ochem

Organic I Review Workbook – The Toolbox

ALL “STAR MOLECULES” () SHOULD BE ORGANIZED AND EMPHASIZED AS THEY CAN

BE CALLED UPON AT ANY MOMENT THROUGHOUT THE COURSE. THEY SHOULD BE

KNOWN BY THEIR STAR/COMMON NAME, IUPAC NOMENCLATURE, LINE ANGLE

STRUCTURE, ACRONYM, SHORTHAND NOTATION, FAVORITE FLAVOR OF ICE CREAM,

FAVORITE ONE REPUBLIC SONG, ETC.

1. Review Basic Geometries/Hybridization/Bonding

Questions:

a) Does the electronegativity of a carbon atom increase or decrease with increasing p- character? Use acetylene and ethylene as examples to help explain your

reasoning. Still stuck? Table 4.1 may provide even more assistance.

b) What is more nucleophilic, a carbon-carbon  bond or  bond?

c) What is lower in energy, the * orbital or * orbital of a C=C bond? d) Are the orbitals described in part c) representative of electrophiles or nucleophiles? e) A lone pair must be in what kind of orbital(s) in order to participate in

resonance/conjugation? s, p, sp, sp2 or sp3. Choose all that apply.

2. Functional Group Recognition / Functional Group Transformation (A+B = C)

Alkene Aldehyde Glycol

Alkyl halide Carboxylic Acid Ketone

Alcohol (alkyl vs aryl) Ether Nitrile

Amine (1°, 2°, 3°) Ester Sulfide

Alkyne Epoxide Thiol

Amide (1°, 2°, 3°) Enol

Questions:

a) Which functional groups above contain the carbonyl/acyl group? b) Is the carbonyl/acyl carbon of a ketone electrophilic or nucleophilic? c) All things being equal, which functional group is the most Bronsted acidic (not

including the carboxylic acid)?

d) The transformation of a functional group can be described as a single functional group starting material (A) being added to a selective environment (B) to generate a new

functional group (C). Basically, A+B = C. With this in mind, which functional

group(s) was (were) NOT synthesized in the first semester (as described in the text)?

e) Which functional group has the most electron rich sp2 oxygen? Provide a structure to support your answer. Resonance comes in handy here….

f) Is a Bronsted acid a nucleophile or electrophile? A Bronsted base? g) How many atoms are sp2 hybridized in acetic acid? h) How many atoms are sp2 hybridized in phenol? i) How many atoms are sp2 hybridized in heroin?

3. Structural Relationships and Language - Review all terms and definitions for the following:

 Constitutional isomers vs Conformation isomers vs Configurational Isomers

 Stereoisomers (Diastereomers, Enantiomers)

 Optical Activity, Racemic, Meso

 Determination of Absolute Configuration

Questions:

a) What term can be used to describe the isomeric relationship above? b) Each molecule above can be described as a vicinal diol. What is a more common and

more utilized term for describing a vicinal diol (Hint: It is often used in common

nomenclature and can be found on the Functional Group List on page 1)? This

functional group will play a vital role as a protection group in Organic 2. (Nothing

ever goes away completely).

c) Assign the configurations for each chiral center? d) Are both molecules optically active? Explain. e) Provide two different synthetic routes to produce each molecule and determine if a

racemic mixture is generated in each case? (i.e. you need to come up with 4 reactions

in total.) If a racemic mixture is not obtained, explain why?

4. Past, Present and Future: Putting it all together!

The reaction below occurs in the presence of H2, Ni (Chapter 3, 6, 16) or sodium borohydride

(NaBH4) (Chapter 6, 16). A recognition of possibilities and a process of elimination can lead

you not only to the correct answer(s) but hopefully an expansion of your current knowledge base.

a) Is the final product chiral? b) What is the index of hydrogen deficiency (IHD) for the starting

material? c) Considering the nature of the hydrogenation mechanism condition, provide two

different line angle structures (with stereochemistry) for a starting material which agree with the

product data provided. d) What is the isomeric relationship between these two possible starting

materials found in c)?

