ORGANIC CHEMISTRY FOR ASPIRING PHARMACISTS
A S S T . P R O F . R A M O N C I T O G A B R I E L O . PA R A G A S , B S P H A R M , R P H P H I L I P P I N E A S S O C I AT I O N O F C O L L E G E S
OF PHARMACY
WHAT WHA T IS CARBON?
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Carbon is the head of the Carbon Family (IV-A) in the periodic table. Carbon is the basic component of ALL ORGANIC COMPOUNDS. COMP OUNDS. What then makes Carbon so special that it is the subject of interest of this course?
WHAT WHA T IS CARBON?
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Carbon is always on excited state.
Having basic knowledge of it’s location in the periodic table, let’s take a look on it’s electronic configuration to assess this property.
WHAT IS CARBON?
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Carbon is always on excited state, making it want the maximum reactions. Carbon as a par t of IV-A Family has four valence (outer) electrons; it can share all the valence electrons, forming four strong COVALENT BONDS.
WHAT IS CARBON?
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Carbon atoms can bond with one another , forming long chains and even rings. Of all other elements, carbon alone has the ability to form an immense diversity of compounds.
WHY STUDY ABOUT CARBON?
Studying the properties of carbon and the different reactions it can have with other elements is important. Why? Simple. Carbon had been an unexplainable “vital force” that puzzled many scientists centuries and decades ago.
WHY STUDY ABOUT CARBON?
Carbon has been the basic component of all the organic compounds that build you. Your cells are made up of some carbon-containing compounds. Reactions in your body cannot proceed without interference of carboncontaining compounds. The food you eat; the meat, the vegetables, the fruits they are made of carbon-containing products. The aroma of coffee, or the taste of fresh apples are all sensed because of some carbon-containing products. Even organic compounds cause you to cry, fear, laugh and fight. Why study Organic Chemistry?
Simple. Because, you’ll need it to pass your course.
GENERAL OVERVIEW
History •
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Jons Jacob Berzelius
“organic”
“Vital Force Theory” or “life-force theory” compounds ONLY originate from living things
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Friedrich Wohler
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Torbern Bergman
Ammonia + cyanic acid org vs inorg
So what is ORGANIC CHEMISTRY?
organic urea
ORGANIC CHEMISTRY VS INORGANIC CHEMISTRY Property
ORGANIC
INORGANIC
Flammability
FLAMMABLE
Not Flammable
Boiling Point
LOW
Solubility in Water Solubility in Non-polar Solvents
Types of Bonding
INSOLUBLE SOLUBLE COVALENT BOND
High
Soluble Insoluble
Ionic Bonding
Isomerism
EXHIBITS
Does not exhibit
Atoms per Molecules
SEVERAL
Few
Structure
COMPLEX
Simple
WHAT ARE ORGANIC COMPOUNDS? •
Carbon-containing compounds
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Naturally occurring; mostly of life origin, and nature based. – However, not all organic compounds are not derived from living organisms, of course. Newly discovered organic compounds were merely synthesized even derived from non-organic compounds, or products of laboratory tests. Exceptions: CO2 , H2CO3 , CO3-, CN-
NATURE OF ORGANIC MOLECULES Of all the hundred plus elements in the periodic table, Organic Chemistry is mostly concerned only for ten! Okay, so Carbon is given. The other nine are:
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Hydrogen:
H
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Carbon Group: C, Si
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Nitrogen Group: N, P
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Oxygen Group: O, S
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Halogen Group: F, Cl, Br, I
NATURE OF ORGANIC MOLECULES •
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There are about 37 million known organic molecules.
There are “rules” that nature follow that help us understand that organic molecules rest largely on understanding of small combinations of atoms. So instead of 37 million separate compounds that we study for some random reactivity, there are only about a dozen families of chemistry whose chemistry is predictable.
CARBON THE KING OF ALL ELEMENTS
CARBON: CHARACTERISTICS CATENATION: bonding successively with other carbons to form chains and rings varying in sizes
CHARACTERISTICS OF COVALENT BONDS Bond
Bond Strength
Bond Length
Bond Angle
Hybridization
C – C
340 kJ/mol
154 pm
109.5˚
sp³-sp³
C=C
610 kJ/mol
133 pm
120˚
sp²-sp²
C=C
830 kJ/mol
120 pm
180˚
sp-sp
Covalent bonds are bonds exhibiting equal sharing of electrons between atoms. These bonds are stable, and they have limitations to attractions. Condition: Atoms cannot stay close together (repulsion) and cannot go to far from one another (loss of attraction). Just the right distance. •
What can you infer from the table above?
