203 – Organic chemistry

Identifying the nucleophile

• lone pair

• negative charge

• C=C double bond

• $\sigma$ Bond to an electropositive atom

curved arrows always from nucleophile to electrophile

configurational isomers

isomers in which bond rotation (only allowed on single bond) does not interconvert them.

two possibilities

• Enantiomers: mirror image from each other, not superimposable (both configurations are changed)

• Diastereomers: stereoisomers not related to each other through a mirror image (only one configuration is changed)

racemic mixture

a 50:50 mixture of two enantiomers

identifying a chiral molecule

• carbon with four different substituents

• no plane of symmetry

Assining priority

• atoms with higher atomic numbers get higher priority

clockwise → R-compound

polarimetry

The observation of the rotation of plane-polarized light by an enantiomer. This is the only way of finding out if a sample is racemic or if it contains more of one enantiomer.

specific rotation $\alpha$

The observed angle through which. the light is rotated given by $\alpha$ is obtained by dividing the path lenght (in dm) through the concentration. Typically measured at 20°C and 589nm. the one enantiomers which rotates the light to the right is given (+/D)

Number of stereoisomers

Usually, a structure with n stereo centers can exist as $2^n$ stereoisomers. These stereoisomers consist of $2^{n-1}$ diasteroisomers, each of which has a pair of enantiomers.

Meso compound

a compound with a sterogenic center, but they are achiral as whole compound.

Separating enantiomers

This process is called resolution a can be don by reacting a racemic mixture with an enantiomerically pure compound. This reaction will lead to diastereoisomers, which can easily be separated. Another, but very expensive method is making a column chromatography with an enantiomerically pure stationary phase.

nucleophilic addition to the carbonyl group

Additions generally consist of 2 steps:

• nucleophilic attack on the carbonyl group (a new C-C bond is formed, and the $\pi$ electrones of the C=O bond are resonated on the Oxygen)

• protonation of the alkoxide anion that results

orbitals explain the reactivity:

• the $\pi$ bond is skewed towards oxygen because of the higher electronegativity. Conversely, the unfilled $\pi^*$ antibonding has a larger coefficient at the carbon atom

• During the reaction the electrones move from th HOMO of the nucleophile to the LUMO of the electrophile (in this case to the $\pi^*$)

• orbital overlap is only efficient when the size and diffusity are similar.

Another factor regarding the reactivity are sterics:

• aldehydes are less stericly hindred than Ketones therefore they react faster (Formaldehyde $CH_2O$ is an extremely reactive aldehyde)

electronic effects:

• an electronegative atom bound to the carbon can also increase the reactivity, because they increase the polarization of the carbonyl group.

releasing strain:

• especially on small rings addition to the C=O bond can release strain, therefore are compounds such as cyclopropanone and cyclobutanone very reactive electrophiles.

Typical Nucleophiles for the reaction with a carbonyl compund

• $BH_4$ (only reacts with aldehydes or ketones) resulting in a alcohol

• $$H_2O$$

• Alcohols (which results in a hemiacetal (OH & OR bound to the same Carbon)) the reaction rate can be increased by adding an acid or base catalyst
  → a formation of an hemiacetal can also be intermolecular

• Bisulfides such as $NaHSO_3$ (the attack occurs from the lone pair of the sulfur to the carbonyl group) → this products are usefull for crystallization of liquid aldehydes and making aldehydes soluble in water

Hemiacteal formation

If you want to work out which is the original alcohol and which is the carbonyl compound in a hemiacetal, you simply need to identify which carbon atom has two bonds to the oxygen; this is the carbonyl compound.

Polarization of an carbon-metal bond

unlike the C=O bond an carbon-metal bond is polarized towards the carbon, making it a nucleophilic center. Metals such as LI,Mg,Na,Al have all a lower electronegativity than carbon.