5. Resonance….Resonance….Resonance –

Allylic and Benzylic…Practice drawing resonance structures for these systems. Use line

angle representations only! Get very, very, very comfortable in drawing structures for

these systems in their radical, cationic and anionic forms. Restriction: When

generating your “allylic” examples make sure you use a system that has a minimum

of 4 carbons in its chain or ring.

6. Bronsted Acids & Bases! It’s #1

 Understand the significance (not calculations) of pKa, Ka, etc.

a) True/False. Increasing Ka represents increasing acidity. b) When does the pH = pKa?

 Review pKa tables (Table 4.1 and Appendix 2) to get a “feel” for functional groups but DON’T MEMORIZE.

 Understand how “The Protocol” (see below) impacts acidity and basicity and how they can help you generate a “feel” for values. First presented in Chapter 4. If you don’t know

an answer to something immediately, hit your “Organic home button” and ….Just ask

SERI.

“The Protocol” – The factors that govern chemical change!

a. Size b. Electronegativity c. Resonance d. Inductive Effect

Exercise 6.1: Provide structures and rank the molecules below in order of decreasing pKa value (i.e.

least acidic  most acidic). Get comfortable using only “The Protocol” for determining your

answers but check with a simple internet/textbook search. Some of these you are going to miss so

make sure to understand any differences using “The Protocol”. Since these numbers are available

there is no need to post your responses on the Discussion Board but please make sure that you

notice….ALL THE STARS!

Phenol, Benzoic Acid, Acetic Acid, Acetone, Acetaldehyde, Acetylene,

Acetonitrile, Ethanol, Lactic Acid, Nitromethane, Pyruvic Acid, Carbonic acid, and

Ammonium chloride.

Question 6.1: Benzoic acid has a lower pKa value than acetic acid. Which factor of the protocol

best explains the acidity difference? Explain.

Exercise 6.2: Provide the acid/base conjugates to complete the expressions below and determine if

the equilibrium favors reactants or products.

a) acetylene + LDA 

b) acetic acid + diisopropylamine 

Exercise 6.3…Putting it all together

The molecule below represents the neutral form of CiproTM, a broad spectrum antibiotic. As the

5th most prescribed antibiotic in the US it is sold as ciprofloxacin hydrochloride monohydrate.

Most amine based pharmaceuticals are routinely administered in some protonated acid form (get

used to this concept for sure). Consider the structure and answer the following:

7. General Reactivity Trends

Example: Carbon Intermediates - Carbocations and Radicals (Chapters 6, 8 and 20, 21, 22)

General Guidelines to Remember:

A. Simple Bronsted Acid / Bronsted Base reactions are #1. Always consider this FIRST!!! B. Lone pair atoms adjacent to p-orbitals are sp2 hybridized (Rule #3). (i.e. Hopefully you

got an answer of “3” for acetic acid in question 2g.)

C. In making predictions…Resonance trumps the inductive effect…unless stated otherwise. D. Resonance occurs only through unhybridized p-orbitals (Review Question 1e).

8. “THE TOOLBOX” – A MUST KNOW “CHEMICAL STOCKROOM” FROM ORGANIC 1

EVERYONE wants an answer to this question, “What do I really need to still know from Organic

1?” The easiest and certainly the most unrealistic answer would be, “everything!” The foundation of

Organic Chemistry hopefully hasn’t completely faded away during your time away but the reality may

be that many of you would score 20-25 points lower on your Organic 1 final exam if you were to take it

right now. This review should help you in your efforts to get caught up from a conceptual perspective

but from a chemistry or “changing a molecule” perspective it is about functional group recognition and

the reagents that induce predictable functional group transformations. In many ways this philosophy is

no different than A+B = C. In order to hit the ground running as soon as possible, I have compiled a list

of what I consider to be the most important reagents that you should review in order to achieve maximum

success in the second semester course. Make sure to know the structural formulas and shorthand

representations for each and take special note of all “STAR MOLECULES”. These individual reagents

and combination of reagents should be recognized for what functional groups they transform as well as

the product functional groups that they create. I know this is restating the obvious but this is the essence

of Organic Chemistry – Functional Group Recognition and Functional Group Transformation. One

final note, the more you refer to these molecules by name and less by “letters and numbers” the better

off you will be. Organic Chemistry is a language all its own. To master it you must speak it, every day!