CHARACTERISTICS OF COVALENT BONDS Given that Carbon is tetravalent, and always at excited state, take a look at the equal sharing of electrons in Methane; the most fundamental and saturated organic compound.
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DEFINING BOND LENGTH AND BOND STRENGTH
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Bond
Bond Strength
Bond Length
Bond Angle
Hybridization
C – C
340 kJ/mol
154 pm
109.5˚
sp³-sp³
C=C
610 kJ/mol
133 pm
120˚
sp²-sp²
C=C
830 kJ/mol
120 pm
180˚
sp-sp
Bond strength is the energy requirement to form a bond between two atoms. It is also the energy requirement necessary to break the bond between atoms. Bond length is the optimum distance between that enables two atoms to attract each other. Not too close, and not to far.
THE PRINCIPLE OF Bond
Bond Strength
Bond Length
Bond Angle
Hybridization
C – C
340 kJ/mol
154 pm
109.5˚
sp³-sp³
C=C
610 kJ/mol
133 pm
120˚
sp²-sp²
C=C
830 kJ/mol
120 pm
180˚
sp-sp
Remember the person that irritates you? Carbon also wants to maintain a distance to other carbons. They get irritated if they stay too close than tolerable for each other. Thus, when a chain is formed, a slight bending of bonds occur. •
Bond angle is the measure of bending that occurs shall bonding be present. The more bonds, the straighter the chain (see the C=C bond).
CARBON: CHARACTERISTICS
HYBRIDIZATION- mixing of 2 or more non-equivalent atomic orbitals to form new set of equivalent orbital TYPES: •
sp3
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sp2
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sp
HYBRIDIZATION •
sp3-sp3: single bond between atoms. The sp3 orbital is shaped long enough, giving you a long sigma bond.
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sp2-sp2: double bond between atoms.
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sp-sp: triple bonds between atoms
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All these hybridization statuses are depending on the number of valence/ outer electrons.
HYBRIDIZATION: CHARACTER S character
sp3 sp2 sp s
P Character
s
px
py
pz
25%
25%
25%
25%
≈ 33%
≈33%
≈33%
-------
50%
50%
-------
-------
100%
-------
-------
-------
Always treat the bond as a 100% character then divide. Question: Which hybrid has the least s character?, the greatest y character?
HYBRIDIZATION •
Direction: Identify the hybridization of the carbons present in the molecular structure of 2,2-dimethylbut-2-ene.
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Draw the structure:
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Tip: To assess, always prioritize the stronger bond (double/ triple).
BOND ANGLE
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Single bond
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Double bond
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Triple bond
BOND TYPES
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Sigma bond: the first bond with any other atom
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Pi bond: any 2nd and third bond with any other atom
SHAPE PREDICTION
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Steric number = sigma+ lone pair
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Based on VSEPR Theory
SHAPE PREDICTION
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Predict the shape of:
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H2O
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NH3
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CH4
FUNCTIONAL GROUPS •
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The chemistry of every molecule is determined by the functional group it contains A group of atoms within a larger molecule that has a characteristic charact eristic chemical behavior . Simpler: a certain group, or part of a molecule that has specific function. That function is to react react,, and behave in a certain manner the time an “attack” of another molecule comes. comes.
FUNCTIONAL GROUPS: C-C MULTIPLE BONDS
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Alkanes: most basic bonding of carbon to another carbon. Single bonds (sigma bonds/ ) connect these carbons, and mostly hydrogen atoms take the place of empty spaces. H3C-CH3 Alkenes: double bond between carbons (one sigma, one pi bond/ ). H2C=CH2 Alkynes: triple bond between carbons (one sigma, two pi). HC=CH
FUNCTIONAL GROUPS: •
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Given again, Carbons can form long chains, it can also branch and join together, forming chains or rings. Hydrogen atoms take the place of remaining spots of the tetrahedron. These are called cyclics. Notice the conformation of cyclohexane. In the past, it has been a big mystery on what differentiates organic compounds with odor and without. August Kekule noticed in his experiments that there is such a compound having six carbons matching with 6 hydrogen atoms, forming a ring with three double bonds; exhibiting odor , but doesn’t have the characters of alkenes. This was later called benzene. This is the base functional group of aromatic
FUNCTIONAL GROUPS: C YC L OA L KA NE
B EN ZE NE / A RO MATI C
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C6H12
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Has the same formula as a typical hexene.