Grignard reagents

Are very good reagent as they react with Methyl, primary, secondary and tertiary alkyl halides. But the reagent cannot contain a functional group which could react with the Grignard. (Grignard reagents are very strong bases)

Mechanism:

• the reaction takes place on the surface of magnesium

• it involves an insertion of magnesium into the carbon-halogen bond

• magnesium is oxidized Mg(0) to Mg(II)

Organolithium reagents

The reagent cannot contain a functional group which could react with the Grignard. (organolithium reagents are very strong bases)

Mechanism:

• because lithium can only donate one electron, two Li are needed to donate one electron to the halide and on to the carbon

• it involves an insertion of lithium into the carbon-halogen bond

• lithium is oxidized Li(0) to Li(I)

making organometallic by deprotonating alkynes

Alkynes are the most acidic of hydrocarbons, with pKas of about 25. They can be deprotonated by more basic organometallics such as butyllithium or ethylmagnesium bromide. Alkynes are sufficiently acidic to be deprotonated even by nitrogen bases. This results in am organometallic reagent.

making organometallic by halogen-metal exchange

organolithiums remove halogen atom from aryl or vinyl compound and the metal takes the place of the halogen.

making organometallic by transmetallation

Organolithiums can be converted to other types of organometallic reagents by transmetallation-simply treating with the salt of a less electropositive metal. The more electropositive Mg or Li goes into solution as an ionic salt, while the less electropositive metal such as Zn takes over the alkyl group. The high reactivity of Grignard reagents and organolithiums sometimes causes unwanted side reactions when they combine with very strong electrophiles (such as acid chlorides). The reaction is more under control when a much less reactive organozinc compound is used.

making carboxylic acids from organometallic and carbon dioxide

Carbon dioxide reacts with organolithiums and Grignard reagents to give carboxylate salts. Protonating the salt with acid gives a carboxylic acid with one more carbon atom than the starting organometallic.

Important details:

• each step of the reaction is completed before the next is begun

• there is no water present during the first two steps

making primary alcohols from organometallics and formaldehyde

Formaldehyde react with organolithiums or Grignard reagents to form primary alcohols. In order to get pure, dry formaldehyde it is necessary to heat ('crack') the polymer (CH,O)n to decompose it.

Making secondary and tertiary alcohols using organometallic reagents

Aldehydes: secondary

ketones: tertiary

making a secondary alcohol by reduction

one can reduce a ketone to obtain a secondary alcohol with for example $NaBH_4$

Oxidation of alcohols

Cr(IV) (orange) compounds are good oxidizing agents: they remove hydrogen from organic compounds and are themselves reduced to Cr(III) (green). Some of the important reagents are related to the polymeric oxide ($CrO_3$)Such as:

• PDC

• PCC

• ($Ca(OCl)_2$ is much stronger)

are preferred reagents especially as they are soluble in organic solvents

Mechanism:

• one hydrogen is removed from the OH group

• the second is removed from the carbon

stronger reagents may oxidize primary alcohols all the way to carboxylic acid, especially when water is involved.

difference between conjugate addition and nucleophilic addition

Nucleophilic addition: nucleophile addition to C=O bond.

Conjugate addition: nucleophile addition to the C=C double bond of $\alpha,\beta$ unsaturated carbonyl compounds. (conjugated to =O bond)

when do nucleophiles do a conjugate addition an when directly to the carbonyl group

• conditions of the reaction
  → 1,2 addition is faster (kinetic product) → lower temperatures shorter reaction time
  →1,4 is more stable (thermodynamic product) → higher temperatures longer reaction times

• the nature of the $\alpha,\beta$- unstaturated carbonyl compund
  → the more reactive the carbonyl group, the more addition (more reactive when O=C-Cl)

• type of the nucleophile
  → hard (rather 1,2 because they are dominated by charges and electrostatics) or soft (rather 1,4 because they are dominated by orbital effects)

Why is direct (1,2) addition faster

Although the carbon atom ß to the C=O group carries some positive charge, the carbon atom of the carbonyl group carries more, and so electrostatic attraction for the charged nucleophiles will encourage it to attack the carbonyl group directly rather than undergo conjugate addition.

Why is conjugate addition more stable

In the conjugate addition product, we gain a C-C $\sigma$ bond, losing a C=C $\pi$ bond, but keeping the C=0 $\pi$ bond. With direct addition, we still gain a C-C bond, but we lose the C=O $\pi$ bond and keep the C=C $\pi$ bond. C=O $\pi$ bonds are stronger than C=C $\pi$ bonds, so the conjugate addition product is more stable.

Hard nucleophiles: bevorzugte Additionsart bei α,β-ungesättigten Carbonylen?

Am ehesten 1,2-Addition (direkter Angriff am Carbonyl-C)

Soft nucleophiles: bevorzugte Additionsart bei α,β-ungesättigten Carbonylen?

