01

Arginine 2.17 9.04 12.48 10.76

Asparagine 2.02 8.80 - 5.41

Aspartic Acid 1.88 9.60 3.65 2.77

Cysteine 1.96 10.28 8.18 5.04

Glutamic Acid 2.19 9.67 4.25 3.22

Glutamine 2.17 9.13 - 5.65

Glycine 2.34 9.60 - 5.97

Histidine 1.82 9.17 6.00 7.59

Leucine 2.36 9.60 - 5.98

Isoleucine 2.36 9.60 - 5.98

Lysine 2.18 8.95 10.53 9.74

Methionine 2.28 9.21 - 5.74

Phenylalanine 1.83 9.13 - 5.48

Proline 1.99 10.60 - 6.30

Serine 2.21 9.15 - 5.68

Threonine 2.09 9.10 - 5.60

Tryptophan 2.83 9.39 - 5.89

Tyrosine 2.20 9.11 10.07 5.66

Valine 2.32 9.62 - 5.96

* You do not need to memorize these pKa’s. You should know how to use them when given. *

L5-6 109, Binder Elimination, Redox, Acids & pKa’s

NEUTRAL AMINO ACIDS

NON-POLAR AMINO ACIDS

+ - + - + - + - + - H3N CO2 H3N CO2 H3N CO2 H3N CO2 H3N CO2 L-Glycine L-Alanine L-Valine L-Leucine L-Isoleucine (Gly, G) (Ala, A) (Val, V) (Leu, L) (Ile, I)

HN S - N CO2 + - + - + - + H3N CO2 H3N CO2 H3N CO2 H2 L-Phenylalanine L-Tryptophan L-Proline L-Methionine (Phe, F) (Trp, W) (Pro, P) (Met, M)

POLAR AMINO ACIDS

H N O O 2 HO HO H2N + - H3N CO2 + - + - + - H3N CO2 H3N CO2 H3N CO2 L-Serine L-Threonine L-Asparagine L-Glutamine (Ser, S) (Thr, T) (Asn, N) (Gln, Q)

HO BASIC AMINO ACIDS HS H H2N N N + - + - H3N CO2 H3N CO2 NH + 2 N L-Tyrosine* D-Cysteine* H (Tyr, Y) (Cys, C) + - + - H3N CO2 H3N CO2 L-Arginine L-Histidine (Arg, R) (His, H) ACIDIC AMINO ACIDS

- + CO2 H3N - O2C

+ - + - + - H3N CO2 H3N CO2 H3N CO2 L-Aspartic Acid L-Glutamic Acid L-Lysine (Asp, D) (Glu, E) (Lys, K)

L5-7 109, Binder Elimination, Redox, Acids & pKa’s

L5-8 109, Binder Amino Acid Biosynthesis CHEM 109, Lecture 6 Amino Acid Synthesis  Organic Synthesis – Reductive Amination - McMurry 26.3  Biosynthesis of Asparagine and Proline – not in the textbook, use lecture notes

Reductive Amination

Applied to racemic amino acid synthesis:

Nucleophilic Acyl Substitution (NAS)

L6-1 109, Binder Amino Acid Biosynthesis Biosynthesis of Proline

**Each step takes place in the active site of an enzyme, which contains all the acids (H+) and bases (:B) necessary to complete each transformation (more on that later). Until then, feel free to use H+ and :B as needed.**

Always consider physiological pH when drawing intermediates and products. - Nitrogen is usually protonated (+), sometimes neutral, NEVER (-) - Carboxylic acids should be deprotonated (-), sometimes protonated / neutral - Phosphates have 2 (-) oxygen atoms per P - Alcohols should always be protonated / neutral

Formation and NADH Reduction of Phosphoester

Intramolecular Reductive Amination

L6-2 109, Binder Amino Acid Biosynthesis Biosynthesis of Asparagine

Hydrolysis of Glutamine

Phosphate Transfers with ATP

Amide Formation

L6-3 109, Binder Amino Acid Biosynthesis Exam 1 Overview Anything in the lecture notes or HW is fair game!

- Structure – Property Relationships

o Link term to definition or figure o Ex. What happens structurally when ethanol boils? o Ex. What happens when NaCl dissolves? When sugar dissolves?