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Has no smell.
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C6H6 Has the unusual case of equal number of carbon and Hydrogen. Has odor/ fragrance.
FUNCTIONAL GROUPS:
Name
Structure
Name Ending
Example
Alkyl Halide
R-X
---------------
CH3Br
Alcohol
R-OH
-ol
CH3CH2OH
Ether
R-O-R
ether (alkoxy alkane)
CH3OCH3
Amine
R-NH2
-amine
CH3NH2
Thiol
R-SH
-thiol
CH3SH
Sulfide
R-S-R
sulfide
CH3SCH3
Carbon Bond
FUNCTIONAL GROUPS:
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These are functional groups with a C=O group, called the carbonyl group (car-boneel).
PRIORITY GROUPS: IN DECREASING PRIORITY
– Carboxylic acid – Acid Anhydrides – Esters – Thioesters – Acid halides – Amides – Nitriles – Aldehydes
NOMENCLATURE
Common •
Uses the name given when it was discovered
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Uses the source: wood alcohol
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Uses prefixes: -n, – iso, -neo
Derived name •
derived from a parent compound
IUPAC •
Most systematic
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Eg. 2-methylhexane
GREEK PREFIXES IN NAMING COMPOUNDS Number of Carbons
Prefix
Example
1
Meth-
Methane
2
Eth-
Ethene
3
Prop-
Propene
4
But-
Butene
5
Pent-
Pentane
6
Hex-
Hexyne
7
Hept-
Heptyne
8
Oct-
Octane
9
Non-
Nonane
10
Dec-
Decane
11
U d
U d
HYDROCARBONS
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Composition
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Combustion process
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Types – Aliphatic (straight or branched; saturated or unsaturated) – Aromatic – Alicyclic or carbocyclic
DERIVATIVES
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Halogen -containing
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– Amines and amides
– Alkyl halide – Aryl halide •
Oxygen -containing – Alcohol, phenol, ether, aldehyde and ketone, carboxylic acid and derivatives
Nitrogen- containing
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Sulfur containing – Thiols or ________ – Thioethers – Thiophenols
SATURATED HYDROCARBONS
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Alkanes or _______ – SINGLE BOND ONLY – General formula: __________ – Type of bond: __________ – Suffix: -ane
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Alkyl group: removal of 1 hydrogen; ends with – yl
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Example: Methane (when 1 hydrogen is removed: _______)
ALKANES: PROPERTIES
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Little chemical affinity for other substances
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Inert to most laboratory reagents
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Show regular increase in boiling point and melting point as weight increases
NOMENCLATURE
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Determine the longest possible chain and name the corresponding alkane name
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Substituents are numbered with the lowest position number
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If 2 or more substituents are present, use prefixes di-, tri-and so on.
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When several different alkyl groups are attached to the parent chain, use alphabetical arrangement
EXAMPLES
– 2,3-dimethylpentane: correct or incorrect? – 1,2-dimethylbutane: correct or incorrect? – 4-methyl-3-ethyl-octane: correct or incorrect?
SATURATED HC
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Cycloalkanes – Carbon rings; can be written in geometric figure – General formula: ______________ named with the prefix cyclo- in front of the corresponding alkane name
NOMENCLATURE
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Additional Rule in Naming Cycloalkane – Step 1: Use the cycloalkane name as the parent chain. – Step 2: Number the substituents starting at the group that has alphabetical priority, and proceed around the ring in the direction that gives the second substituent the lower possible number.
UNSATURATED HCS
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Alkenes or _______ – Double bonds – Bond angle: _______ – Type of bond: _______ – General Formula: __________ – Same nomenclature as alkane but change – a ne to -ene
IUPAC NAMING
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Nomenclature: Determine the longest change havi having ng the DOUBLE – Determine bond
– Number Number the longest continuous chain so the double bond will receive the lowest possible number – If If more than one same substituents are present, use prefi pr efix xes di-, tri tri-- tet tetrara- and so on.