Am ehesten 1,4-Addition (konjugierte Addition)

Borderline nucleophiles: welche Addition ist möglich?

Beide (1,2 und 1,4), z. B. CN⁻

Wodurch zeichnen sich soft nucleophiles aus?

Größer und diffuser (stärker polarisierbar)

Beispiele für hard nucleophiles (anionisch)

F⁻, OH⁻, RO⁻, SO₄²⁻, Cl⁻

Beispiele für hard nucleophiles (neutral)

H₂O, ROH, ROR', RCOR'

Beispiele für hard nucleophiles (N und metallorganisch)

NH₃, RMgBr, RLi

Beispiele für borderline nucleophiles

N₃⁻, CN⁻, RNH₂, R¹R²NH, Br⁻

Beispiele für soft nucleophiles (anionisch)

I⁻, RS⁻, RSe⁻, S²⁻

Beispiele für soft nucleophiles (neutral)

RSH, RSR', R₃P

Welche π-Systeme gelten als soft nucleophiles?

Alkene und aromatische Ringe

Hard, borderline oder soft: RMgBr?

Hard (1,2-Addition)

Hard, borderline oder soft: RLi?

Hard (1,2-Addition)

Hard, borderline oder soft: CN⁻?

Borderline (kann beides)

Hard, borderline oder soft: Br⁻?

Borderline

Hard, borderline oder soft: I⁻?

Soft (1,4-Addition)

Hard, borderline oder soft: RS⁻?

Soft (1,4-Addition)

Hard, borderline oder soft: RNH₂?

Borderline

Hard, borderline oder soft: NH₃?

Hard

Hard, borderline oder soft: RO⁻?

Hard

Thiols as nucleophiles in conjugate addition

on of the best nucleophiles for 1,4 addition. Remarkably no acid/base catalyst is needed

Welche Intermediate treten bei konjugierten Additionen unter basischen Bedingungen auf?

Enolate

Welche Intermediate treten bei konjugierten Additionen unter sauren Bedingungen auf?

Enole

Alkohole als Nucleophile (NaOH, H₂O): wie entsteht das eigentliche Nucleophil?

Base deprotoniert den Alkohol zu einer kleinen Menge Alkoxid (da der pKa des Alkohols etwas höher ist als der von Wasser)

Alkohole als Nucleophile: Warum reicht eine katalytische Menge Base?

Das Enolat wird durch Wasser protoniert und dabei wird Hydroxid regeneriert

Warum werden konjugierte Additionen meist in protischen Lösungsmitteln durchgeführt?

Das Lösungsmittel (z. B. Alkohol oder Wasser) liefert das Proton für das Enolat

Amine als Nucleophile: Wird eine Base benötigt?

Nein, Amine sind neutrale Nucleophile und liefern selbst das Proton für das Enolat

Amine als Nucleophile: Mechanismus in Kurzform

1. Amin greift das β-C an (konjugierte Addition) → 2. Enolat-Intermediat (N⁺–H) → 3. Protonierung des Enolats durch das Ammonium

Konjugierte Addition unter sauren Bedingungen (HCl + Enon): Schritt 1?

Protonierung der Carbonylgruppe (Enon wird durch positive Ladung noch elektrophiler)

Konjugierte Addition unter sauren Bedingungen (HCl + Enon): Schritt 2?

Chlorid greift das β-C an → Enol

Konjugierte Addition unter sauren Bedingungen (HCl + Enon): Schritt 3?

Tautomerie des Enols zur Ketoform (Protonentransfer von O auf C) → Chlorketon

Wie fördert man die konjugierte Addition von Grignard-Reagenzien?

Mit katalytischen Mengen Cu(I)-Salz (z. B. CuCl, 0.01 eq)

Welche Rolle spielt Kupfer bei Grignard-Reagenzien?

Transmetallierung des Grignard-Reagenz zu einem Organokupfer-Reagenz

Warum addieren Organokupfer-Reagenzien konjugiert?

• Sie sind weicher (soft) als Grignards und addieren an die weichere C=C-Doppelbindung

• Cu ist diffus → guter Orbitalüberlapp und bessere Affinität zur β-Position

Warum reicht eine katalytische Menge Cu(I)?

Nach der Addition wird das Kupfersalz recycelt und kann weiteres Grignard transmetallieren

Wie bereitet man Lithiumcuprate (R₂CuLi) her?