- Acid-Base Chemistry o Know the pKa’s from lecture 1, use to predict pKa of new molecule o Draw products of acid-base reaction, predict direction of equilibrium

Be ready to draw any the following mechanisms given starting materials and either the name of mechanism or the product(s). Formal charges must be clearly represented, where appropriate. The exact start and end point of arrows is important!

- Electrophilic Addition to Alkenes

- SN1 & SN2

- Nucleophilic Addition to Aldehydes & Ketones

- Nucleophilic Acyl Substitution (NAS)

- Aldol & Claisen Condensation Reactions (forward and reverse)

- E1, E2, & E1cB

- Reduction with NADH & Oxidation with NAD+

o Be able to draw the core structure of NADH if given NAD+ & vice versa

- Polyprotic acids: given pKa’s, draw all ionic forms over given pH range

- Amino Acid Synthesis

o Similar or identical to examples in today’s notes or HW!

L6-4 109, Binder Peptides & Enzymes CHEM 109, Lecture 7 Peptides – McM 26.9 o Biosynthesis – Ribosomes Enzymes – Nature’s Reaction Factories! – McM 26.10-11

PEPTIDES

Tripeptide template: [ (Nitrogen) – (Carbon w Side Chain) – (Carbonyl) ]…

Primary (1) Structure 

Secondary (2) Structure 

Tertiary (3) Structure 

Quaternary (4) Structure 

L7-1 109, Binder Peptides & Enzymes

Enzymes

E or Enz = Enzyme; S = Substrate (Reactant); P = Product

Reactions Mechanisms & the Active Site

- Reactants = Substrates

- Reagents = Cofactors - small organic molecules; not catalysts / not regenerated

o Ex. Glycolysis requires NAD+

- Amino acid residues = side chains off enzyme’s peptide backbone

o Acids

o Bases

o Covalently bind substrate

- Stabilizing Factors hold substrates and cofactors in place via IMF’s!!

H-bonding Ion-Dipole

H O H H O H O H H H O H H O

CH2O H

L7-2 109, Binder Peptides & Enzymes Active Site Example: Conjugate Addition of Water

Active Site Example: Citrate Synthase (Citric Acid Cycle)

L7-3 109, Binder Peptides & Enzymes Active Site Example: Oxidation of an Alcohol

Next time…Carbohydrates & Polysaccharides

L7-4 109, Binder Peptides & Enzymes

Table 26.2 (McM) Classification of Enzymes* Class Some Subclasses Function Oxidoreductases Dehydrogenases Introduction of double bond Oxidases Oxidation Reductases Reduction

Transferases Kinases Phosphate transfer Transaminase Amino transfer

Hydrolases Lipases Ester hydrolysis Nucleases Phosphate hydrolysis Proteases Amide hydrolysis

Lyases Decarboxylases Loss of CO2 Dehydrases Loss of H2O

Isomerases Epimerases Isomerization of chiral center

Ligases Carboxylases Addition of CO2 Synthetases Formation of new bond *You are not expected to memorize these, but they can be useful clues in determining the type of reaction take place since most names are pretty self-explanatory!

L7-5 109, Binder Carbs, Polysaccharides, Plastics CHEM 109, Lecture 8 Monosaccharide Nomenclature o Fischer projections (no rotation) and o Hemiacetals: Ring-closing of D-monosaccharides Disaccharides: Formation & Hydrolysis Polysaccharides & Digestions

CARBOHYDRATES

Monosaccharide Classification

Prefix: aldo- or keto- for aldehyde or ketone, respectively

Infix: -tri-, -tetr-, -pent-, -hex-, -hept-, etc. for the number of carbons

Suffix: -ose for sugars!

Examples (more in Lecture 7 HW):

D-aldotriose L-ketopentose

Equilibrium between open and closed sugars:

Draw the C2-epimer of glucose in open and closed form (Haworth & chair):

Lots more practice in the homework!