The Chemical Stockroom

Halogenators: Acids:

Bromine and Chlorine (never for free-radical) Sulfuric Acid, Nitric Acid, Hydrochloric Acid

N-Bromosuccinimide Hydrobromic Acid, p-Toluenesulfonic Acid

Oxidizers: Bases:

m-Chloroperoxybenzoic acid Sodium Hydroxide, Sodium Hydride

Osmium Tetroxide (Osmic acid) Sodium Methoxide & Sodium Ethoxide

Ozone Pyridine, Sodium Acetylide

Hydrogen Peroxide Lithium Diisopropylamide

Mercuric Acetate, Mercuric Sulfate Ammonia, Methylamine, Dimethylamine

Pyridinium Chlorochromate Triethylamine, Sodium Bicarbonate

Chromic Acid (Know the recipe for this magic potion)

Reducers: Solvents:

H2 with Pt/C, Pd/C, Ni/C Acetone, Water, Methanol, Ethanol

H2, Lindlar’s Catalyst (another magic potion) Isopropanol, Acetonitrile, Tetrahydrofuran

Sodium Borohydride Diethylether , Benzene, Toluene

Lithium Aluminum Hydride (back-ordered – can’t use yet)

Dimethylsulfide

Lithium or Sodium metal in ammonia Substitution Systems:

Diborane in Tetrahydrofuran

Di-siamylborane in Tetrahydrofuran p-Toluenesulfonylchloride

Phosphorus tribromide, Thionyl chloride

tert-Butyldimethylchlorosilane

Other Carbon Sources: Tetrabutylammonium fluoride in water

Ethylene,Propylene, Ethylene oxide, Propylene oxide, Styrene, Cyclohexanol, Cyclopentanol

Other Reagents:

Any other non-listed star molecule is also available in “The Stockroom”. As our stars expand, so

will our knowledge base and our stockroom.

Practicing THE TOOLBOX!

A) Regioselectivity and Stereoselectivity. Determine all products (including stereoisomers) and circle the major product. Make sure you can recognize the difference in the terms “hydration”

vs “hydrolysis” – The environmental conditions (i.e. reagents) are often the same but the terms

and chemical outcomes are very different.

B) Not all A+B = C’s are the same. Consider the molecule below and apply three different hydration conditions which can produce monoalcohols. Show the stereochemistry for all

possible products produced in each case based on the mechanism for each condition.

C) Follow the Road Map. Provide the conditions necessary to complete the Road Map below and answer all questions when presented. Some statements are INACCURATE. Make any necessary

changes to the products within the Road Map in order to satisfy the conditions presented (i.e. you

can change the products but don’t change the reagents.)

D) Functional Group Control Leads To Directed Synthesis. Provide the condition(s) or the major products necessary to complete the Road Map below.

E) Decisions, Decisions…Eliminate the Competition!!! Choose the best conditions to complete the synthesis below. (Hint: Using halogens directly in the presence of light/heat is NOT a

good option.)

F) Carbon-Carbon Forming Reactions – Using Hammer and Nails!

G) Reactions of Epoxides (Chapter 11)…How HEAVY is the hammer?….aka….Choosing a Path

Example 8.1: No patient is alike….Create the Change…Then Evaluate!!! Provide conditions to

satisfy each reaction scheme and make sure each reagent is available in the “Chemical Stockroom”.

H) All Roads Point to the Carbonyl and Multistep Reactions! Welcome to Organic 2! Provide all missing conditions to the Road Map below. Pay attention to the step restrictions.

I) Put It All Together....Practice, Practice, Practice!!!

J) Multistep Synthesis. Provide all the conditions and product intermediates to complete the syntheses below. Make sure to only use reagents that are available in the “Chemical Stockroom”

and pay attention to the stated restriction.

K) Multistep Synthesis. Provide all the conditions and product intermediates to complete the

syntheses below. Make sure to only use reagents that are available in the “Chemical Stockroom”

and pay attention to the stated restriction.