IUP IU PA C NA NAMI MING NG
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Alkadienes: 2 carbon-carbon car bon-carbon double bonds; indicate the position of double bond + prefix + diene – indicate
– 1,3-butadiene 1,3-butadiene – Isoprene Isoprene units
AR A R O M ATI ATIC CS
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Pleasant odor possessed by there substances (this meaning has been dropped)
Benzene is the parent substance >> Isolated by ____________ in 1825.
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AROMATICS
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According to August Kekule, carbon atoms in a benzene molecule are arranged in a six-membered ring with one hydrogen atom bonded to each carbon atom and with three carbon-carbon double bonds Orbital hybridization is sp2. For convenience, benzene is written either in the following ways…
HUCKEL’S RULE OF AROMATICITY
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4n + 2 = πe (electrons in double bond); if n is whole number, then aromatic! – Benzene: Aromatic or not? – What is the name of the compound/s if πe = 10? – Cyclobutadiene: aromatic or not?
REFRESH! •
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Is the figure below an aromatic compound?
Is it cyclic? YES. Are the pi bonds conjugated/ non-successive? YES. Does it follow Hückel’s rule? NO. 4 pi electrons = 4n + 2 4n = 2
MONOSUBSTITUTED
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Nitrobenzene
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Ethylbenzene
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Chlorobenzene
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Bromobenzene
MONOSUBSTITUTED BENZENES •
Toluene
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Phenol
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Aniline
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Acetophenone
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Benzaldehyde
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Benzoic acid
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Benzonitrile
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Styrene
DISUSBTITUTED BENZENES
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The prefixes ortho – , meta – and para – (o- , m- and p-) are used as prefixes – Ortho – adjacent – Meta – one carbon apart – Para – opposite
POLYSUBSTITUTED BENZENES
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Monosubsituted aromatic compounds will serve as a parent name, with the principal substituents assumed to be the carbon 1. – Examples •
1,3,5 – trinitrobenzene
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1,2,4 – tribromobenzene
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2,4,6 – trinitrotoluene
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5 – bromo – 2 – chlorophenol
POLYCYCLIC AROMATIC COMPOUNDS / FUSED AROMATIC RING SYSTEM •
Napthalene
Anthracene
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Correlation: Benzopyrene
Phenanthrene
Pyrene
REACTION MECHANISM
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Reaction mechanism – a process by which a chemical reaction occurs.
ADDITION REACTION
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Two reactants react together to form a single new product with no atoms “left over” – Ex: ethylene + HCl
ELIMINATION REACTION
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Opposite of addition reaction
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Single reactant splits into two products – Ex: chloroethane
SUBSTITUTION REACTION
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Two reactants exchange parts to give two new products – Ex: methane + chlorine
REARRANGEMENT REACTIONS
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Single product undergoes a reorganization of bonds and atoms to yield a single isomeric products Ex: conversion of cis-butene to trans-butene
REACTIONS OF AROMATIC COMPOUNDS •
Electrophilic aromatic substitution – Bromination – Chlorination – Nitration – Sulfonation
ALKANE REACTIONS
The main type of reaction for alkanes is substitution. Presence of initiator is as well needed. Alkanes are strong and stable, so it takes special conditions before they can react. Initiators may include UV or any Light. •
Example:
AROMATIC REACTIONS
AROMATIC REACTIONS So let us introduce to you the reactivity of aromatic compounds. In General Organic Chemistry, we are only talking about Benzene (C6H6), and sometimes Naphthalene (C10H8). Resonance makes a benzene ring stable. Anything that is stable is hard to react with, because they want to remain stable. It takes special conditions before aromatics react, and attain once more stability .