L8-1 109, Binder Carbs, Polysaccharides, Plastics Formation of Disaccharides (Glycosidic Linkage)

Hydrolysis of Disaccharides

L8-2 109, Binder Carbs, Polysaccharides, Plastics Complex Carbohydrates: Ex. Starch

Polysaccharides Amylose (20% of starch) Amylopectin (80% of starch)

Carbon Cycle:

When you eat…

L8-3 109, Binder Carbs, Polysaccharides, Plastics Plastics: Synthetic Polymers

Name Repeating Unit Monomer Applications High-density Milk jugs, polyethylene (HDPE) insulation, pipes Low-density Packaging polyethylene (LDPE) film, insulation, flexible bottles Polypropylene (PP) Appliances, car parts

Poly(vinylchloride) Pipes, floor (PVC or V) covering

Poly(vinylidene Packaging chloride) (Saran) film

Polytetrafluoroethylene Nonstick (PTFE or Teflon) coating, stopcocks

cis-1,4-polyisoprene Tires, shoes, sports equipment

Poly (methyl Display signs, methacrylate) (PMMA) plexiglass, dentures

Polystyrene (PS) Packaging, drinking cups

Metabolism Overview (Big picture)

Next time…Glycolysis – McMurry 29.5

L8-4 109, Binder Glycolysis Phase 1 CHEM 109, Lecture 9 Glycolysis – Active site examples – types of binding, roles of co-factors & AA residues

Glycolysis - Know the structures of glucose & pyruvate. CHO H OH Phase 1 CHO HO H Phase 2 O 2 H OH 2 H OH steps 1-5 - CH OPO 2- steps 6-10 CO2 H OH 2 3

CH2OH Glyceraldehyde- Glucose 3-phosphate Pyruvate (GAP)

Phase 1 (today)

Mechanism Overview in Phase 1 of Glycolysis

- Nucleophilic Acyl Substitution - Tautomerization

- Nucleophilic Addition with Dehydration - Retro-aldol

L9-1 109, Binder Glycolysis Phase 1 Step 1 – Hexokinase active site

Step 2 – Glucose-6-Phosphate Isomerase (Tautomerizations)

Step 3 – Phosphofructokinase (nearly identical to step 1 - try on your own)

L9-2 109, Binder Glycolysis Phase 1 Step 4 – Aldolase (see HW #1.10 for simpler – not real - version) 1. Covalent binding of F-1,6-BP to active site via iminium bond to a lysine residue 2. Retro-aldol to form GAP & enaminol 3. Release of DHAP from lysine residue

Step 5 – Triose Phosphate Isomerase

Next time…Phase 2 – Profit!

L9-3 109, Binder Glycolysis Phase 1

L9-4 109, Binder Glycolysis #2, Decarb. CHEM 109, Lecture 10 Glycolysis Phase 2 Decarboxylation Overview Lecture 10 HW = re-print lecture blanks, fill in missing intermediates and mechanisms – these notes are your answer key (check webcast too)

Last time…Phase 1 left us with 2 x GAP

This time…Phase 2 – Profit!

Step 6 – GAP Dehydrogenase 1. Covalent binding of GAP to active site via thiohemiacetal bond with cysteine residue 2. Oxidation to thioester via NAD+ 3. Phosphorylation 4. Release product from active site

L10-1 109, Binder Glycolysis #2, Decarb. Step 7 – Phosphoglycerate kinase

Step 8 – Phosphoglycerate mutase

Step 9 – Enolase

Step 10 – Pyruvate kinase

L10-2 109, Binder Glycolysis #2, Decarb. Preview to fates of Pyruvate…

Decarboxylation  loss of CO2

O O TPP ylid O- TPP ylid SCoA O OH Acetyl CoA CO 2 Pyruvate CO2 Ethanol (a-keto acid)

L10-3 109, Binder Glycolysis #2, Decarb.

L10-4 109, Binder Fates of Pyruvate Fates of Pyruvate - Anaerobic metabolism – not in McMurry text 1. Lactate – enantioselective NADH reduction 2. Ethanol & CO2 (yeast) – TPP ylide binding - Aerobic metabolism (mammals) – McMurry 29.6 3. Acetyl CoA – TPP ylide binding & lipoamide transfer

Why aerobic vs. anaerobic? Glucose  Pyruvate 2 ADP  2 ATP 2 NAD+  2 NADH

1. Anaerobic Metabolism in Mammals

Other fates of pyruvate (#2-3) involve decarboxylation (-CO2)

TPP – the decarboxylation cofactor

2. Yeast anaerobic metabolism (fermentation)

a. Addition of TPP ylid to ketone b. Decarboxylation c. Protonation of enaminol d. Acetaldehyde formation & release of TPP ylid e. Reduction with NADH

