Source: KRE Table Part 1 (Synthesis Problems, New Bond Identification)
Tags: KRE, key reaction equivalent, synthesis, new bond, C-C bond, Grignard, Wittig, organometallic, organic chemistry II, Iverson, CH 320N, University of Michigan
Difficulty: Intermediate | Prerequisites: CH 210 or equivalent (functional groups, basic carbonyl chemistry, nucleophilic addition)
This material covers the first half of the KRE (Key Reaction Equivalent) table used to solve synthesis problems in Organic Chemistry II. The core skill here is pattern recognition: you look at a product, count the carbons, find where new C-C or C=C bonds formed, and then match that pattern to the correct reaction. These KREs deal specifically with carbon-carbon bond-forming reactions, which are among the most powerful and most tested transformations in the course. You should already be comfortable drawing Lewis structures, identifying functional groups, and recognising carbonyl compounds before diving in.
When you see a new C-C bond in a product, the position of that bond relative to nearby functional groups (such as -OH, -CN, or -COOH) tells you exactly which reaction was used. Grignard reagents, Wittig reagents, HCN, and alkyne anions each leave a characteristic fingerprint in the product. Learn the fingerprints and the synthesis problem solves itself.
KRE (Key Reaction Equivalent)
A pattern-matching tool for synthesis. You identify the structural feature in the product (new bond location, nearby functional groups) and match it to a known reaction. In simple terms, it is the "fingerprint" a reaction leaves behind.
Grignard reagent (RMgBr)
An organomagnesium compound that acts as a strong nucleophilic carbon source. It attacks electrophilic carbons (carbonyls, epoxides, CO₂). Think of it as a carbanion delivery system.
Wittig reagent (phosphorus ylide)
A reagent containing a phosphorus-carbon double bond that reacts with aldehydes or ketones to form alkenes. The type of Wittig (alkyl vs enolate) determines whether you get the Z or E alkene.
Organometallic
A compound with a carbon-metal bond (C-Mg, C-Li, C-Cu). These reagents are nucleophilic at carbon and are used to form new C-C bonds.
Gilman reagent (R₂CuLi)
A lithium diorganocuprate. Less reactive than Grignard reagents, so it reacts selectively with epoxides at the less substituted carbon.
Alkyne anion (acetylide)
Formed by deprotonating a terminal alkyne with a strong base. Acts as a carbon nucleophile that adds to carbonyls, producing propargylic alcohols.
Racemic
A 50:50 mixture of both enantiomers. Many of these nucleophilic additions to carbonyls create a new stereocentre, and without a chiral catalyst, both enantiomers form equally.
The Grignard reagent (RMgBr) is the workhorse of C-C bond formation. The KRE approach asks: where is the new C-C bond, and what functional group sits on or near the carbon where the bond was made?
KRE pattern: a new C-C bond that is two carbons away from an -OH group.
What happened: the Grignard opened an epoxide. The nucleophilic carbon of RMgBr attacked the less hindered carbon of the epoxide ring.
Reagents: 1) RMgBr (or R₂CuLi / RLi), 2) H₃O⁺ (mild aqueous workup).
Stereochemistry note: the organometallic attacks the less substituted carbon of the epoxide via backside attack (SN2).
KRE pattern: a new C-C bond on the same carbon as a secondary -OH group.
What happened: the Grignard added to the carbonyl carbon of an aldehyde. Aldehydes have one H on the carbonyl carbon, so after addition and workup you get a secondary alcohol.
Reagents: 1) RMgBr, 2) H₃O⁺ (mild).
Product is racemic when the addition creates a new stereocentre.
KRE pattern: a new C-C bond on the same carbon as a tertiary -OH group.
What happened: the Grignard added to the carbonyl carbon of a ketone. Ketones have two carbon substituents on the carbonyl, so the product is a tertiary alcohol.
Reagents: 1) RMgBr, 2) H₃O⁺ (mild).
KRE pattern: a new C-C bond on a carboxylic acid in which one carbon atom was added.