2 Äquivalente Organolithium + 1 Äquivalent Cu(I)-Salz (z. B. CuBr, Et₂O, −78 °C)

An welcher Position addieren Lithiumcuprate an α,β-ungesättigte Carbonylverbindungen?

Immer an der β-Position (1,4-Addition)

Warum wird bei Lithiumcuprat-Additionen Me₃SiCl zugegeben?

Es fängt das negativ geladene Intermediat ab und bildet einen Silylenolether, die Reaktion verläuft deutlich besser

Was passiert mit dem Silylenolether am Ende der Reaktion?

Er hydrolysiert (Quenching, H⁺/H₂O) zum Keton

1,4- vs. 1,2-Addition: Welche Reaktionsbedingungen begünstigen die konjugierte Addition (bei reversiblen Additionen)?

Thermodynamische Kontrolle: hohe Temperaturen, lange Reaktionszeiten

1,4- vs. 1,2-Addition: Welche Reaktionsbedingungen begünstigen die direkte Addition an C=O?

Kinetische Kontrolle: niedrige Temperaturen, kurze Reaktionszeiten

Welche C=O-Gruppen begünstigen die konjugierte Addition?

Unreaktive C=O-Gruppen (Amid, Ester)

Welche C=O-Gruppen begünstigen die direkte 1,2-Addition?

Reaktive C=O-Gruppen (Aldehyd, Acylchlorid)

Welcher β-Kohlenstoff begünstigt die konjugierte Addition?

Ein unhinderter β-Kohlenstoff

Welcher β-Kohlenstoff begünstigt die direkte 1,2-Addition?

Ein gehinderter β-Kohlenstoff

Welche Organometallreagenzien begünstigen 1,4-Addition?

Organokupfer-Verbindungen oder katalytisches Cu(I)

Welche Organometallreagenzien begünstigen 1,2-Addition?

Organolithium-Verbindungen und Grignard-Reagenzien

Ungesättigte Nitrile: Warum greift das Nucleophil an C=C und nicht an C≡N?

Das Nitril-C ist als elektrophiles Zentrum eher unreaktiv, daher sind keine besonderen Bedingungen nötig

Was ist Cyanoethylierung?

Konjugierte Addition eines Nucleophils (z. B. Et₂NH) an Acrylnitril → Aminonitril (86 % Ausbeute)

Warum ist das Anion nach Addition an ein Nitril stabilisiert?

Die Ladung ist wie bei einem Enolat delokalisiert (auf C oder N)

Wie wird das Produkt der Cyanoethylierung gebildet?

Protonierung am Kohlenstoff stellt das Nitril wieder her → Aminonitril

Primäres Amin + Acrylnitril: Was kann passieren?

Das Produkt ist noch nucleophil, daher kann eine zweite Addition erfolgen (z. B. MeNH₂ → MeN(CH₂CH₂CN)₂)

Konkurrenz zwischen Element der 1. Reihe (N, O) und der 2. Reihe (S, P): Wer gewinnt?

Das Element der 2. Reihe (z. B. S): Thiol reagiert vor Alkohol (HOCH₂CH₂SH + Acrylnitril → S-Addukt)

Nitroverbindungen: Wie stark elektronenziehend ist die NO₂-Gruppe?

Etwa doppelt so stark wie eine Carbonylgruppe

Warum ist die konjugierte Addition an Nitroalkene sehr zuverlässig?

NO₂ ist stark elektronenziehend und als elektrophiles Zentrum unreaktiv

reaction of an acid chloride with an alcohol

reaction of an acid chloride with an alcohol

Cl is the leaving group and the final product is an ester.

pKa as a guide to leaving group ability (carbonyl substitution reactions)

the lower the pKa of HX, the better the leaving group $X^-$ in carbonyl substitution reactions.

General scema for substitution reactions on a carbonyl group

Relationship between nucleophilicity and leaving group ability

a good nucleophile is a bad leaving group and vice versa

Reaktivitätsreihenfolge der Carbonsäurederivate (am reaktivsten → am wenigsten reaktiv)

Acylchlorid > Anhydrid > Ester > Amid > Carboxylat

Warum sind Acylchloride am reaktivsten?

Sehr schwache Delokalisierung des Cl-Elektronenpaars in die C=O-Gruppe, daher stärker elektrophiler carbon der carbonyl Gruppe.