L11-1

109, Binder Fates of Pyruvate Fermentation, add the arrows…

3. Aerobic Metabolism (mammals) – Pyruvate Dehydrogenase Complex

L11-2

109, Binder Fates of Pyruvate Reaction Overview

Lecture Process / Chemistry Mechanism

7 – Peptides & Carbohydrate Nomenclature

8 – Disaccharides

9 – Glycolysis #1

10 – Glycolysis #2

11 – Fates of Pyruvate

12 - Lipids

L11-3

109, Binder Fates of Pyruvate Active Site Recap

Acids Bases

Reducing Agent Oxidizing Agent

Decarboxylation Phosphate Transfer

Acyl Transfer Covalent Binding to Enzyme

Stabilizing Factors (Place-Holders)

L11-4

109, Binder Lipids CHEM 109, Lecture 12 Lipids (Reading: McMurry 27.1-3, 27.5) - Classification - Mevalonate Pathway to Isopentenyl Diphosphate (IPP) - Conversion of IPP to Terpenoids o Carbocation Rearrangements (RRGT): Hydride & Methyl Shifts

General Lipid Classifications - Fatty acids, triacylglycerols, terpenes, and steroids o Be able to identify and/or construct these given the components

Fatty Acids & Triacylglycerols

Terpenes & Terpenoids

OPP Isoprene unit Isopentenyl some Diphosphate monoterpenoids:

(-)-b-Pinene (+)-(S)-Carvone (+)-(R)-Limonene l-Menthol

Steroids

L12-1 109, Binder Lipids Mevalonate Pathway to Isopentenyl Diphosphate (IPP) Fill in the boxes! Test your knowledge of reaction names, co-factors, etc.

L12-2 109, Binder Lipids The IPP Building Block – process overview

Geranyl Diphosphate (GPP) & Farnesyl Diphosphate (FPP): Mono- and Sesquiterpenoid Scaffolds Add or follow arrows, fill in the boxes…

L12-3 109, Binder Lipids

Monoterpenoids: Biosynthesis of Citrus Oil from GPP via C+ Rearrangements Add or follow arrows, fill in the boxes…

Sesquiterpenoids: Biosynthesis of a Tobacco Component via C+ Rearrangements Add or follow arrows, fill in the boxes…

And thus concludes Exam 2 material (Lectures 6-12)!

L12-4 109, Binder Basicity of Amines; Nucleic Acids CHEM 109, Lecture 13 Nucleic Acids & Nucleotide Structure - Heterocycles – Aromaticity & Basicity - H-Bonding

Heterocycles

Rules for Aromaticity

1. There must be a ring! 2. All atoms in ring are sp2 (conjugated/resonance) 3. Huckel Rule (4n+2)

Hybridization Review + NH3 H H H S N # of electron groups Hybridization O N 4 sp3 - HO O CO2 3 sp2 Amoxicillin

HN NC N N 2 sp N Fictional Molecule

What is the hybridization of each N atom?

Which N lone pairs are involved in resonance?

Which N atoms are basic?

Are any more basic than others?

L13-1 109, Binder Basicity of Amines; Nucleic Acids Basicity of N-Heterocycles You do not need to memorize these pKa’s or heterocyclic ring structures-names, but you should develop a general understanding of relative basicity, as determined by conjugate acid stability and other factors.

Pyrrole vs. pyrrolidine: Which is the stronger base and why?

Pyridine vs. piperidine: Which is the stronger base and why?

Imidazole: Which N is basic and why?

Who’s the base? Pyrimidine Purine

L13-2 109, Binder Basicity of Amines; Nucleic Acids Nitrogen Basicity Flowchart

Use the examples on pages 1 and 2 to develop a set of criteria for N to be basic and any trends about relative basicity.

Devise a series of questions you’d ask about a new N-containing molecule to determine whether each N is basic and, if possible, rank those basic N’s by basicity. Format these questions into flow chart format.

Unrelated flow chart Ex. “Do I feel comfortable in this dress?” –yes wear it! | No ↓ Don’t wear it

L13-3 109, Binder Basicity of Amines; Nucleic Acids Nucleobases - Which H’s are available to serve as H-bond donors? - Which lone pair are available to serve as H-bond acceptors?