AROMATIC REACTIONS: SUBSTITUTION
Reagents: Benzene + HNO3 H2SO4
Mechanism: As illustrated •
• •
General Reaction Scheme:
Product: Nitrobenzene Examples:
AROMATIC REACTIONS: SUBSTITUTION
Reagents: Benzene + SO3 H2SO4
Mechanism: As illustrated
General Reaction Scheme:
Examples:
• •
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Product: Benzenesulfonic Acid
AROMATIC REACTIONS: SUBSTITUTION Reagents: Benzene + Br-Br FeBr 3 Catalyst • •
General Reaction Scheme:
Mechanism: See Next Slide •
Product: Bromobenzene Examples:
AROMATIC REACTIONS: SUBSTITUTION
AROMATIC REACTIONS: SUBSTITUTION
Reagents: Benzene + X-X (Cl, I) FeCl3 or FeI3 Catalyst • •
General Reaction Scheme:
Mechanism: As illustrated •
Product: Halobenzene Examples:
FRIEDEL-CRAFTS ALKYL ATION ACYLATION Yes, these two geniuses discovered the process. Today, in the industry, alkylation and acylation of aromatics are two of the most useful processes of electrophilic aromatic substitution. Alkylation is done by the introduction of an alkyl to replace one H around the benzene ring. Acyl means Carboxylic Acid Chloride, thus acylation is the introduction of carboxylic acid chloride (RCOOCl), or acid anhydride. •
Remember: It is crucial to remember that only the FriedelCrafts Aromatic Reactions utilize Aluminum-halide catalysts
FRIEDEL-CRAFTS ALKYLATION •
General Reaction Scheme:
FRIEDEL-CRAFTS ACYLATION •
Closely related with the alkylation, it has the same mechanism, but different reagents.
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Example:
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General Reaction Scheme:
REDUCTION OF BENZENE: HYDROGENATION •
If the Benzene Ring is introduced with Hydrogen Gas (H-H), take note: THERE IS NO REACTION. The reason is the inertia/ inert character of benzene, and the pressure requirements of H2 H2
No Reaction (NR) •
If however, Benzene reacts with H-H under some “blah-blah” conditions, or any condition regarding pressure, a reaction occurs, producing cyclohexane.
REDUCTION OF BENZENE: HYDROGENATION H2
No Reaction (NR) •
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If however, Benzene reacts with H-H under some “blah-blah” conditions, or any condition regarding pressure, a reaction occurs, producing cyclohexane.
Exam Technique: If you see any “blah -blah” conditions, let the reaction proceed by copying the whole structure without the aromatic ring.
OXIDATION OF BENZENE: KMNO 4 •
Same as Reduction/ Hydrogenation of the Benzene ring, Benzene will not react as well with KMnO4, a strong oxidizing agent, under simple conditions. KMnO4 No Reaction
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Only with Water , will benzene react with and oxidant.
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Benzoic Acid is always the product.
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Exam Tip: Aromatic Redox is really tricky. Always remember that only at ‘blah-blah’ conditions, benzene is reduced, oxidized. Don’t get confused!
STEREOCHEMISTRY A N D REGIOSPECIFICITY T H E S C I E N C E O F E L E M E N TA L POSITIONING AND STRUCTURES
CONCEPTS •
Chirality – Chiral carbon: four different substituents attached to carbon atom optically _______
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Optical Activity:
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Instrument: __________
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Rotations: – Clockwise: _________ – Anticlockwise: __________ – Racemic
Chiral carbon is
BASICS OF STEREOCHEMISTRY CHIRAL •
Chirals are any compounds with carbon (chiral center) that has 4 different groups surrounding it.
ACHIRAL •
Achirals have two or more identical groups around its chiral center. (Carbon that causes chirality)
TO THE LEFT OR TO THE RIGHT? Configuration is the term used to name the drawing of specific three-dimensional representation of a chiral molecule with the chirality center surrounded by R-groups. Steps follow: •
RULE 1 Look at the four atoms directly attached to the chirality center, and rank them according to atomic number. The atom with the highest atomic number has the highest ranking (first), and the atom with the lowest atomic number (usually hydrogen) has the lowest ranking (fourth).
TO THE LEFT OR TO THE RIGHT? •
•
•
RULE 2 If a decision can’t be reached by ranking the first atoms in the substituent, look at the second, third, or fourth atoms away from the chirality center until the first difference is found. RULE 3 Multiple-bonded atoms are equivalent to the same number of single bonded atoms. Configuration tells you of the rotation of chirals. The two classifications are S (sinister, Left) and R (rectus, Right).