L) Retrosynthesis – Breaking It Down is the Way to Go! You must learn to fight the urge of solving problems from left to right. This is a great example where you have to think about

deconstructing the large molecule into smaller fragments rather than trying to guess at what

smaller fragments are needed to build it up. Consider the Road Map synthesis of Demerol®

below and answer the following:

1) Provide the structures for (1) and (2). 2) Provide the condition(s) necessary to satisfy (3) and (4). 3) Provide the mechanism for the conversion of (5) into Demerol®. Make sure to show proper

flow of electrons, all nonzero formal charges and important contributing resonance structures

(if necessary).

M) Multistep Synthesis. Just a little twist on the original. Consider the same starting material from multistep problem I) and synthesize 1-pentanol. Restriction: You are only able to use

1.0 equivalent of strong base.

N) Multistep Synthesis. “Chasing the Tail” (5 and 6 atom ring formation is very favorable – i.e. intramolecular reactions tend to be kinetically more favorable than intermolecular reactions.)

Provide all the conditions and product intermediates to complete the synthesis below.

Restriction: You can only use reagents that are available in the “Chemical Stockroom”.

9. Organic Diagnostics. …and now for something completely different….or 1+1 does not always

equal 2.

Getting Ready For Your Examination Future! In my opinion, a diagnostician must be more apt at

recognizing when the data analysis is incorrect than confirming something is correct. BTW, I LOVE

THESE….

A student planned out the following syntheses below. If the boxed part of the reaction statement is

correct, write “Correct.” Otherwise, change what is in the box to make the statement correct. USE

THE BOXES PROVIDED FOR YOUR ANSWER.

10. Mechanism Review / Overview

A significant number of reactions that you have seen thus far have involved neutral organic

functional groups and neutral environmental conditions. The driving force for many of these reactions

is the favorable enthalpy change as a result of “pi to sigma, pi to sigma, pi to sigma” (sorry I can ‘t help

it) addition reactions (see Rule #4). But, since the primary driving force of most chemical reactions is

to obtain “neutrality” (see Rule #1), these reactions although energetically favorable tend to be incredibly

slow. That is unless we “Charge it, Change it, and then Uncharge it.” This is of course suggesting the

role of acid and base catalysts. We will encounter Organic mechanisms this semester that will involve

as many as 6 or 7 steps and in most cases (if not all) more than half of the steps are nothing more than

proton transfer reactions. The ability to perform simple proton transfers, from a mechanistic viewpoint,

is paramount in writing intelligible Organic mechanisms and for making good diagnostic decisions of

outcome. After all, nothing is kinetically or more thermodynamically favorable than proton transfer (see

Rule #2). The reactions that you studied in Organic 1 that did not involve “pi to sigma, pi to sigma, pi

to sigma” transformations were typically driven by the “neutrality” rule and most famously highlighted

when describing the SN2 and E2 reactions. So there it is, in one paragraph (albeit a long one), the

mechanism classifications that you studied in Organic 1. It is very important to re-familiarize yourself

with these terms as we will continue to utilize them throughout Organic 2:

A. Addition Mechanism – Involves pi to sigma transformations 1. Stepwise 2. Concerted

B. Elimination Mechanism – Involves sigma to pi transformations 1. Stepwise

2. Concerted C. Substitution Mechanism – Exchanges one atom/group for another atom/group.

1. Stepwise

2. Concerted D. Rearrangement Mechanism – No change in molecular formula but functional groups can

change or remain the same (e.g. CBD to THC or lycopene to -carotene respectively).

Not all reactions carry the same level of significance and other terms can be used interchangeably

to describe a mechanism that has been used. For instance, if cyclohexene is converted into cyclohexanol

it would be clear to anyone who has studied Organic Chemistry that the molecular formula of the starting

material has had water added to it and therefore the transformation required an Addition Mechanism.

Simply stating that a “hydration process” has occurred would be acceptable and more often than not –

preferred. The same could be said for “oxidation” and “reduction” reactions. These terms could be used

for either an Addition or Elimination reaction. Only, the conditions of the environment can provide

the distinction (e.g. H2/Ni on C versus PCC). Therefore, it is more preferred to describe these reactions

using Redox terminology.

Putting it into Practice: a) Consider the multistep synthesis below and state what mechanism (from the

options above) is being used in each step. b) Provide a mechanism for steps 3 and 4. Make sure to show

all relevant lone pairs, use proper arrow flow and include all non-zero formal charges in your

mechanisms.