Nucleoside = (Nucleobase + Ribose) - H2O

Nucleotide = (Nucleobase + Ribose + Phosphate) – 2 H2O

Hydrogen Bonding in DNA / RNA - Many options for pairing; only one is naturally occurring per pair - H-bond donor (has the H) = d; H-bond acceptor (has the lone pair) = a

G-C Base Pair A-T Base Pair

NH2

N N

Adenine

Next time…nucleobase / DNA mutations, introduction to medicinal chemistry

L13-4 109, Binder Mutations, Medicinal Chemistry CHEM 109, Lecture 14 UV-Visible Spectrum & DNA Mutations Phosphodiester Formation and Cleavage Introduction to Medicinal Chemistry - Reading – Palleros (online) - Drug Design: Pharmaceutical, Pharmacokinetic, and Pharmacodynamic Phases

UV-Visible Spectrum

UVA (400 – 320 nm)

UVB (320 – 280 nm)

*UVC (280 – 100 nm)

Mutations – Thymine Dimer

What’s the deal with nitrites?

L14-1 109, Binder Mutations, Medicinal Chemistry Phosphodiester Formation

Phosphodiester Cleavage (Restriction Endonucleases)

L14-2 109, Binder Mutations, Medicinal Chemistry Medicinal Chemistry

Pharmaceuticals  substance given to alleviate symptoms or treat the cause of a disease

Potential vs. Effectiveness of a Drug Target

Administration: Enteral Parenteral (oral/rectal) (IV, intramuscular, subcutaneous, sublingual, topical, inhalation)

Barriers to drug effectiveness of a drug are broken down into 3 phases:

1. Pharmaceutical Phase

2. Pharmacokinetic Phase

3. Pharmacodynamic Phase

L14-3 109, Binder Mutations, Medicinal Chemistry Pharmaceutical Phase: Administration to Absorption Dosage form: tablet, solution, vapor - In addition to the drug itself, ‘dose’ may also include…

Potential for enzymatic degradation – what happens where?

Saliva

Stomach

Intestines

Pharmacokinetic Phase: Absorption, Distribution, Metabolism, Elimination (ADME)

Absorption into bloodstream requires drug to cross cell-membrane(s)

Structures of two antibiotics at physiological pH – in what conditions would each be absorbed?

Blood-brain barrier

Distribution into circulatory system

Metabolism – will it make it to its target receptor intact?

HYDROLYSIS = easiest metabolic process to predict (look for carboxylic acid derivatives)

Excretion

Half-life

L14-4 109, Binder Mutations, Medicinal Chemistry Pharmacodynamic Phase: drug interacts with receptor, elicits effects

Specific Drug-Receptor Interactions

Covalent Binding vs. Intermolecular Forces

Therapeutic Index, TI = LD50 / ED50

Lethal Dose, LD50 - concentration at which 50% of test subject die

Effective Dose, ED50 – dose at which 50% of patients get desired effect

Biophores – screening of 10s-1000s of potential targets (“hits”)

Pharmacophore

Toxicophore

Metabophore

Auxophore

L14-5 109, Binder Mutations, Medicinal Chemistry Identification of Pharmacophore through “derivatization of a lead” Opioid alkaloids:

What is the pharmacophore for the collection of compounds above?

Next time…-lactam antibiotics, ex. penicillin

L14-6 109, Binder Solubility Potential, -Lactam Antibiotics CHEM 109, Lecture 15 Medicinal Chemistry: Solubility Potential (Palleros – online) -Lactam Antibiotics

Solubility Potential - Hydrocarbons are insoluble in water - Adding polar functional groups increases water solubility - The more functional groups, the more carbons the molecule can contain and still be soluble

Calculate the solubility potential of morphine and its HCl salt.

L15-1 109, Binder Solubility Potential, -Lactam Antibiotics Effects of pKa on Solubility and Binding

Pharmaceutical & Pharmacokinetic Phases

- + extracellular fluid HA + H2O A + H3O

cell membrane HA

HA + H O - + cytoplasm 2 A + H3O

Pharmacodynamic Phase – binding of drug to receptor

Food for thought: how are pKa’s effected if water is not the solvent??

Receptor

Hydrophobic pocket of peptide backbone effects pKa’s (typically we think of pKa as dissociation in water, this is different!)