TO THE LEFT OR TO THE RIGHT?
OPTICALLY… As pharmacists, the rotation of compounds are very important for us. In Physical Pharmacy, potency is discovered with rotation. Two rotations are seen in a polarizer; the Levorotatory (left) and the Dextrorotatory (Right). These two are very important in drug formulations. •
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Dextrometorphan, an antitussive, is more potent than its levorotatory counterpart. Levothyroxine Sodium, a reformulated thyroid hormone is more effective in treatment of acute hyperthyroidism. Esomeprazole is the equal formulation of the levo-dextro rotatories of the drug. This is non-potent, because dextro counteracts the effect of levo, the more potent. Omeprazole, the marketed drug that is potent is more levorotatory.
ISOMERS
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Same molecular formula, different in structure
STRUCTURAL ISOMERS Structural Isomers – differ in order of arrangement of the atoms or bond – a] Chain Isomers •
Differ in the arrangement of C atoms
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(n-butane) and Isobutane
– b] Position Isomers •
Differ in position of the substituent or unsaturated bonds (C=C, C =C)
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1-butene and 2-butene
– c] Functional Isomers •
Differ in their functional group
STEREOISOMERS Stereoisomers – atoms are in the same order but different orientation in space.
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•
– Enantiomer •
Geometric Isomers
– Cis-Trans Isomers •
Cis : same side
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Trans: opposite side
Optical Isomers
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Non-superimposable MIRRORIMAGE
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Same physicochemical properties
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D and L isomers
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Ex. D and L-glyceraldehyde
Diastereomer – With at least 2 chiral centers, NOT MIRROR IMAGE, not superimposable; different physico-chemical properties
CONFORMATIONAL ISOMERS OR CONFORMERS •
Conformational Isomers or conformers – Involves single bond only – Eg. CH3CH3 – Sawhorse representation – Newman – Ball and stick model
CONSTITUTIONAL ISOMER STRUCTURES •
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Constitutional Isomers are isomers with relationship to a functional group. This functional group plays a big role on giving the compound an identity.
Skeletal: Atom-stick model. – Branched : when substituents attach to the main chain. – Straight: you form a straight chain. – Tip: In the exam, if you are asked to give the isomer of a straight chain, give a branched structure; vise-versa. Same goes with the next.
CONSTITUTIONAL ISOMER STRUCTURES •
Positional Isomer : the position of the R Group, or the functional group is differed . CH3CH2COOH =
•
CH3COOCH3
Functional Group: give a derivative. – Alkenes – Cycloalkanes – Alcohol – Ether
(Alco-Et)
– Aldehyde – Ketone
(Alco-Ket)
– Alkynes – Cycloalkenes – Alkadienes – Carboxylic Acid – Ester
(Carbo-ster)
CONFORMERS
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Conformers are a result in the twist of one component of an organic compound . There are two types of structures. Sawhorse: Slant and line bonded.Take note of steric effect, prevent nearing of two identical elements to form bulk. Instability occurs when there is steric effect. The Right conformer is more stable. Cl C H
Cl Cl
C C
H
H
H
H
C H
H
Cl
H
CONFORMERS
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Newman: a structure where the front and back of the compound is emphasized.
There are two types of Newman Projection. Eclipsed and Staggered (Stable).
STEREOISOMERS
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Same connection, different representation in 3D.
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Geometric: the similarity of sides of two identical/ unidentical substituents. – Cis: same side – Trans: opposite sides
– The rule is that you cut the middle of double bond, then you see if the compound has the substituents are on the same side or not (ex: UP - UP). Prioritize the one with a larger atom. no.
STEREOISOMERS
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E-Z Rule/ Convention/ Notation: used when there is a long chain and more than three or more substituents surrounding the carbons of a double bond . – Entgegen: (ent-gay-guhn) opposite sides. Prioritize the one with a higher atomic number. (German for Opposite)
– Zusammen: (tsu-zah-mhn) same side. Still prioritize the atoms with higher atomic number. (German for Together)
TAUTOMERIZATION •
Tautomerization – Tauto “same”; meros “part” – Special kind of isomerism – Rapid interconversion between two substances – KETO-ENOL TAUTOMERS – Eg. Propanone to 2-propanol