What happened: the Grignard attacked CO₂, extending the carbon chain by exactly one carbon. After acidic workup, you get a carboxylic acid.
Reagents: 1) CO₂, then RMgBr, 2) H₃O⁺ (mild).
How to spot it: count the carbons. If the product is a carboxylic acid with one more carbon than your available Grignard reagent, CO₂ was the electrophile.
The Wittig reaction converts a C=O into a C=C. The geometry of the new alkene (Z or E) depends on the type of ylide used.
KRE pattern: a new Z (cis) C=C bond in the product.
What happened: a non-stabilised (alkyl) phosphorus ylide reacted with an aldehyde or ketone. The betaine intermediate collapses through a four-membered ring, and kinetic control favours the Z geometry.
Reagent structure: the ylide has only alkyl groups, no electron-withdrawing groups adjacent to the carbanion. Written as R-CH=PPh₃.
KRE pattern: a new E (trans) C=C bond in the product.
What happened: a stabilised phosphorus ylide (one bearing a carbonyl or other electron-withdrawing group adjacent to the negative charge) reacted with an aldehyde or ketone. Thermodynamic control favours the E geometry.
Reagent structure: a carbonyl group sits next to the ylide carbon. Written as Ph₃P=CH-C(=O)-R.
Key detail: look for a C=C bond where one end connects to a carbonyl. If the alkene is E and a C=O is right next door, the stabilised (enolate) Wittig is the answer.
KRE pattern: a new C-C bond from a CN group on the same carbon as an -OH group.
What happened: HCN (or NaCN in acidic conditions) added to an aldehyde or ketone. The cyanide ion attacked the carbonyl carbon, and protonation gave the -OH.
Product: a cyanohydrin (the carbon bears both -OH and -CN).
Stereochemistry: racemic when a new stereocentre forms, because cyanide can attack from either face of the planar carbonyl.
KRE pattern: a new C-C bond from an alkyne on the same carbon as an -OH group.
What happened: a terminal alkyne was deprotonated (NaNH₂ or n-BuLi) to form the acetylide anion, which then attacked the carbonyl carbon of a ketone or aldehyde.
Reagents: 1) acetylide anion (RC≡C⁻), 2) H₃O⁺ (mild).
Product: a propargylic alcohol (an alcohol with a triple bond on the same carbon).
Stereochemistry: racemic when a new stereocentre forms.
Product Feature | Reaction | Reagents | Notes |
|---|---|---|---|
New C-C, -OH two carbons away | Grignard + epoxide | 1) RMgBr or R₂CuLi, 2) H₃O⁺ | SN2 at less substituted C |
New C-C, secondary -OH on same C | Grignard + aldehyde | 1) RMgBr, 2) H₃O⁺ | Racemic |
New C-C, tertiary -OH on same C | Grignard + ketone | 1) RMgBr, 2) H₃O⁺ | Tertiary alcohol |
New C-C, -COOH with one extra C | Grignard + CO₂ | 1) CO₂, RMgBr, 2) H₃O⁺ | Chain extended by 1 C |
New Z C=C | Alkyl Wittig | Non-stabilised ylide + carbonyl | Kinetic product |
New E C=C | Enolate Wittig | Stabilised ylide + carbonyl | Thermodynamic product |
New C-C, -CN and -OH on same C | HCN + carbonyl | HCN (or NaCN/H⁺) | Cyanohydrin, racemic |
New C-C, alkyne and -OH on same C | Acetylide + carbonyl | 1) RC≡C⁻, 2) H₃O⁺ | Propargylic alcohol, racemic |
Grignard reactions are the backbone of pharmaceutical synthesis. Many drug molecules contain carbon-carbon bonds that were forged by adding an organometallic reagent to a carbonyl. The Wittig reaction is used industrially to produce vitamin A and beta-carotene, where precise alkene geometry is essential for biological activity. Cyanohydrin chemistry shows up in the manufacture of certain amino acids and acrylic plastics.