**Ionization states dictate whether drug can bind to receptor**

L15-2 109, Binder Solubility Potential, -Lactam Antibiotics Natural Products – broad class of naturally occurring substance, typically secondary metabolite (no essential metabolic function for the organism)

- Terpenoids (Lectures 12)

- Non-ribosomal Polypeptides (today)

- Alkaloids (Lecture 16)

- Fatty acid-derived substances & Polyketides

- Enzyme Cofactors

-Lactam Antibiotics are derived from non-ribosomal tripeptides

But first…what’s a ribosomal (normal) tripeptide look like?

For each antibiotic below, can you draw the tripeptide from which each was derived?

NH + 3 H H H S N

O N O Cephalexin (a cephalosporin)

H H H S N N O - O CO2 Penicillin G

H H - H S O2C N

+ N H NH3 O - O CO2 Isopenicillin N

L15-3 109, Binder Solubility Potential, -Lactam Antibiotics Penicillin’s Mechanism of Action: Deactivation of Bacterial Transpeptidase

Bacterial cell walls surrounded by murein, synthesized by Transpeptidase (aka penicillin-bind protein, PBP)

Next time…Morphine Day!

L15-4 109, Binder Morphine Biosynthesis CHEM 109, LECTURE 16 Alkaloid Natural Products – Opioid Family – Morphine - Pharmaceuticals, -kinetics, and –dynamics - Biosynthesis HW – Carry out the 9 starred mechanisms using acids (H+) and bases (:B) – not for credit, but for exam prep!

Poppy – Papaver somniferum – “flower of joy” - Sap from seed pod = crude opium (schedule II drug) - Central Asia - Latin America – Columbia & Mexico

Morphium – Greek god of dreams

1803 – Extraction of Morphine 10x more powerful – “miracle drug” analgesic (pain relief)

1820’s – commercial production (Merck) 1874 – Heroine synthesis from morphine 1898 – 1924 - medicinal use of heroine

DEA Controlled Substances Act (1970) “Schedules” based on medical use, abuse potential, and dependence

Schedule I No currently accepted medical use, lack of Heroin, LSD, Marijuana, accepted safety for use under medical peyote, MDMA supervision, high potential for abuse

Schedule II High potential for abuse, several psychological Dilaudid, methadone, or physical dependence oxycodone, fentanyl, codeine, hydrocodone Schedule III Less potential for abuse, moderate-to-low Tylenol with <90 mg physical dependence, high psychological codeine per dose, dependence ketamine, anabolic steroids

Schedule IV Low potential for abuse Xanax, valium

Schedule V Lower potential for abuse Cough medicine with <200mg/100mL codeine http://www.deadiversion.usdoj.gov/schedules/#define

L16-1 109, Binder Morphine Biosynthesis Morphine - Pharmaceutical Phase

- Enteral or parental – IV and inhalation (“chasing the dragon”) most common o Administered as HCl salt

Pharmacokinetics

- Adsorption – crosses membranes, including BBB - Distribution – detected in plasma after 20 min IV or 30 min oral o 40-50% reaches central nervous system - Metabolism - Subject to first pass metabolism

- Excretion - Half-life of 120 minutes

Pharmacodynamics

- Multiple opioid receptors for endogenous opioids (ex. endorphins = “endogenous morphine”) - Pain inhibition

O N N N N OH O O OEt

OH Morphine Meperidine Methodone Pharmacophore

L16-2 109, Binder Morphine Biosynthesis Biosynthesis of Morphine – select reactions

Two Tyrosine derivatives combine for first cyclization step in a process similar to reductive amination and electrophilic substitution on the aromatic ring.

Two consecutive methylations are carried out using S-Adenosylmethionine (SAM)

L16-3 109, Binder Morphine Biosynthesis (S)-N-Methylcoclaurine is converted into Salutaridine, which is reduced, acylated, and cyclized to form Thebaine.

Thebaine undergoes demethylation and reduction to form Codeinone, which is subsequently reduced to Codeine and demethylation to produce Morphine.

CHEM 109 – What have we learned?... - Acid-base chemistry - Intuitive arrow-pushing (not memorizing mechanisms!) - Amino acid, carbohydrate, lipid metabolism and/or catabolism - Enzymes, the perfect synthetic organic chemists! - Structural characteristics of DNA & RNA; mutations - Introduction to Medicinal Chemistry

Next time…Q&A – not a review session (BYOQ) Course evals help me be a better teacher – Please complete soon! o Constructive feedback – course materials, organization, etc.

L16-4