Students often confuse the Grignard + aldehyde pattern (secondary -OH) with the Grignard + ketone pattern (tertiary -OH). The key is counting substituents on the carbon bearing the -OH: two non-H groups means aldehyde was the electrophile, three means ketone.
Students sometimes think the Wittig reaction gives an alcohol. It does not. The Wittig produces an alkene and triphenylphosphine oxide (Ph₃P=O) as a byproduct. No -OH group is formed.
The Z/E selectivity of the Wittig is a frequent exam error. Non-stabilised (alkyl) ylides give Z alkenes; stabilised (enolate) ylides give E alkenes. Many students reverse this.
When counting carbons for the Grignard + CO₂ pattern, students forget that CO₂ contributes one carbon. If the carboxylic acid product has n carbons, the Grignard reagent has n-1 carbons.
⚠️ Synthesis problems on the exam will give you a target molecule and ask you to propose reagents. The entire strategy begins with identifying new bonds and matching them to KREs.
⚠️ You will be expected to distinguish between Grignard + aldehyde (secondary alcohol) and Grignard + ketone (tertiary alcohol) based on the product structure alone.
⚠️ Z vs E selectivity of the Wittig reaction is a high-frequency test point. Know which ylide gives which geometry.
⚠️ Racemic products: any nucleophilic addition that creates a new stereocentre at a carbonyl gives a racemic mixture unless stated otherwise. Exams may ask you to identify this.
⚠️ The Grignard + CO₂ pattern is easy to miss if you do not count carbons carefully. Always count.
True or False: A new C-C bond on the same carbon as a secondary -OH indicates a Grignard reacting with a ketone.
False. Secondary -OH = Grignard + aldehyde. Tertiary -OH = Grignard + ketone.
Fill in the blank: A non-stabilised (alkyl) Wittig reagent produces a ______ alkene.
Z (cis)
True or False: HCN addition to a carbonyl produces a racemic cyanohydrin.
True.
Fill in the blank: When a Grignard reacts with CO₂, the product after workup is a ______.
Carboxylic acid
True or False: A new C-C bond two carbons away from an -OH group indicates a Grignard reacting with an aldehyde.
False. Two carbons away = Grignard + epoxide.
Q: You are given a target molecule that is a tertiary alcohol with a new C-C bond on the carbon bearing the -OH. What reaction does this indicate, and what are the reagents?
A: Grignard addition to a ketone. Reagents: 1) RMgBr, 2) H₃O⁺ (mild aqueous workup).
Q: A product contains a new E alkene with a carbonyl group directly adjacent to the double bond. Which Wittig reagent was used?
A: A stabilised (enolate) Wittig reagent, because the carbonyl adjacent to the ylide carbon stabilises the negative charge and thermodynamic control produces the E alkene.
Q: Your product is a carboxylic acid with six carbons. Your starting Grignard reagent has five carbons. What was the electrophile?
A: CO₂. The Grignard added to CO₂, contributing exactly one carbon to give the six-carbon carboxylic acid.
Q: A target molecule is a cyanohydrin (it has both -CN and -OH on the same carbon). What reagent was used and what was the starting material?
A: HCN was added to a ketone or aldehyde. The carbonyl is the starting material; HCN provided both the cyanide nucleophile and the proton.
Q: How do you distinguish between a Grignard + aldehyde product and a Grignard + epoxide product?
A: Count the distance from the new C-C bond to the -OH. If the -OH is on the same carbon as the new bond, it is Grignard + aldehyde (or ketone). If the -OH is two carbons away, it is Grignard + epoxide.
This material connects directly to Part 1B of the KRE table, which covers carbonyl transformations (acetals, hemiacetals, imines, esters). Many synthesis problems require combining a C-C bond-forming step from this document with a functional group interconversion from Part 1B. The Grignard reaction relies on nucleophilic addition to carbonyls, which is the same fundamental mechanism that governs aldol reactions covered later in the course.
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